Computer Automated log P Calculations Based on ... - ACS Publications

J. Chem. Inf. Comput. Sci. 1994,34, 752-781

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Computer Automated log P Calculations Based on an Extended Group Contribution Approach Gilles Klopman,’ Ju-Yun Li, Shaomeng Wang? and Mario Dimayugat Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106 Received September 27, 1993” A program for the automatic calculation of the logarithm of the partition coefficient between n-octanol and water (log P) for organic compounds was developed. The log P model was derived from a multivariate regression analysis based on a database consisting of 1663 organic molecules with diverse structures. The parameters used in the model are basic functional groups and correction factors which were automatically identified by the Computer Automated Structure Evaluation (CASE) program. The CASE program was used to identify the correction terms for members of each congeneric series with large deviations. This approach was found to be better than our previously reported methodologies and accurate enough to give good log P estimations, even for the most complex molecules. INTRODUCTION The logarithmof the partition coefficientbetween n-octanol and water (log P) has often been used to represent molecular lipophilicity, which seems to be a key factor related to the transport process through cell membranes and to many other biological events.14 Indeed, log P has been found to be a crucial parameter in many quantitative structurebioactivity relationship (QSBR)studies and has been widely used in the practice of today’s rational drug design method^.^^^ Therefore, accessibility to accurate log Pvalues for compoundsof interest may be essential for the correct prediction of their biological activity. The experimental determination of the log P value of a compound is a relatively easy task, although it may be time consuming. However, it was found that there is an increasing need for reliable estimates of log P values for new compoundsoften not synthesized as yet, particularly for drug design purposes. Several approachesfor the estimationsof log Pvalues have been proposed;’ all of them are directly or indirectly based on the chemical structure of the compounds. One of the earliest approacheswith wide applicability is known as the fragmental constant method pioneered by Rekker et al. and based on the assumption that log P has an additive+nstitutive nature.* These authors used a “reductionist approach” to derive the fragmental contribution to calculate the log P values. Leo and Hansch developed a similar method based on fragment constants by a “constructionist approach” at about the same time.9*10These approaches work well for many simple compounds but have limitations for a number of complex compounds where correction factors have to be introduced. Thus, major efforts have been made to include a large number of correction factors to improve the accuracy of the calculations.’ Meanwhile, both K l ~ p m a n ’ s and ~ ~ JCrippen’~’~J~ ~ groups have been using atomic and group contributions for the calculationsof log Pvalues. Their approachesemploy multiple regression analysis to establish a statistical model based on a learningdatabase. An exampleof this approach was recently published by Klopman and Wang, who used the Computer Automated Structure Evaluation (CASE) program to develop a model for the calculations of log P,in which simple atomic ‘v1*

* To whom all correspondence should be addressed.

t Present address: Laboratory of Medicinal Chemistry, National Cancer

Institute, National Institutes of Health, Bethesda, MD 20892. Present address: Biofor, Inc., P.O. Box 629, Waverly, PA 18471. e Abstract published in Aduance ACS Abstracts, March 15, 1994.

*

0095-2338 194j 1634-0752s04.50~0

types and star centered fragments were used as descriptors. Good results were obtained for a database consisting of 935 organic compounds (1.2 = 0.93, SD = 0.39). Molecular properties have also been used as descriptors to correlate with log P values. Klopman and Iroff used atomic charges as parameters to estimate the log Pvalues for simple organic compounds.” Bodor et al. have recently developed two log P estimation models in which charge densities, molecular surfaces, molecular volumes, ovalities, molecular weights, dipoles of molecules, etc., were used as regression parameter~.~*J~ In their recent publication, a nonlinear equation was obtained with 18 molecular parameters for a database of 302 compounds. Good results were obtained (1.2 = 0.978, SD = 0.31), although the applicability of this approach needs to be verified outside the relatively small database used in the study. An attempt to estimate the log P values of some simple organic compounds using Monte Carlo simulation has been also reported.20-22This approach demands a great amount of computer time and is difficult to parametrize for the n-octanollwater system. Although this approach is not practical at the present time, it is a promising approach for the future. Among all the current log P estimation approaches, the group contribution approach shows several advantages. It is conceptually simple and able to give fast and rather accurate estimations for many organic compounds. Poor estimations for certain compounds using group contribution alone were found to be primarily due to the interaction between groups in these compounds. Therefore, the inclusion of some correction factors representing group interactions should improve the accuracy of the log P estimation. Identification of these interactions (correction factors) normally requires detailed studies on the chemical structures and is somewhat ad hoc, as demonstrated by Leo and H a n s ~ h . ~ J ~ In this paper, we employed the CASE p r ~ g r a m to ~~,~~ automatically identify these correction factors. Then, we combined the basic group parameters and correction factors to develop a log P estimation model. METHODS The establishment of an error free learning database is extremely important for the developmment of a reliable log Pestimation model. The log Pvalues reported in the literature were determined by various methods under different exper0 1994 American Chemical Society

COMPUTER AUTOMATED LOG P CALCULATIONS

J. Chem. In$ Comput. Sci., Vol. 34, No.4, 1994 753

imental conditions. Therefore, some care has to be taken in the process of selecting entries for the learning database. Factors such as the solvent system, buffer solutions, and consistency of data have to be considered. For example, in caseswhere the experimentallog Pvalue of the samecompound is reported by different sources, the deviation should not be greater than 0.4 log unit. The predictive ability and applicability of a log Pestimation model is strongly affected by the size of the learningdatabase. Hence, we extended our previous database of 935 compounds to 1663 compounds. These compounds mainly came from Hansch and Leo's compilation9J0with the additionof a number of compounds from the collection of Suzuki and KudoZ5and Viswanadhan et al.28.29 The molecular structures were encoded using the Klopman Line Notation (KLN) code.26A set of basic group parameters were defined, and a program was developed to automatically identify the Occurrence of each group parameter in the compounds. The basic group parameters consist of two fundamental types: (1) heavy atoms with both their hybridization and the number of hydrogen@)attached to them and (2) fundamentalfunctionalgroups (OH, CHO, COOH, COO, CONH2, CONH, CON, CON=, CO, CS, NO, N02, PO, SO, S02, NH2, NH, CN, SH, etc.). In some cases, the nearest heavy atoms are also specified. The log P values and occurrence of the group parameters for all the compounds of the database were then submitted to a multivariate linear regression analysis. An equation correlating the log P values to the basic group parameters was obtained in the form of eq 1,

log P = u

+cbiBi

(1)

where u is a constant, bi is the contribution coefficient of the ith group, and Bi is the number of Occurrences of the ith group. This equation implies that the effects of interactions between groups are negligible. The significance of each parameter and the equation resulting from their use was evaluated by our analysis of their statistical t and F values, respectively. Although eq 1 gave reasonably good log P retrofit values for many compounds of the database, there still was a significantnumber of compoundsshowing unacceptably high deviations. This was interpreted as an indication that the interactions between some groups in these compounds have a substantial effect on their log Pvalues. We postulated that most of these effects could be due to substructures not represented by our set of basic group parameters. The CASE me tho do log^^^ then could be used to identify these substructures which may be responsible for the large error when eq 1 is used. The CASE methodology has been described on a number of 0ccasions.2~~~~ Basically,the CASE program is an artificial intelligencesystemcapable of identifyingstructural descriptors that may be associated with the properties of the molecules which are examined, such as biological activity or physicochemical property. Ageneral schemeof the program is shown in Figure 1. Molecular structures and the index of activity are required by the program as the input. A break-point activity value is chosen between the active and inactive molecules of the learning set to ensure a suitable distribution between active and inactive molecules in the data set for the discriminant analysis. Specifically, CASE takes each molecule of the learning set and breaks it into all possible linear fragments of 2-10 connected heavy atoms. These fragments are labeled as active or inactive, depending on whether or not the parent molecule is active. The occurrence of these fragments then

Index of Activity

Chemical Structure Input (KIN, SMILES,Gnphicr)

I

(Biologicalacdvily)

DATABASE

L-J Substructure Generator

I

Calculation of Properties (QM,MW. log P,WS)

STATISTICALEVALUATION Discrinim Aralyrir

b

b

DESIGN

PREDICI'IONS

MODE OF ACI'ION

Figure 1. General scheme of the CASE program.

is submitted to a series of statistical analyses to identify those whose distribution is significantlyskewed toward either actives or inactives in the entire database. Furthermore, these significant fragments are used as descriptorsin a quantitative structure-activity relationship (QSAR) analysis to yield a linear regression equation that best describes the activity of the compounds in the database. In this study, we are interested in finding substructures responsible for the calculation error in eq 1 using the CASE program. To do so, we took the difference between the log Pvalue estimated from eq 1 and the experimentalvalueentered as input for the CASEanalysis. Subsequently,in the fragment generation step, the fragments are labeled as active if they originate from compounds with positive error or inactive if they originate from compounds with negative error. The significant fragments identified by the CASE analysis were subsequently used for the development of the final log P estimation model in addition to the basic group parameters. These additional substructure parameters enable the new log P model to account for effects of group interaction and serve as correctionfeatures. Hence, the final log Pestimation model obtained is of the form log P = u

+ z b i B i+ z c j C j

where u, bj, and cj are regression coefficients,Bi is the number of Occurrences of the ith basic group, and Cj is the number of Occurrences of the jth correction factor identified by the CASE program. RESULTS AND DISCUSSION (1) log P Estimation Model Usiog Group Contribution Alone. Our log P calculation model was established on the

basis of a learning database of 1663 compounds with diverse structures. A graphics program GMK2' was used to ensure that the structures entered in the program were correct. The initial model was established on the basis of the basic group contribution parameters alone. There are 68 fundamental group parameters, as shown in Table l. Of these, 64 were found signifcant enoughto beused in thelinear regreasion analysis. The model generated a 9value equal to 0.838 and showed a standard deviation equal to 0.577. The standard error of 0.58 is fairly good consideringthe sizeof the database and the number of parameters used. The 1663 compounds were divided into 12 classes on the basis of their chemical structure. The log P estimation error for each classof compoundsis listedin Table 2, and a histogram

754 J. Chem. In5 Comput. Sci., Vol. 34, No. 4, 1994

KLOPMANET AL.

Table 1. List of Fundamental Group Parameters param 1. -CH3 2. - C H r 3. -CH< 4. >c< 5. =CH2 6. =CH7. =C< 8. =C= 9. a C H 10. -c= ll.-C*Hr 12. -C*H< 13. >C*< 14. =C*H15. =c*< 16. -F 17. -F 18. -C1 19. -C1 20. -Br 21. -Br 22. -I 23. -I 24. -OH 25. -OH 26. -OH 27. -OH 28. -OH 29. -O*30. -031.-CHO 32. -COOH 33. -COOH 34. -COO-

remarks

param 35. -c*oo36. X O N H z 37. -CONH38. -CON< 39. -CON= 40.4041. -C*O42. -NO 43. -Po 44.4045. -NH2 46. -NH2 47. -NH2 48. -NH2 49. -NH50. -N< 51. -N*H52. -N*< 53.4bN 54. - G N 55. =NH 56. =N57.=N*58. -NO2 59. -NO2 60. S H 61.4462. S I 63. =S 64. -CS65. 4 0 2 66. S I 0 2 61. -P.= 68. -P-(c< 5 . =CHI 6.4H7. =c< 8. =c= 9. m H 10. -c= 11.-C*Hr 12. -C*H< 13. >C*< 14.=C*H15. =C*< 16. -F 17. -F 18.41 19. -C1 20. -Br 21. -Br 22. -I 23. -I 24. -OH 25. -OH 26. -OH 27. -OH 28. -OH 29. -O*30. -031.-CHO 32. -COOH 33. -COOH 34. -Coo35.-C*OO36. -CONH2 37. -CONH38. -CON< 39. -CON= 40. -CO41. -C*O42. -NO 43. -PO 44. -SO45. -NH2 46. -NH2 47. -NH2 48. -NH2 49. -NH50. -N< 5 1. -N*H52. -N*< 53. O N 54. O N 55. =NH 56. =N57.=N*58. -NO2 59. -NO2 60. S H 61.462. S*63. =S 64.4% 65.302 66. S * 0 2 67. -P= 68. -+(e) 69. HO-C=N70. HOCO-C-N7 1. - N H - N 4 H - X 72. HCO-X 73. NH2(1,o)-CO-NH2(I .o) 74.OH(o)-CO-NH2(1,o) 75. -CO-NH(o)-CO76. -CH2( 1,o)-NH-CHq I .o)77. -CH~(I.O)- 3 n12 including cycloalkane

a An asterisk indicates the atom in a ring system; Cam refers to an aromatic carbon atom; a symbol in the parentheses indicates the open valence, not filled by hydrogen; a number in the parentheses indicates the acceptable number of hydrogen atoms.

"T

Estimation error

Experimental Log P Figure 3. Correlation between the experimental and calculated log

P. values could not be evaluated. The final log P estimation model was obtained by correlating the remaining 94 parameters with the log P values through a multivariate linearregression analysis (n = 1663, ? = 0.928, SD = 0.3817, F(94, 1568) = 217.77). The standard deviation of 0.38 is within the experimental error range of 0.4 in spite of the fact that a relatively small number of parameters were used in our model for such a large database. A plot of the experimental log P values vs the calculated log P values for all the compounds in the database is shown in Figure 3. This figure shows good agreement between the experimental and calculated log P values for the 1663 compounds with diverse structures. The histogram of estimation errors is shown in Figure 4, where a near-Gausian error distribution curve centered at zero is seen. The experimental and calculated log P values of the 1663 compounds, as well as the estimation errors, have been summarized in Table 4. There are 71 compounds showing deviations greater than or equal to 0.8 log unit, as shown in Table 5. To improve the calculation for these outliers will require the development of new correction factors. We found

Figure 4. Distribution of estimation error.

that each of these 71 outliers contain at least one unique fragment in its structure. The inclusion of these unique fragments would definitely improve the accuracy of the log P estimation. However, we did not include these unique fragments in our final log P model because (1) they are not statisticallysignificantand their value based on one compound may not lead to a stablecorrelation and (2) in somecompounds, a number of unique fragments exists, which makes it difficult to decide which of these should be used as the correction factor. Nevertheless, in the future when more compounds containing these unique fragments become available, their contribution to the log P values may be evaluated and hence be included in our log P model. Table 2 also shows the average deviation for the 12 classes of compounds, as defined before, in the final model. As can be seen, the final model gives accurate log P values not only for the simple compounds but also for the complex ones. Comparing these values in Table 2, it can be seen that the accuracy of the calculated log P values for amino acids, hydrocarbons, and multifunctional compounds was greatly improved by the inclusion of these correction factors. Overall, the standard deviation has been reduced by about 0.2 log unit from 0.58 to 0.38, and the r2 value has been increased from 0.84 to 0.93.


COMPUTER AUTOMATED LOG P CALCULATIONS Table 4. Experimental, Calculated log P Values, and Estimation Error formula

log Pcb

log PrC

Aliphatic Hydrocarbons 1.13 1.81 0.94 1.77 1.72 2.36 1.99 1.46 2.34 2.31 2.40 2.76 2.89 1.98 3.00 3.11 3.62 2.30 2.47 2.86 2.45 3.44 4.1 1 3.85 3.82 5.18 3.20 4.78

1.27 1.38 1.09 1.70 1.23 2.08 1.90 1.75 2.51 2.12 2.11 2.71 2.78 1.92 2.52 3.45 3.48 2.41 2.41 2.37 2.73 3.16 4.18 4.05 4.15 5.57 3.47 4.49

0.14 -0.43 0.15 -0.07 449 -0.28 -0.09 0.29 0.17 -0.19 -0.29 -0.05 -0.11 -0.06 -0.48 0.34 -0.14 0.11 -0.06 -0.49 0.28 -0.28 0.07 0.20 0.33 0.39 0.27 -0.29

Aromatic Hydrocarbons 2.13 benzene 2.69 toluene 2.53 ethynylbenzene 3.16 styrene 3.15 ethylbenzene 3.18 p-xylene 3.20 m-xylene 3.13 o-xylene 2.92 indene 3.33 indane 1-phenyl-1-propene 3.35 3.27 cyclopropylbenzene 3.23 allylbenzene 3.42 1,3,5-trimethylbenzene 3.53 1-ethyl-2-methylbenzene 3.55 1,2,3-trimethylbenzene 3.68 propylbenzene 3.66 isopropylbenzene 3.65 1,2,4-trimethylbenzene 3.35 naphthalene 1,2,4,5-tetramethylbenzene 4.00 4.1 1 tert-butylbenzene p-cymene 4.10 but ylbenzene 4.26 2-methylnaphthalene 3.86 1-methylnaphthalene 3.87 acenaphthylene 4.03 acenaphthene 3.92 biphenyl 4.09 2,6-dimethylnaphthalene 4.31 2,3-dimethylnaphthalene 4.40 1,8-dimethylnaphthalene 4.26 1,7-dimethyInaphthalene 4.44 1,5-dimethylnaphthalene 4.38 1.4-dimethylnaphthalene 4.37 1.3-dimethylnaphthalene 4.42 1,2-dimethylnaphthalene 4.31 2-ethylnaphthalene 4.38 1-ethylnaphthalene 4.39 hexamethylbenzene 4.31 fluorene 4.18 diphenylmethane 4.14 1,4,5-trimethylnaphthalene 4.90 2,3,6-trimethylnaphthalene 4.73 phenanthrene 4.57 anthracene 4.54 1-methylfluorene 4.97 stilbene 4.81

2.45 2.86 2.46 3.06 3.27 3.27 3.27 3.27 3.07 3.03 3.49 3.02 3.48 3.68 3.68 3.68 3.69 3.62 3.68 3.47 4.09 4.07 4.03 4.10 3.88 3.88 3.72 3.68 4.23 4.29 4.29 4.29 4.29 4.29 4.29 4.29 4.29 4.29 4.29 4.91 4.08 4.64 4.70 4.70 4.48 4.48 4.49 4.85

0.32 0.17 -0.07 -0.10 0.12 0.09 0.07 0.14 0.15 -0.30 0.14 -0.25 0.25 0.26 0.15 0.13 0.01 -0.04 0.03 0.12 0.09 -0.04 -0.07 -0.16 0.02 0.01 -0.3 1 -0.24 0.14 -0.02 -0.11 0.03 -0.15 -0.09 -0.08 -0.13 4.02 -0.09 4.10 0.60 -0.10 0.50 -0.20 -0.03 -0.09 -0.06 -0.48 0.04

name ethylene ethane ProPYne propylene cyclopropane propane 1,3-butadiene 2-butyne isobutylene 2-butene 1-butene isobutane butane 1-pentyne cyclopentane neopentane pentane 1,4-~yclohexadiene 1,3-~yclohexadiene cyclohexene 1,541exadiene cyclohexane n-hexane 2,3-dimethylbutane 2,2-dimethylbutane n-octane azulene diphenylacetylene

log Pea

758 J. Chem. In$ Comput. Sci., Vol. 34, No. 4, 1994

KLOPMANET AL.

Table 4 (Continued) formula 77. C M H I Z 78. C d i 4 79. Ci6Hio 80. CigHiz 8 1. CH40 82. CzH40 83. C2HsO 84. C2H6O 85. C3Hs0 86. C3Hs0 87. C3HsO 88. C4H40 89. C4H60 90. C4HgO 91. C4HgO 92. C4Hi00 93. C4Hi00 94. C4Hio0 95. C4Hio0 96. C4Hio0 97. C ~ H i z 0 98. CsHizO 99. C ~ H i 2 0 100. CsHizO 101. C~H120 102. CsHizO 103. C6HsO 104. C ~ H I ~ O 105. C6Hi40 106. C6Hi40 107. CaHi40 108. C6H140 109. C7HgO 110. C7HgO

111.C7HgO 112. C7HgO 113. C7HgO 114. CsH& 115. CsHioO 116. CsHioO 117. CsHioO 118. CsHioO 119. CsHioO 120. CsHioO 121. CgHioO 122. CsHioO 123. CsHioO 124. CgHioO 125. CsHioO 126. CgHioO 127. CgHioO 128. CgHioO 129. CsHisO 130. C9HioO 131. CgHioO 132. C9H120 133. C9H120 134. C9H120 135. C9H120 136. CioHsO 137. CioHgO 138. CioHizO 139. CioHirO 140. CioHi40 141. CioHi40 142. CioHi40 143. CioHi40 144. CioHiiO 145. CioHi40 146. C1oHi60 147. Ci2Hio0 148. CizHioO 149. CizHioO 150. CiZHZ60 151. Ci3H120 152. Ci3Hiz0

log Pc" Aromatic Hydrocarbons 9,lO-dihydroanthracene 4.25 diphenylethane 4.80 pyrene 5.18 benz[a]anthracene 5.61 Alcohols, Ethers, and Phenols methanol -0.66 ethylene oxide -0.30 dimethyl ether 0.10 ethanol -0.31 0.17 allyl alcohol 2-propanol 0.05 1-propanol 0.34 furan 1.34 2,5-dihydrofuran 0.46 ethylvinyl ether 1.04 tetrahydrofuran 0.41 diethyl ether 0.89 tert-butyl alcohol 0.37 sec-butyl alcohol 0.61 isobutyl alcohol 0.65 butanol 0.88 2-methyl-2-butanol 0.89 2,2-dimethylpropanol 1.36 isopentyl alcohol 1.42 3-pentanol 1.21 pentanol 1.40 3-methyl-2-butanol 1.28 phenol 1.46 cyclohexanol 1.23 butyl ethyl ether 2.03 dipropyl ether 2.03 3,3-dimethyl-2-butanol 1.48 hexanol 2.03 anisole 2.10 p-cresol 1.94 o-cresol 1.95 m-cresol 1.96 benzyl alcohol 1.10 benzofuran 2.67 ethoxybenzene 2.51 p-methylbenzyl alcohol 1.59 o-methylbenzyl alcohol 1.58 m-methylbenzyl alcohol 1.60 p-ethylphenol 2.26 o-ethylphenyl 2.47 m-ethylphenol 2.40 2-phenyl-1-ethanol 1.36 3,s-dimethylphenol 2.35 3,4-dimethylphenol 2.23 2,6-dimethylphenol 2.36 2,5-dimethylphenol 2.33 2,4-dimethylphenol 2.30 1.35 benzyl methyl ether 3.15 octanol 1.95 cinnamyl alcohol 2.94 allyl phenyl ether 3.18 phenyl propyl ether 2.88 2-prop-2-yl-1-phenol 2.93 2-propl-yl-1-phenol 1.85 7-phenylpropyl alcohol 2.84 2-naphthol 2.98 1-naphthol 1.95 phenylcyclopropylcarbinol 2.70 1-methoxy-3-phenylpropane 3.27 o-( 1-methylpropy1)phenol 2.94 p-( 1,l-dimethylethy1)phenol 3.30 thymol 2.35 &phenylbutyl alcohol 3.30 thymol 3.31 o-( l,l-dimethylethyl)pheno1 2.14 1-hydroxyladamantane 3.20 p-phenylphenol 3.09 o-phenylphenol 3.23 m-phenylphenol 5.13 1-dodecanol 2.67 diphenylmethyl alcohol 3.79 benzyl phenyl ether name

log Pcb

log PrC

4.44 5.05 4.74

0.19 0.25 -0.44 -0.1 1

5.50

-0.72 -0.12 -0.02 -0.31 -0.10 0.15 0.11 0.92 0.64 0.84 0.60 0.8 1 0.76 0.56 0.46 0.52 1.17 0.91 0.87 0.98 0.94 0.91 1.46 0.63 1.64 1.64 1.36 2.18 1.58 1.87 1.87 1.87 1.06 1.94 2.00 1.47 1.47 1.47 2.29 2.29 2.29 1.47 2.28 2.28 2.28 2.28 2.28 1.76 3.01 1.69 2.21 2.41 2.64 2.70 1.89 2.48 2.48 1.68 2.59 3.05 3.09 3.05 2.30 3.05 3.09 1.42 3.24 3.24 3.24 4.67 2.88 3.37

-0.06 0.18 -0.12 0.00 -0.27 0.10 -0.23 -0.42 0.18 -0.20 0.19 -0.08 0.39 -0.05 -0.19 -0.36 0.28 -0.45 -0.55 -0.23 -0.46 -0.37 0.00 -0.60 -0.39 -0.39 -0.12 0.15 -0.5 1 -0.07 -0.08 -0.09 -0.04 -0.73 -0.5 1 -0.12 -0.1 1 -0.13 0.03 -0.18 -0.1 1 0.1 1 -0.07 0.05 -0.08

-0.05 -0.02 0.41 -0.14 -0.26 -0.73 -0.77 -0.24 -0.23 0.04 -0.36 -0.50 -0.27 -0.1 1 -0.22 0.15 -0.25 -0.05 -0.25 -0.22 -0.72 0.04 0.15 0.01 -0.46 0.21 -0.42

J. Chem. If. Comput. Sei., Vol. 34, No.4, 1994 759

COMPUTER AUTOMATED LOG P CALCULATIONS Table 4 (Continued) formula

name

log PC"

log Pcb

log P*C

3.13 3.06

3.29 3.29

0.16 0.23

0.59 -0.24 0.88 0.29 0.91 0.58 1.02 0.81 1.38 1.78 1.48 1s o 1.98 1.58 1.78 2.26 2.76 1.90 1.88 2.19 2.28 3.18 2.07 2.42 3.58 3.18 3.08

0.36 0.13 0.78 0.54 0.96 0.56 1.16 0.91 1.37 1.61 1.32 1.12 1.79 1.49 1.73 1.73 3.03 1.95 1.70 1.91 1.90 3.44 2.12 2.74 2.66 2.86 3.49

-0.23 0.37 -0.10 0.25 0.05 -0.02 0.14 0.10 -0.01 -0.17 -0.16 -0.38 -0.19 -0.09 -0.05 -0.53 0.27 0.05 -0.18 -0.28 -0.38 0.26 0.05 0.32 -0.92 -0.32 0.41

-0.54 -0.17 0.18 0.33 0.72 0.83 0.73 0.79 1.21 1.88 1.26 1.81 2.27 2.37 2.12 1.49 1.41 2.75 2.08 2.09 2.1 1 2.64 1.96 1.83 1.86 2.11 1.84 2.62 2.32 2.42 2.56 2.42 2.42 2.30 4.09 3.10 2.99 2.78 2.77 4.20 3.59 3.05 3.97

-0.23 -0.30 0.21 0.1 1 0.32 1.1 1 0.62 0.53 1.04 1.36 1.65 1.79 2.20 2.20 1.57 1.57 1.48 2.12 1.69 1.98 1.98 1.99 1.99 1.99 1.89 1.98 1.89 2.20 2.40 2.40 2.40 2.40 2.31 2.40 3.84 2.81 2.62 2.75 2.82 4.67 2.94 3.19 3.35

0.3 1 -0.13 0.03 -0.22 0.28 -0.1 1 -0.26 417 -0.52 0.39 -0.02 -0.07 -0.17 -0.55 0.08 0.07 -0.63 -0.39 -0.11 -0.13 -0.65 0.03 0.16 0.03 -0.13 0.05 -0.42 0.08 -0.02 -0.16 -0.02 -0.11 0.10 -0.25 -0.29 -0.37 -0.03 0.05 0.47 -0.65 0.14 -0.62

-0.57 -0.34 -0.13

-0.94 0.03 -0.52

-0.37 0.37 -0.39

Alcohols, Ethers, and Phenols phenyl-p-tolylcarbinol phenyl-o-tolylcarbinol Aldehydes and Ketones propionaldehyde acetone but yaldehyde 2-butanone 2-pentanone 1-hexyn-Sone 1-hexen-S-one cyclohexanone 2-hexanone hexaldehyde benzaldehyde 4-cyclopropy l-2-butanone 2-heptanone acetophenone phenylacetaldehyde o-methylbenzaldehyde 2-octanone cinnamaldehyde acrylophenone propiophenone p-methylacetophenone 2-nonanone methyl styryl ketone 5-phenyl-2-pentanone 9-fluorenone benzophenone benzalacetophenone Acids and Esters formic acid acetic acid methyl acetate propionic acid crotonic acid propyl formate ethyl acetate butyric acid ethyl propionate hexanoic acid phenyl formate benzoic acid ptoluic acid m-toluic acid benzoic acid methyl ester acetic acid phenyl ester phenylacetic acid valproic acid cinnamic acid m-tolyl acetate p-tolyl acetate ethyl benzoate acetic acid benzyl ester phenylacetic acid methyl ester (p-methylpheny1)aceticacid o-tolyl acetate 3-phenylpropionicacid cinnamic acid methyl ester j3-phenylpropionic acid methyl ester phenylacetic acid ethyl ester 4-ethylphenyl acetate 2-ethylphenyl acetate 4-phenylbutyric acid acetic acid j3-phenylethyl ester decanoic acid 1 -naphthonic acid cinnamic acid ethyl ester 2-isopropylphenyl acetate 4-phenylbutyric acid methyl ester dodecanoic acid phenyl benzoate diphenylacetic acid benzyl benzoate Amines and Nitriles methylamine acetonitrile ethylamine

-0.40

760 J. Chem. Inf. Comput. Sci., Vol. 34, No. 4, 1994

KLOPMANET AL.

Table 4 (Continued) formula

name

log Pea

log Pcb

log PrC

0.16 0.03 0.27 -0.03 0.48 0.15 0.57 0.81 0.70 0.74 0.88 0.40 0.81 1.33 1.45 0.90 1.11 1.33 1.49 1.44 1.70 1.73 2.06 1.56 1.82 1.39 1.29 1.42 1.09 2.12 1.91 2.07 2.57 1.56 1.74 2.31 2.16 1.41 2.16 2.15 1.52 2.68 2.82 2.68 1.96 1.76 2.45 1.83 2.85 2.80 2.61 2.79 2.68 2.25 2.28 3.3 1 2.40 2.73 3.34 3.50 3.13 3.16 4.22

0.45 -0.31 0.34 -0.03 -0.11 0.32 0.74 0.31 0.76 0.38 0.24 0.42 0.94 1.15 0.72 0.92 1.15 1.36 0.44 1.59 1.59 1.57 1.96 1.26 2.01 1.33 1.33 1.33 0.85 1.98 1.92 1.92 2.38 1.81 1.75 1.71 2.42 1.26 2.42 2.42 1.69 2.40 2.04 2.29 2.03 1.75 2.84 1.68 2.12 2.12 2.12 2.83 2.32 1.94 1.94 2.54 2.09 2.96 2.70 3.37 3.79 3.08 3.49

0.29 -0.34 0.07 0.00 -0.59 0.17 0.17 -0.50 0.06 -0.36 -0.64 0.02 0.13 -0.18 -0.73 0.02 0.04 0.03 -1.05 0.15 -0.1 1 -0.16 -0.10 -0.30 0.19 -0.06 0.04 -0.09 -0.24 -0.14 0.01 -0.15 -0.19 0.25 0.01 -0.60 0.26 -0.15 0.26 0.27 0.17 -0.28 -0.78 -0.39 0.07 -0.01 0.39 -0.15 -0.73 -0.68 -0.49 0.04 -0.36 -0.31 -0.34 -0.77 -0.31 0.23 -0.64 -0.13

-1.05 -0.21 -0.77 0.64 1.15 1.16 1.09 1.61 1.18 0.45 1.14 1.48 1.41

4.39 -0.01 0.00 0.53 1.05 0.98 1.44 1.47 0.94 0.94 1.32 1.52 1.16

0.66 0.20 0.77 -0.11 -0.10 -0.18 0.35 -0.14 -0.24 0.49 0.18 0.04 -0.25

Amines and Nitriles 228. C3HsN 229. C3H7N 230. C3H9N 23 1. C3H9N 232. C3H9N 233. CsH9N 234. C4HiiN 235. CIHIIN 236. C ~ H I I N 237. C4HiiN 238. C4HiiN 239. C ~ H I I N 240. CsHiiN 241. C ~ H I ~ N 242. CsHi3N 243. C6H7N 244. CsHiiN 245. C ~ H I ~ N 246. C ~ H I ~ N 247. CsHisN 248. C ~ H I S N 249. CsHisN 250. CsHisN 25 1. C7HsN 252. C7H9N 253. C7H9N 254. C7H9N 255. C7H9N 256. C7H9N 257. C7Hi7N 258. C7H17N 259. C7Hi7N 260. C7Hi7N 261. CsH7N 262. C s H i i N 263. CBHIIN 264. C s H i i N 265. CsHiiN 266. C s H i i N 267. CsHiiN 268. C s H i i N 269. CsH19N 270. CsHi9N 271. CsH19N 272. C9H7N 273. C9Hi3N 274. C9Hi3N 275. C9HisN 276. C9HisN 277. C9Hi3N 278. C9Hi3N 279. C9HziN 280. C9HziN 281. CioH9N 282. CioH9N 283. CioHisN 284. CloHisN 285. CiiHi7N 286. C i z H i i N 287. C i z H i i N 288. C I ~ H I ~ N 289. Ci3Hi3N 290. Ci4HisN 29 1. CaH70N 292. C4H90N 293. C4H90N 294. C7H70N 295. C7H7ON 296. CeH90N 297. CsH90N 298. CsH90N 299. CsH90N 300. CsH90N 301. CsHlsON 302. CsH170N 303. C9H90N

propionitrile allylamine trimethylamine isopropylamine propylamine methylethylamine diethylamine butylamine ethyldimethylamine see butylamine isobutylamine ?err-butylamine ethylallylamine butylmethylamine amylamine ani1ine diallylamine propylallylamine cyclohexylamine triethylamine butyldimethylamine dipropylamine hexylamine benzonitrile N-methylaniline p-toluidine o-toluidine m- toluidine benzylamine propylbutylamine propyl-sec-butylamine propylisobutylamine heptylamine phenylacetonitrile 2-ethylaniline N,N-dimethylaniline N-ethylaniline 8-phenylethylamine N-methyl-o-toluidine N-methyl-p-toluidine methylbenzylamine dibutylamine 2-ethylhexylamine ethyldiisopropylamine cinnamonitrile amphetamine N-propylaniline 7-phenylpropylamine

N,N-dimethyl-o-toluidine N,N-dimethyl-m-toluidine N,N-dimethyl-p-toluidine tripropylamine 2-ethylhexylamine 1-naphthamine 2-naphthamine N,N-diethy lanilhe b-phenylbutylamine yphenylpropyl-dimethylamine 2-aminobiphenyl diphenylamine N-benzylaniline diphenylmethylamine N-methyl-N-benzylaniline Amides and Anilide N-methylacetamide butylamide N,N-dimethylacetamide benzamide formanilide acetanilide N-methylformanilide p-methylformanilide m-methylbenzamide phenylacetamide allylisopropylacetamide propylisopropylacetamide cinnamamide

0.66

-0.08 -0.73

J. Chem. Inf: Comput. Sci., Vol. 34, No. 4, 1994 761

COMPUTER AUTOMATED LOG P CALCULATIONS Table 4 (Continued) ~~

formula 304. C9HiiON 305. C9HiiON 306. C9HiiON 307. C9HiiON 308. CgHloON 309. CioHisON 310. CloHi3ON 311. CloH1,ON 312. Ci3HiiON 313. CisHioON

log PC"

name Amides and Anilides propionanilide 7-phen ylpropionamide N,N-dimethylbenzamide N-methylacetanilide p-methoxy-N, N-dimethylaniline p-isopropylbenzamide butyranilide isobutvranilide benzahlide cinnamanilide

log Pt

log P/

1.61 1.03 0.62 1.07 1.42 2.14 2.05 2.02 2.70 3.61

1.40 1.36 1.37 1.37 1.72 1.71 1.81 1.75 2.35 2.98

-0.21 0.33 0.75 0.30 0.30 -0.43 -0.24 -0.27 -0.35 -0.63

1.81 2.28 1.95 2.52 2.74 3.12 3.20 3.74 4.45

1.63 2.08 1.93 2.20 2.47 2.65 2.89 3.41 3.84

-0.18 -0.20 -0.02 -0.32 -0.27 -0.47 -0.31 -0.33 -0.6 1

0.08 0.18 0.65 1.01 1.47 2.01 1.85 2.37 2.30 2.45 1.75 2.24 2.95 2.08 2.66 2.63 2.52 3.19

0.04 0.45 0.87 1.25 1.28 1.70 1.54 1.95 1.95 1.95 1.96 2.17 2.37 2.37 2.58 2.58 2.99 2.56

-0.04 0.27 0.22 0.24 -0.19 -0.3 1 -0.3 1 -0.42 -0.35 -0.50 0.21 -0.07 -0.58 0.29 -0.08 -0.05 0.47 -0.63

S-Containing Hydrocarbons thiophene butanethiol diethyl sulfide thiophenol methylthiobenzene benzothiophene phenylethyl sulfide 2-phenylthiophene diphenyl sulfide 323. CH302N 324. CzHs02N 325. CoH702N 326. C4H902N 327. C4H902N 328. CsH1102N 329. CsHs02N 330. C7H702N 33 1. C7H702N 332. C7H,02N 333. C7H702N 334. CsH702N 335. CsH902N 336. CsH902N 337. C9H902N 338. CgH902N 339. CgHg02N 340. CloH702N

Nitro Hydrocarbons nitromethane nitroethane nitropropane 2-methyl-2-nitropropane nitrobutane nitropentane nitrobenzene p-nitrotoluene o-nitrotoluene m-nitrotoluene a-nitrotoluene b-nitrostyrene

1,3-dimethyl-2-nitrobeenzene b-nitroethylbenzene 4-methyl-8-nitrostyrene 2-methyl-&nitrostyrene j3-methyI-fl-nitrostyrene 1-nitronaphthalene Amino Acids glycine alanine valine methionine ornithine histidine isoleucine leucine lysine phenylalanine

35 1. CC4 352. CHCl3 353. CH2F2 354. CHzClz 355. CH3F 356. CH3CI 357. CH3Br 358. CH3I 359. C2HClj 360. C2HzF2 36 1. C2HoCI3 362. C2H3Br 363. C2H4F2 364. CzH4C12 365. C2H4C12 366. CzHsCl 367. C2HsBr 368. C2HsI 369. C3HsBr 370. C3HsC12 37 1. C3H7CI 372. CaH7Br 373. C3H7Ci 374. C4HgBr 375. C4HgC1

Halogenated Hydrocarbons carbon tetrachloride chloroform difluoromethane dichloromethane methyl fluoride methyl chloride methyl bromide methyl iodide trichloroethylene 1,l-difluoroethylene 1,l ,I-trichloroethane vinyl bromide 1,I-difluoroethane 1,2-dichloroethane 1,l-dichloroethane ethyl chloride ethyl bromide ethyl iodide allyl bromide 1,3-dichloropropane 2-chloropropane 1-bromopropane chloropropane 1-bromobutane 1-chlorobutane

-3.00 -2.83 -2.10 -1.87 -2.89 -2.52 -1.69 -1.57 -2.82 -1.43 2.83 1.97 0.20 1.25 0.5 1 0.91 1.19 1.51 2.29 1.24 2.49 1.57 0.75 1.48 1.79 1.43 1.61 2.00 1.79 2.00 1.90 2.10 2.04 2.75 2.55

-3.29 -2.80 -2.04 -1.49 -3.12 -2.32 -1.62 -1.62 -2.70 -1.02 2.04 1.54 0.69 1.14 0.44 0.67 0.98 1.17 2.22 1.29 1.99 1.19 1.04 1.55 1.49 1.09 1.39 1.58 1.60 1.97 1.44 1.81 1.so 2.22 1.92

-0.29 0.03 0.06 0.38 -0.23 0.20 0.07 -0.05

0.12 0.41 -0.79 -0.43 0.49 -0.11 -0.07 -0.24 -0.21 -0.34 -0.07 0.05 -0.05

-0.38 0.29 0.07 -0.30 -0.34 -0.22 -0.42 -0.19 403 -0.46 -0.29 -0.54 -0.53 -0.63

KLOPMANET AL.

762 J. Chem. If. Comput. Sci., Vol. 34, No. 4, 1994 Table 4 (Continued)

formula

name

-

log Pea

log P,b

log P/

2.33 3.37 2.22 3.39 3.38 3.38 3.64 3.75 2.27 2.84 2.99 3.72 3.80 2.79 2.92 3.33 3.42 3.42 2.92 4.04 2.95 3.09 2.95 3.55 3.72 4.56 4.61 4.71 4.59

2.10 2.64 2.88 2.88 2.88 2.88 3.25 3.25 1.79 2.23 2.41 4.19 3.88 2.68 3.36 2.64 2.64 2.64 2.76 4.14 2.87 3.18 3.06 3.28 3.59 4.39 4.01 4.01 4.01

-0.23 -0.73 0.66 -0.51 -0.50 -0.50 -0.39 -0.50 -0.48 -0.61 -0.58 0.47

-1.23 -0.54 -0.21 -0.35 0.08 -1.89 -1.30 -1 .oo -1.21 -0.52 -0.46

-0.90 -0.75 -0.25 -0.07 -0.31 -1.20 -0.96 -0.43 -0.18 -0.86 -0.09 -0.37 -0.57 0.06 0.27 0.50 0.10 0.14 0.43 0.65 0.30 -0.35 -0.26 0.10 0.26 -0.06 0.28 -0.06 0.46 0.09 0.27 -0.10 0.48 0.09 -0.3 1 0.32 0.85 -0.24 -0.33 -0.46 -0.32 0.28 -0.26 -0.43 0.22 0.90

Haloaenated Hvdrocarbons 1-fluoropentane

1-bromopentane hexafluorobenzene p-dichlorobenzene o-dichlorobenzene m-dichlorobenzene o-dibromobenzene m-dibromobenzene fluorobenzene chlorobenzene bromobenzene hexachlorocyclohexane 1-bromohexane a,a,a-trifluorotoluene a,a,a-trichlorotoluene p-chlorotoluene o-chlorotoluene m-chlorotoluene a-bromotoluene 1-methylpentachlorocyclohexane 2-chloro-1-ethylbenzene 8-phenylethyl bromide y-phenylpropyl fluoride y-phenylpropyl chloride y-phenylpropyl bromide

a-(2,2,2-trichloroethyl)styrene 4-chlorobiphenyl 3-chlorobiphenyl 2-chlorobiphenyl

0.08 -0.11 0.44 -0.69 -0.78 -0.78 -0.16 0.10 -0.08 0.09 0.11 -0.27 -0.13 -0.17 -0.60 -0.70 -0.58

Nucleosides

440. CsHsNs 441. C4H4N6 442. CsHiiNs 443. CsHiaNs 444. CioHisNs 445. CioHisONs 446. C4HsONp 447. CsH70Ns 448. C4H40Na 449. CsH40N4 450. CsH4N4

Ado dAdo ddAdo ddeAdo FddAdo Guo dGuo ddGuo ddeGuo dDAPR ddDAPR FddDAPR Urd dUrd ddUrd ddeUrd FddUrd dThd ddThd ddeThd FddThd CYd dCyd ddCyd ddeCyd FddCyd F6ddP F62AddP Br6ddP Br62AddP C16ddP C162AddP I6ddP I62AddP ddI

-1.71 -1.50 -0.88 -1.07 -0.48 -1.17 -0.63 -0.81 -0.27 -2.51 -1.77 -1.30 -1.42 -0.91 0.00 -0.05 0.35 0.33 0.23 0.21 0.52 0.52 -1.24

-2.13 -1.29 -0.46 -0.42 -0.23 -3.09 -2.26 -1.43 -1.39 -1.38 -0.55 -0.32 -2.28 -1.44 -0.61 -0.57 -0.38 -1.03 -0.20 -0.16 0.03 -2.86 -2.03 -1.20 -1.16 -0.97 0.28 -0.11 0.8 1 0.42 0.50 0.11 1.00 0.61 -1.55

Nucleobases adenine adenine, 8Aza 9-propyladenine 9-butyladenine 9-pentyladenine 9 4 1-(hydroxymethyl)buty1))adenine cytosine guanine guanine, 8Aza hypoxanthine purine

-0.09 -0.96 0.74 1.25 1.79 0.66 -1 -73 -0.91 -0.71 -1.11 -0.37

0.23 -0.1 1 0.50 0.92 1.33 0.34 -1.45 -1.17 -1.14 -0.89 0.53

0.05



name

log Pea

log Pc”

log P/

-0.07 -0.62 -1.07 -1.87 -0.59 -0.95 -0.35 -0.21 -0.28 -1.20 -1.03

-0.37 -0.45 -0.86 -1.91 -0.91 -0.62 -0.40 -0.09 -0.30 -0.48 -1.12 -0.37 -0.45

-0.30 0.17 0.21 -0.32 0.33 -0.05 0.12 -0.02 0.72 -0.09 -0.37 -0.67

-1.67 2.46 1.90 1.90 -0.14 0.53 0.38 1.06 0.47 -0.60 -0.37 -0.06 0.12 0.32 -1.23 0.82 -0.07 0.16 0.47 -0.13 -0.48 1.59 -0.70 -0.05 -1.29 -1.77 2.79 0.28 0.64 -1.32 -0.25 1.25 1.83 0.54 1.25 0.61 0.24 -1.26 2.12 0.84 0.82 -0.35 0.74 0.76 -0.82 -0.15 -0.18 -0.41 -0.87 -0.8 1 -1.71 -0.43 0.32 0.66 0.82 0.82 -1.31 -1.95 -1.31 -1.18 0.16 -0.21 -1.70

-0.40 -0.36 -0.54 -0.34 -0.26 -0.51 0.06 -0.29 0.06 0.45 0.16 0.46 0.31 0.23 -0.12 0.94 0.85 0.13 0.24 -0.03 -0.06 -0.18 0.65 0.52 -0.83 -0.46 0.83 0.36 0.51 -0.36 -0.25 0.8 1 0.13 0.46 0.02 0.02 0.40 0.43 0.65 0.13 -0.10 0.31 0.31 0.19 -0.02 -0.09 -0.03 0.33 -0.77 -0.05 0.08 0.09 0.08 -0.09 1.04 1.22 0.18 -0.33 0.07 0.26 0.23 0.01 -0.71

Nuclwb thioguanine thymine uracil uracil, 5Aza uracil, 6Aza 5-fluorouracil 5-chlorouracil 5-bromouracil 2-thiouracil 1-methyluracil 5-formyluracil 1,3-dimethyluracil 5-ethyl-6-azauracil

0.00 0.22

-0.04

Multifunctional Compounds 464. CH402N2 465. CzF4C12 466. CzHNoBr2 467. C2HN3Br2 468. C2H20NF3 469. CzHzONC13 470. CzHoOFo 47 1. C2H3OCla 472. C2H302Br 473. C2H40NF 474. C2H4ONCI 475. C2H40NBr 476. C2H4ONI 477. C2H402S 478. C2H403 479. CzHsON 480. CzHsOF 481. C2HsOCl 482. C2HsOBr 483. C2H502N3 484. C2Hs03N 485. C2H& 486. CzH6OS 487. C&N2 488. CzH602N2 489. C2H7ON 490. C3HN2Br3 49 1. C3H4N2 492. CsH4N2 493. C3H9ON 494. CsHsOz 495. C3H3NS 496. C ~ H I N Z I 497. CsHsON 498. CsHsOFs 499. CsH302N3 500. CjH302No 501. C3H402N2 502. C3HsNS 503. C3H50F3 504. CsHsOzBr 505. C3HbNzS 506. C&02S 507. C3H602N3Cl 508. C3H603 509. C3H702N 5 10. C3H702N 5 1 1. CoHsONz 5 12. C3Hs02N2 5 13. C3HsOzNz 5 14. C3H803 5 15. C3H904P 5 16. C4H3N3 517. C4HsN 5 18. C ~ H ~ N Z 519. C4H4N2 520. C4H40N2 521. C4H4ON2 522. GH40N2 523. C4H403N2 524. C4HsN3 525. C4HsN3 526. C4HsON3

hydroxyurea

1,2-dichIoro-l,1,2,2-tetrafluoroethane 4,5-dibromo- 1,2,3-triazole 3,Sdibromo- 1,2,4-triazole trifluoroacetamide 2,2,2-trichloroacetamide 2,2,2-trifluoroethanol 2,2,2-trichloroethanol bromoacetic acid fluoroacetamide chloroacetamide bromoacetamide iodoacetamide mercaptoaceticacid hydroxyacetic acid acetaldoxime 2-fluoroethanol 2-chloroethanol 2-bromoethanol 1-methyl-1-nitrosourea 2-nitroethanol dimethyl disulfide methyl sulfoxide N-nitrosodimethylamine 1-methyl-1-hydroxyurea 2-hydroxylethylamine 2,4,5-tribromoimidazole imidazole pyrazole 1-amino-2-propanol dimethoxymethane thiazole 4-iodopyrazole isoxazole

2,2,3,3,3-pentafluoropropanol 4-nitropyrazole 5-nitroimidazole hydantoin ethyl isothiocyanate 1,1,1-trifluoro-2-propano1 a-bromopropionicacid ethylenethiourea 3-mercaptopropionic acid 1-(2-chloroethyl)-l-nitrosourea hydroxypropionic acid methyl N-methylcarbamate urethane N-ethylurea 1-ethyl-1-hydroxyurea 3-ethyl-1-hydroxyurea glycerol trimethyl phosphate 4-cyanopyrawle pyrrole pyrazine pyrimidine p yrazin-2-one

2-pyrimidone 4-p yrimidone barbituric acid 2-aminopyrazine 2-aminopyrimidine 2-amino-4-pyrimidone

-1.27 2.82 2.44 2.24 0.12 1.04 0.32 1.35 0.41 -1.05 -0.53 -0.52 -0.19 0.09 -1.11 -0.12 -0.92 0.03 0.23 -0.10 -0.42 1.77 -1.35 -0.57 -0.46 -1.31 1.96

-0.08 0.13 -0.96 0.00 0.44 1.70 0.08 1.23 0.59 -0.16 -1.69 1.47 0.7 1 0.92 -0.66 0.43 0.57 -0.62 -0.06 -0.15 -0.74 -0.10 -0.76 -1.79 -0.52 0.24 0.75 -0.22 -0.40 -1.49 -1.62 -1.38 -1.44

-0.07 -0.22 -0.99

764 J . Chem. In5 Comput. Sci., Vol. 34, No. 4, 1994

KLOPMANET AL.


name Multifunctional Compounds 3-(methylthio)-4amino- 1.2.4-triazin-5-one 2,2,2-trifluoroethyl acetate 2-methylimidazole y-thiobut yrolactone y-butyrolactone 2-(acety1amino)-1,3,4-thiadiazole-5-sulfamide succinic acid malic acid 2-azacyclopentathione &&&trichloro-tert-butyl alcohol a-bromobutyric acid dichlorovinyl phosphate-0,Odimethyl 2-methyl-2-imidazoline N-ethylbromoacetamide N-nitrosopyrrolidine

N-nitroso-4-thiomorpholine 1,Cdioxane N-nitrosomorpholine

N,N’-dinitrosopiperazine a-hydroxybutyric acid pyrrolidine morpholine

l-nitroso-l,3,3-trimethylurea piperazine N-nitrosodiethylamine 2,3-butanediol 2-ethoxyethanol

bis(2-hydroxyethy1)amine 1-hydroxy-3-propylurea

2,3,4,5,6-pentachloropyridine 2,3-dichloropyridine 2,5-dichloropyrimidine 2,6-dichloropyridine 3,5-dichloropyridine 2-chloropyridine 3-chloropyridine 2-bromopyridine 3-bromopyridine 4-bromopyrdine hypoxanthine 2-nitropyridine 3-nitropyridine uric acid pyridine 2-hydroxypyridine pyridine 1-oxide pentafluoropropionicacid ethyl ester 2-aminopyridine 2-methylpyrazine 3-aminopyridine 4-aminopyridine 1-methyl-2-(hydroxymethyl)-5-nitroimidam 3-methylthio-4-amino-6-methyl1,2,4-triazin-5-one acetylacetone 8-valerolactone N-nitroso-4-piperidone 1,3-diacetylurea butyl thiocyanate N-nitrosopiperidine 3-hydroxy-N-nitrosopiperidhe

4-hydroxy-N-nitrosopiperidine 2-methyl-N,N’-dinitrosopiperazine D-ribose L-arabinose piperidine 4-methylmorpholine N-butylurea

4-methyl-N-nitrosopiperazine propyl N-methylcarbamate 1-isopropoxyethanol diethoxymethane 1-hydroxy-3-butylurea pentafluorophenol pentachlorophenol 2,3,4,6-tetrachlorophenol 2,4,5-trichlorophenol 2,4,6-trichlorophenol

log P.“

log P,b

log Pr’

0.38 1.18 0.49 0.60 -0.64 -0.26 -0.59 -1.26 -0.05 2.03 1.42 1.40 0.52 0.34 -0.19 0.40 -0.27 -0.44 -0.85 -0.36 0.46 -1.08 0.36 -1.17 0.48 -0.92 -0.54 -1.43 -0.22 3.53 2.11 2.40 2.15 2.56 1.28 1.33 1.42 1.60 1.54 -1.31 0.48 0.60 -2.92 0.64 -0.58 -1.30 2.12 0.58 0.23 0.11 0.28 -0.03 -0.16 0.34 -0.35 -0.47 -0.68 2.03 0.63 -0.47 -0.89 -0.28 -2.32 -3.02 0.85 -0.33 0.41 0.20 0.95 0.05 0.84 0.32 3.23 5.12 4.10 3.72 3.38

-0.15 1.31 0.66 1.00 -0.50 -0.75

-0.53 0.13 0.17 0.40 0.14 -0.49 0.19 -0.02 0.22 0.10 -0.18 -0.28 0.09 0.46 0.17 0.39 0.73 0.28 0.07 0.00 -0.62 0.78 0.35 0.12 0.30 0.60 0.42 -0.34 -0.17 0.94 0.39 0.10 0.35 -0.06 0.57 0.52 0.6 1 0.43 0.49 0.10 0.68 0.56 0.57 0.56 0.53 1.07 0.06 -0.04 1.oo 0.43 0.26 -0.45 0.40 -0.29 0.21 0.26 0.46 -0.27 -0.29 -0.02 0.40 -0.09 -0.10 0.65 -0.65 0.56 0.01 -0.59 -0.27 0.18 -0.26 -0.30 -0.68 -0.39 -0.02 -0.30 0.04

-0.40 -1.28 0.17 2.13 1.24 1.12 0.61 0.80 -0.02 0.79 0.46 -0.16 -0.78 -0.36 -0.16 -0.30 0.7 1 -1 -05 0.78 -0.32 -0.12 -1.77 -0.39 4.47 2.50 2.50 2.50 2.50 1.85 1.85 2.03 2.03 2.03 -1.21 1.16 1.16 -2.35 1.20 -0.05 -0.23 2.18 0.54 1.23 0.54 0.54 -0.48 0.24 0.05 -0.14 -0.21 -0.22 1.76 0.34 -0.49 -0.49 -0.37 -2.42 -2.37 0.20 0.23 0.42 -0.39 0.68

0.23 0.58 0.02 2.55 4.73 4.08 3.42 3.42


J. Chem. In! Comput. Sci., Vol. 34, No. 4, 1994 765


name Multifunctional Compounds 2,4,6-tribromophenol

2,4,6-tribromoresorcinol 2,6-dichloro-4-nitrophenol 2,6-dibromo-4-nitrophenol 1,3,5-trinitrobenzene 2-cyanopyridine 3-cyanopyridine 4-cyanopyridine 2,5-dichlorophenol 2,4-dichlorophenol 2,4-dibromophenol quinone p-chloronitrobenzene 3-chloro-1-nitrobenzene 2-chloro-1-nitrobenzene 4-bromo-1-nitrobenzene 3-bromo-1-nitrobenzene 3-iodonitrobenzene m-dinitrobenzene o-dinitrobenzene p-dinitrobenzene 3,5-dinitrophenol 2,4-dinitrophenol 2,6-dinitrophenol 2,Sdinitrophenol benzotriazole iodobenzene 2,3-dichloroaniline 3,4-dichloroaniline p-fluorophenol m-fluorophenol o-fluorophenol p-chlorophenol o-chlorophenol m-chlorophenol o-bromophenol p-bromophenol m-bromophenol m-iodophenol o-iodophenol p-iodophenol N-hydroxybenzoquinone picolinic acid

3,4-dichlorobenzenesulfonamide 3-hydroxypicolinic acid m-nitrophenol o-nitrophenol p-nitrophenol 2-nitroresorcinol m-fluoroaniline o-fluoroaniline p-fluoroaniline m-chloroaniline o-chloroaniline p-chloroaniline m-bromoaniline o-bromoaniline p-bromoaniline nicotinamide 2-fluoroisoniazide 2-chloroisoniazide p-dihydroxybenzene m-dihydroxybenzene o-dihydroxybenzene 3-hydroxypicolinamide m-nitroaniline o-nitroaniline p-nitroaniline m-chlorobenzenesulfonamide o-chlorobenzenesulfonamide p-chlorobenzenesulfonamice p- bromobenzenesulfonamide o-nitrobenzenesulfonamide p-nitrobenzencsulfonamide m-nitrobenzenesulfonamide 2-methylpyridine 3-methylpyridine 4-methylpyridine

log Pea

log Pcb

log P:

3.96 4.37 2.94 3.05 1.18

3.97 3.86 3.11 3.47 1.48 0.88 0.88 0.88 2.77 2.77 3.13 0.44 2.20 2.20 2.20 2.38 2.38 2.74 1.51 1.51 1.51 1.77 1.77 1.40 1.58 1.24 2.77 2.23 2.23 1.68 1.68 1.68 2.1 1 2.1 1 2.1 1 2.30 2.30 2.30 2.65 2.65 2.65 1.31 -2.17 1.86 -1.86 1.61 1.43 1.80 1.31 1.14 1.14 1.14 1.58 1.58 1.58 1.76 1.76 1.76 0.15 0.21 0.64 1.34 1.34 1.34 0.76 1.19 0.89 1.49 1.21 1.21 1.21 1.39 0.53 0.53 0.53 1.61 1.61 1.61

0.01 -0.51 0.17 0.42 0.30 0.38 0.52 0.42 -0.43 -0.53 -0.09 0.24 -0.19 -0.26 -0.04 -0.17 -0.26 -0.20 0.02 -0.07 0.02

0.50

0.36 0.46 3.20 3.30 3.22 0.20 2.39 2.46 2.24 2.55 2.64 2.94 1.49 1.58 1.49 2.32 1.51 1.25 1.75 1.34 3.25 2.78 2.69 1.79 1.93 1.71 2.35 2.15 2.50 2.35 2.43 2.63 2.93 2.65 2.91 1.08 -1.98 1.44 -1.27 2.01 1.79 1.91 1.36 1.30 1.26 1.15 1.88 1.90 1.83 2.10 2.29 2.26 -0.37 -0.1 1 0.11 0.59 0.80 0.88 0.65 1.37 1.44 1.39 1.29 0.74 0.84 1.36 0.34 0.64 0.55

1.11 1.20 1.22

-0.55 0.26 0.15 -0.17 -0.10

-0.48 -0.55 -0.46 -0.11 4-25 -0.03 -0.24 -0.04 -0.39 -0.05 -0.13 -0.33 -0.28 0.00 -0.26 0.23 -0.19 0.42 -0.59 -0.40 -0.36 -0.11 -0.05 -0.16 -0.12 -0.01 -0.30 -0.32 -0.25 -0.34 -0.53

-0.50 0.52 0.32 0.53 0.75 0.54 0.46 0.11 -0.18 4.55

0.10 -0.08 0.47 0.37 0.03 0.19 -0.11 -0.02 0.50

0.41 0.39

766 J . Chem. In$ Comput. Sci., Vol. 34, No. 4, 1994

KLOPMAN ET AL.


name Multifunctional Compounds N-phenylhydroxyamine m-aminophenol a-pyridylmethanol j3-pyridylmethanol y-pyridylmethanol o-aminophenol p-aminophenol 6-aminonicotinamide isoniazid 1 hydroxypentachlorocyclohexane benzenesulfonamide pphenolsulfonamide 2-amino-4-picoline a-pyridilmethylamine j3-pyridylmethylamine y-pyridylmethylamine

-

2-amino-5-methylpyridine 4,6-dimethylpyrimidine o-diaminobenzene

m-aminobenzencsulfonamide N-phenylsulfamide sulfanilamide romidazole citric acid trimethadione metronidazole 4-ketovaleric acid methyl ester adipic acid 2-azacycloheptanthion 2-azacycloheptanone a-chloroisovalerylurea

2-methyl-N-nitrosopiperidine 3-methyl-N-nitrosopiperidine 4-methyl-N-nitrosopiperidine pentyl carbamate tert-pentyl carbamate

2,6-dimethyl-N-nitrosomorpholine 2,6-dimethyl-N,N’-dinitrosopiperazine 1-nitroso-3,3-diethyl- 1-methylurea 2-butox yet hano diethy 1aceta1 1-nitrosodiisopropylamine N-nitrosodipropylamine

N,N.N‘,N’-tetramethylethylenediamine 2,4,5,6,7-pentachlorobenzimidazole p-bromophenyl isothiocyanate phenylenetetrazole 3-cyano-l-nitrobenzene 4-cyano-1-nitrobenzene 4-nitrophenyl isothiocyanate 3,5-diiodosalicylic acid phenyl isothiocyanate phenyl thiocyanate benzothiazole

trifluoromethylthiobenzene 1-phenyl-4-chlorotetrazole trichloromethylthiobenzene o-cyanophenol m-cyanophenol p-cyanophenol zoxazolamine trifluoromethoxybenzene m-trifluoromethylphenol o-trifluoromethylphenol m-fluorobenzoic acid pfluorobenzoic acid m-chlorobenzoic acid o-chlorobenzoic acid p-chlorobenzoic acid m-bromobenzoic acid p-bromobenzoic acid m-iodobenzoic acid o-iodobenzoic acid p-iodobenzoic acid phenyl trifluoromethyl sulfone 5-bromosalicylic acid m-nitrobenzoic acid p-nitrobenzoicacid

log P.”

log P,b

log PrC

0.79 0.17 0.06 -0.02 0.06 0.57 0.04 0.70 -1.14 2.54 0.31 0.06 0.56 -0.21 -0.32 -0.38 1.02 0.62 0.15 -1.20 0.40 -0.78 -0.38 -1.72 -0.37 -0.10 -0.13 0.08 0.75 -0.19 1.oo 0.71 0.99 1.05 1.35 0.94 0.32 0.08 1.11 0.83 0.84 1.63 1.63 0.30 4.53 4.03 0.14 1.17 1.19 3.62 4.56 3.28 2.54 2.02 3.57 1.48 3.18 1.61 1.70 1.60 2.46 3.17 2.95 2.80 2.15 2.07 2.68 1.98 2.65 2.87 2.86 3.13 2.40 3.02 2.68 2.87 1.83 1.89

1.16 0.81 0.68 0.68 0.68 0.81 0.81 -0.50 -0.01 2.91 0.56 0.44 0.95 0.47 0.47 0.47 0.95 1.64 0.27 -0.10 0.58 -1.03 -0.16 -1.18 -0.36 -0.06 0.54 0.43 0.90 0.09 0.84 0.75 0.75 0.75 1.06 1.03 0.65 0.03 1.54 0.7 1 0.93 1.46 1.61 0.90 4.56 3.91 0.50 1.23 1.23 3.04 4.48 3.07 1.88 2.27 3.16 1.98 3.84 1.14 1.14 1.14 1.56 2.28 2.56 2.56 2.01 2.01 2.45 2.45 2.45 2.63 2.63 2.98 2.98 2.98 1.86 2.93 1.76 1.I6

0.37 0.64 0.62 0.70 0.62 0.24 0.77 -1.20 1.13 0.37 0.25 0.38 0.39 0.68 0.79 0.85 -0.07 1.02 0.12 1.10 0.18 -0.25 0.22 0.54 0.01 0.04 0.67 0.35 0.15 0.28 -0.16 0.04 -0.24 -0.30 -0.29 0.09 0.33 -0.05 0.43 -0.12 0.09 -0.17 -0.02 0.60 0.03 -0.12 0.36 0.06 0.04 -0.58 -0.08 -0.21 -0.66 0.25 -0.41 0.50 0.06 -0.47 -0.56 446 -0.90 -0.89 -0.39 -0.24 -0.14 -0.06 -0.23 0.47 -0.20 -0.24 4-23 -0.15 0.58 -0.04 -0.82 0.06 -0.07

-0.13


J. Chem. Inf. Comput. Sci., Vol. 34, No. 4. 1994 767

Table 4 (Continued) ~

formula

name Multifunctionai Comaounds 5-nitrosalicylic acid 3,5-dinitrobenzamide p-trifluoromethylaniline 7-azaindole benzimidazole 4-cyano-2-methylpyridine 2-cyano-6-methylpyridine indazole o-phenylenethiourea 1-phenyltetrazole m-fluorobenzamide p-fluorobenzamide m-chlorobenzamide p-chlorobenzamide m-bromobenzamide p- bromobenzamide p-iodobenzamide

1,2-methylenedioxybenzene o-hydroxybenzaldehyde tropolone 2-fluoro-4-aminobenzoic acid 3-fluoro-4-aminobenzoic acid 2-chloro-4-aminobenzoicacid 3-chloro-4-aminobenzoicacid 2-bromo-4-aminobenzoic acid 3-bromo-4-aminobenzoicacid 2-iodo-4-aminobenzoic acid 3-iodo-4-aminobenzoic acid p-c yanobenzenesulfonamide salicylic acid m-hydroxybenzoic acid p-hydroxybenzoic acid m-nitrobenzamide p-nitrobenzamide p-nitroformanilide 2,4-di hydroxybenzoic acid 2,6-dihydroxybenzoic acid 2,5-dihydroxybenzoic acid 2,4-dinitrotoluene 2-nitro-4-aminobenzoicacid thiobenzamide 1-methylbenzotriazole 2-acetylpyridine 4-acetylpyridine 3-acetylpyridine benzaldoxime 2-methyl-4-chlorophenol 3-methyl-4-chlorophenol m-chlorobenzyl alcohol p-chlorobenzyl alcohol isonicotinicacid methyl ester nicotinic acid methyl ester m-hydroxybenzamide p- hydroxy benzamide benzohydroxamicacid salicylamide p-aminobenzoic acid o-aminobenzoicacid p-fluorosulfonyltoluene 3-hydroxy-4-aminobenzoic acid p-aminosalicylic acid m-nitrobenzyl alcohol p-nitrobenzyl alcohol p-nitroanisole m-nitroanisole m-aminobenzamide p-aminobenzamide benzoylhydrazine 2-acetaminopyridine 3-acetaminopyridine 4-acetaminopyridine a-pyrid ylethanamide 8-pyridylethanamide y -pyridylethanamidc phenylurea phenylthiourea methyl phenyl sulfoxide p-(methy1thio)phenol

log PC"

log Pcb

log P,'

2.34 0.83 1.95 1.82 1.46 0.81 0.84 1.82 1.66 1.09 0.91 0.91 1.51 1.51 1.65 1.76 1.99 2.08 1.70 0.53

2.43 0.47 2.03 1.29 1.29 1.29 1.29 1.66 0.71 1.oo 0.75 0.75 1.18 1.18 1.37 1.37 1.72 1.64 1.93 0.95 0.29 0.29 0.73 0.73 0.92 0.92 1.27 1.27 0.24 2.09 1.68 1.68

0.09 -0.36 0.08 -0.53 -0.17 0.48 0.45 -0.16 -0.95 -0.09 -0.16 -0.16 -0.33 -0.33 -0.28 -0.39 -0.27 -0.44 0.23 0.42 -0.17 -0.29 0.23 -0.79 0.26 -0.48 0.45 -0.26 0.01 -0.17 0.18 0.10 -0.27 -0.32 -0.41 0.54 0.20 0.24 -0.06 -0.03 -0.16 -0.10 0.28 0.51 0.68 0.44 -0.26 -0.58 -0.23

0.46 0.58 0.50 1.52 0.66 1.40 0.82 1.53 0.23 2.26 1S O 1.58 0.77 0.82 1.43 1.44 2.20 1.74 1.98 0.38 1.49 1.13 0.83 0.54 0.43 1.75 2.78 3.10 1.94 1.96 0.87 0.81 0.39

0.25 0.26 0.89 0.68 1.21 2.74 -0.32 0.87 1.21 1.26 2.03 2.16 0.33 0.02 0.19 0.61 0.41 0.59 -0.65

-0.71 -0.65 0.82 0.73 0.55

1.78

0.50 0.50

1.02 1.98 2.40 1.98 1.92 0.35 1.33 1.03 1.11 1.11 1.11 2.19 2.52 2.52 1.71 1.71 1.19 1.19 0.41 0.41 0.13 1.14 0.08 1.14 1.40 -0.04 0.38 1.03 1.03 1.55 1.55 -0.12 -0.12 0.37 0.60 0.60 0.60 -0.34 -0.34 -1.24 0.54 1.03 0.67 2.36

-0.25 0.32 0.38 0.02 0.16 -0.13 0.25 -0.60 -0.07 -1.34 0.28 -0.49 -0.18 -0.23 -0.48 -0.61 -0.45 -0.14 0.18 -0.01 0.19 0.01 0.31 0.37 -0.59 -0.28 0.30 0.12 0.58

KLOPMANET AL.

768 J. Chem. Znf: Comput. Sci., Vol. 34, No.4, 1994 Table 4 (Continued) formula

name Multifunctional Compounds m-hydroxybenzyl alcohol o-hydroxybenzyl alcohol p-hydroxybenzyl alcohol o-methoxyphenol m-methoxyphenol pmethoxyphenol 2,4-diaminobenzoic acid 3,4-diaminobenzoic acid p-nitro-N-methylaniline methyl phenyl sulfone 2-carboxylicacid ethyl thiophene 3,7-dimethylxanthine furoic acid ethyl ester 2-ethylpyridine 2,6-lutidine m-(methy1thio)aniline o-(methy1thio)aniline 1-(methy1thio)pentachlorocyclohexane 2 4a-pyridy1)ethanol 2-(/3-pyridyl)ethanol 2-(ypyridyl)ethanoI m-aminobenzyl alcohol m-methoxyaniline o-methoxyaniline p-methoxyaniline 2-methylisoniazide 1-hydroxy-1-methyl-2,3,4,5,6-pentachlorocyclohexane 2-methoxyisoniazide m-meth ylbenzenesulfonamide o-methylbenzenesulfonamide pmethylbenzenesulfonamide 2-(a-pyridyl)ethylamine 2-(&pyridyl)ethylamine 1-(ypyridy1)ethylamine

2-methoxy-3,4,5,6-tetrachlorocyclohexane ipromidazole ormidazole DA3838 1,3-diallylurea

3-(methylthio)-4-amino-6-prop-l-yl1,2,4-triazine-5-one 3-methoxy-4-amino-6-isopropyl1,2,4-triazine-5-one quinuclidine 2-azacyclooctanethione 2-azacyclooctanone carbromal

2,6-dimethyl-N-nitrosopiperidine 3,5-dimethyl-N-nitrosopiperidine 1-nitrosotriethylurea 4,5,6,7-tetrachloro-2-trifluoromethylbenzimidazole

4,5,6,7-tetrabromo-2-trifluoromethylbenzimidamle 4,5,7-trichloro-2-trifluoromethylbenzimidamle 4,5,6-tribromo-2-trifluoromethylbenzimidazole 4,7-dichloro-2-trifluoromethylbenzimidmle 4,5-dichloro-2-trifluoromethylbenzimidazole 4,6-dichloro-2-trifluoromethylbenzimidazole 5,6-dichloro-2-trifluoromethylbenzimidazole 5,6-dibromo-2-trifluoromethylbenzimidamle 5-chloro-6-nitro-2-trifluoromethylbenzimidazole 5-chloro-2-trifluoromethylbenzimidamle 4-chloro-2-trifluorometh ylbenzimidazole 5-bromo-2-trifluoromethylbenzimidazole 5-nitro-2-trifluoromethylbenzimidazole phthalic anhydride 2-chloroquinoxaline 5-chloroquinoxaline 6-chloroquinoxaline 2-trifluoromethylbenzimidazole p-trifluoroacetamide bromobenzene trifluoroacetophenone m-cyanobenzoic acid p-cyanobenzoic acid 4-carboxyphenyl isothiocyanate m-trifluoromethylbenzoic acid 2,4-dichloro-&nitrotyrene 2,4,5-trichlorophenoxyaceticacid

2-chloro-5-nitro-j3-nitrostyrene 5-bromoindole quinoxaline

log Pea

log Pcb

log Pr'

0.49 0.73 0.25 1.32 1.58 1.34 -1.14 -0.70 2.04 0.47 2.33 -0.78 1.52 1.69 1.68 1.45 1.20 3.75 0.12 0.12 0.10 -0.05 0.93 0.95 0.95 -0.37 2.94 -0.10 0.85 0.84 0.82 0.08 0.00 -0.01 2.99 1.06 0.60 -0.63 0.64 1.01 -0.06 1.20 1.oo 0.24 1.54 1.36 1.53 1.54 3.97 4.81 3.78 4.08 2.87 3.49 3.49 3.99 4.15 3.21 3.39 2.93 3.51 2.68 -0.62 2.23 1.75 2.10 2.67 3.34 2.15 1.48 1.56 3.52 2.95 3.26 3.36 2.23 3.00 1.32

0.94 0.94 0.94 1.47 1.47 1.47 -0.58 -1.11 1.98 1.17 2.04 -1.24 1.33 2.02 2.02 1.82 1.82 4.63 1.09 1.09 1.09 0.41 0.93 0.93 0.93 0.40 3.69 0.00 0.97 0.97 0.97 0.88 0.88 0.88 3.04 1.22 0.75 -0.53 0.87 1.07 0.12 0.53 1.26 0.45 1.66 1.15 1.15 1.06 5.01 5.75 4.36 4.91 3.70 3.70 3.70 3.70 4.07 3.02 3.05 3.05 3.23 2.37 -0.67 2.49 2.49 2.49 2.40 2.51 2.19 1.47 1.47 3.29 2.90 3.48 3.30 2.80 2.51 1.83

0.45 0.21 0.69 0.15 -0.11 0.13 0.56 -0.41 -0.06 0.70 -0.29 -0.46 -0.19 0.33 0.34 0.37 0.62 0.88 0.97 0.97 0.99 0.46 0.00 -0.02 -0.02 0.77 0.75 0.10 0.12 0.13 0.15 0.80 0.88 0.89

0.05 0.16 0.15 0.10 0.23 0.06 0.18 -0.67 0.26 0.21 0.12 -0.21 -0.38 -0.48 1.04 0.94 0.58 0.83 0.83 0.21 0.21 -0.29 -0.08 -0.19 -0.34 0.12 -0.34 -0.3 1 -0.05 0.26 0.74 0.39 -0.27 -0.83 0.04 -0.01 -0.09 -0.23 -0.05 0.22 -0.06 0.57 -0.49 0.51


J. Chem. Znf. Comput. Sci., Vol. 34, No. 4, 1994 769


name Multifunctional Comwunds p-trifluorometh ylbenzamide trifluoroacetanilide cinnoin-bone m-cyanobenzamide p-c yanobenzamide p-cyanoformanilide quinazolin-Cone quinazoline-2,4-dione quinazoline-2,3-dione 4-chloro-fi-nitrost yrene 3-chloro-8-nitrostyrene 4-chloro-j3-nitrostyrene piperonal 3-chloro-5-flurophenoxyaceticacid 2,4-dichlorophenoxyaceticacid 3,4-dichlorophenoxyaceticacid 3-bromo-4-chlorophenoxyaceticacid 3-iodo-5-fluorophenoxyaceticacid 3-iodo-4-chlorophenoxyaceticacid m-phthalic acid 2,B-dinitrost yrene 3,B-dinitrost yrene 4,o-dinitrost yrene 3-nitro-4-chlorophenoxyaceticacid indole benzyl isothiocyanate benzyl thiocyanate 4-methylphenyl isothiocyanate

5-chloro-2-methylthiobenzimidazole 2-aminoquinazolin-4-one p-chloroacetophenone p-bromoacetophenone 2-fluorophenyl acetate 3-fluorophenyl acetate m-flurophenylacetic acid o-flurophenylacetic acid p-flurophenylacetic acid 3-chlorophenylacetate p-chlorophenylacetic acid m-chlorophenylaceticacid 2-chlorophenyl acetate 2-bromophenyl acetate m-bromophenylacetic acid p-bromophenylacetic acid 2-iodophenyl acetate m-iodophenoxylaceticacid p-iodophenoxylaceticacid 2,3-dichlorophenylN-methylcarbamate 2,5-dichlorophenylN-methylcarbamate 3,4-dichlorophenylN-methylcarbamate 3,5-dichlorophenylN-methylcarbamate 2 42,4,6-tribromophenoxy)ethanol m-acetylnitrobenzene p-acet ylnitrobenzene

3-hydroxy-@-nitrostyrene 4-hydroxy-&nitrostyrene m-flurophenoxyaceticacid o-flurophenoxyacetic acid p-flurophenoxyacetic acid m-chlorophenoxyaceticacid o-chlorophenoxyaceticacid p-chlorophenoxyacetic acid 2-bromophenoxyaceticacid 3-bromophenoxyaceticacid 4-bromophenoxyaceticacid 2-iodophenoxyacetic acid 3-iodophenoxyaceticacid 4-iodophenoxyaceticacid 2-nitrophenyl acetate 3-nitrophenyl acetate 4-nitrophenyl acetate m-nitrophenylacetic acid pnitrophenylacetic acid p(fluorosulfony1)phenylacetic acid m-nitrophenoxyacetic acid o-nitrophenoxyacetic acid p-nitrophenoxyacetic acid 3,5-dinitro-4-methylbenzamide

log Pc"

log Pcb

log Pr'

1.71 2.21 0.82 0.52 0.48 1.08 0.77 0.55 0.20 2.44 2.57 2.85 1.05 2.20 2.81 2.81 2.75 2.42 3.10 1.66 1.80 1.82 1.89 1.85 2.14 2.83 1.99 3.92 3.22 0.60 2.35 2.43 1.76 1.74 1.65 1S O 1.55 2.32 2.12 2.09 2.18 2.20 2.37 2.31 2.55 2.62 2.64 2.48 2.44 2.80 3.03 3.42 1.42 1.49 2.07 2.12 1.48 1.26 1.41 2.03 2.02 1.99 2.10 2.22 2.45 2.44 2.19 2.69 1.55 1.82 1.49 1.45 1.39 1.84 1.37 1.22 1.48 0.68

1.63 1.67 1.25 0.21 0.21 0.74 0.41 0.16 1.07 2.83 2.83 2.83 1.38 2.21 2.64 2.64 2.83 2.74 3.18 2.01 2.14 2.14 2.14 1.96 1.67 3.49 2.30 3.48 2.84 0.21 2.15 2.33 1.79 1.79 1.69 1.69 1.69 2.23 2.13 2.13 2.23 2.41 2.31 2.3 1 2.76 2.67 2.67 2.53 2.53 2.53 2.53 3.58 1.46 1.46 2.06 2.06 1.55 1.55 1.55 1.99 1.99 1.99 2.17 2.17 2.17 2.53 2.53 2.53 1.54 1.54 1.54 1.45 1.45 0.90 1.30 1.30 1.30 0.88

-0.08 -0.54 0.43 -0.3 1 -0.27 -0.34 -0.36 -0.39 0.87 0.39 0.26 -0.02 0.33 0.01 -0.17 -0.17 0.08 0.32 0.08 0.35 0.34 0.32 0.25 0.11 -0.47 0.66 0.31 -0.44 -0.38 -0.39 -0.20 -0.10 0.03 0.05 0.04 0.19 0.14 4.09 0.01 0.04 0.05

0.21 -0.06 0.00 0.2 1 0.05 0.03 0.05

0.09 -0.27 -0.50

0.16 0.04 -0.03 -0.01 -0.06 0.07 0.29 0.14 -0.04 -0.03 0.00 0.07 -0.05 -0.28 0.09 0.34 -0.16 -0.01 -0.28 0.05 0.00 0.06 -0.94 -0.07 0.08

-0.18 0.20


KLOPMANET AL.

Table 4 (Continued) formula 994. CsHsN4 995. CsHsOS 996. CsHsONF 997. CsHsONCl 998. CsHsONI 999. CsHs02 1000. CsHaO2 1001. CsHsO2 1002. CsHs02 1003. CsHs02 1004. CsHs02S 1005. CsHs02S 1006. CsHs02N2 1007. CsHs02NF 1008. CaHs02NF 1009. CsHsOzNF 1010. CsHs02NCl 1011. CsHsOzNCl 1012. CsHs02NCI 1013. CsHs02NBr 1014. CsHu02NBr 1015. CsHs02NBr 1016. CsHe02NI 1017. CaHs02NI 1018. CsHs02NI 1019. CsHsO3 1020. CsHs03 1021. CsHsO3 1022. CsHsO3 1023. CsHsO, 1024. CsHsO3 1025. CsHsO3 1026. CsHs03 1027. CsHs03 1028. CsHsO3 1029. CsHsO3 1030. CsHsO3 1031. CsHsO3 1032. CsHsO3 1033. CsHaO3 1034. CsHsOsNCl 1035. CsHs03N2 1036. CsHs04 1037. CsHs04 1038. CsHsO, 1039. CsHsO& 1040. CsHaOiN2 1041. CsHs04N2 1042. CsHa04N2 1043. CsH9NS 1044. CaH90N 1045. CsHgON 1046. CsHgON 1047. CsH902N 1048. CsHsOzN 1049. CsHg02N 1050. CsH902N 1051. CsH902N 1052. CsH902N 1053. CsHg02N 1054. CsH902N 1055. CsH902N 1056. CsH902N 1057. CsH902N 1058. CsH902N 1059. CsH902N 1060. CsHg02N 1061. CsH902N 1062. CsH902N 1063. CsH902N 1064. CsH902Cls 1065.CsH903N 1066. CsHg03N 1067. CsHioNzS 1068. CsHloON2 1069. CsHloON2 1070. CsHloON2 1071. CsHioO2

name Multifunctional Communds hydrazaline acetylthiobenzene p-fluoroacetanilide pchloroacetanilide p-iodoacetanilide m-acetylphenol p-acetylphenol o-hydroxyacetophone p-methoxybenzaldehyde 1,Cbenzodioxane phenylthioacetic acid p-( methy1thio)benzoicacid isophthalamide 2-fluorophenyl N-methylcarbamate 3-fluorophenyl N-methylcarbamate 4-fluorophenyl N-methylcarbamate 4-chlorophenyl N-methylcarbamate 2-chlorophenyl N-methylcarbamate 3-chlorophenylN-methylcarbamate 3-bromophenylN-methylcarbamate 4-bromophenylN-methylcarbamate 2-bromophenyl N-methylcarbamate 2-iodophenyl N-methylcarbamate 3-iodophenyl N-methylcarbamate 4-iodophenyl N-methylcarbamate vanillin m-carbomethoxyphenol m-hydroxyphenylacetate isovanillin m-methoxybenzoicacid o-methoxybenzoicacid p-methoxybenzoic acid methyl salicyate o-vanillin mandelic acid phenoxyacetic acid 3,4-methylenedioxy benzyl alcohol p-hydroxybenzoic acid methyl ester m-hydroxyphenylaceticacid p-hydroxyphenylacetic acid 3-amino-4-chlorophenoxyaceticacid p-nitroacetanilide m-hydroxyphenoxyaceticacid o-hydroxyphenoxyaceticacid p-hydroxyphenoxyaceticacid p-methylsulfonylbenzoicacid 2-nitrophenyl N-methylcarbamate 3-nitrophenyl N-methylcarbamate 4-nitrophenyl N-methylcarbamate thioacetanilide p-aminoacetophone ethyl 4-pyridyl ketone o-methylbenzaldoxime p-aminophenyl acetate m-hydroxyacctoanilide o-hydroxyacetoanilide phydroxyacetoanilide m-methoxyformanilide p-methoxyformanilide 3-methyl-4-aminobenzoicacid nicotinic acid ethyl ester isonicotinicacid ethyl ester phenoxyacetamide picolinic acid ethyl ester phenyl N-methylcarbamate N-phenyl glycine 2-methyl-4-aminobenzoicacid p-methoxybenzamide o-methoxybenzamide m-methoxybenzamide 1-acetoxy-2,3,4,5,6-pntachlorocyclohexane 2-methoxy-4-aminobenzoicacid p-nitrophenetole 1-methyl-1-phenyl-2-thiourea @-(a-pyridy1)propanamide @-(8-pyridy1)propanamide @-(y-pyridy1)propanamide 1,3-dimethoxybenzene

log Pea

log Pcb

log PrC

1.OO 2.23 1.47 1.87 2.46 1.39 1.35 1.92 1.59 2.01 1.91 2.74 -0.21 1.25 1.48 1.28 2.01 1.64 2.03 2.25 2.17 1.77 1.96 2.52 2.46 1.31 1.89 1.23 0.97 2.02 1.59 1.96 2.46 1.37 0.62 1.34 1.05 1.96 0.85 1.96 1.16 1.66 0.76 0.85 0.65 0.67 1.02 1.39 1.47 1.71 0.41 0.77 2.53 -0.16 0.73 0.72 0.36 1.25 1.03 0.54 1.32 1.43 0.76 0.87 1.24 0.62 0.31 0.86 0.87 0.94 3.40 -0.38 2.53 0.85 -0.27 -0.26 -0.25 2.21

1.65 1.98 1.20 1.63 2.17 1.38 1.38 2.11 1.32 2.00 1.96 2.69 -0.52 1.44 1.44 1.44 1.87 1.87 1.87 2.06 2.06 2.06 2.41 2.41 2.41 1.21 1.46 1.46 1.21 1.80 1.80 1.80 2.19 1.94 0.59 1.34 1.12 1.46 1.36 1.36 1.34 0.95 1.22 1.22 1.22 1.38 1.19 1.19 1.19 1.96 0.84 1.53 2.60 0.92 0.86 0.86 0.49 1.06 1.06 0.49 1.61 1.61 0.54 1.61 1.59 -0.35 0.49 0.54 0.54 0.54 3.73 0.09 1.97 1.06 0.08 0.08 -0.83 1.59

0.65 -0.25 -4.27 -0.24 -0.29 -0.01 0.03 0.19 -0.27 -0.01 0.05 -0.05 -0.31 0.19 -0.04 0.16 -0.14 0.23 -0.16 -0.19 -0.11 0.29 0.45 -0.11 -0.05

-0.10 -0.43 0.23 0.24 -0.22 0.21 -0.16 -0.27 0.57 -0.03 0.00 0.07 -0.50 0.51 -0.60 0.18 -0.71 0.46 0.37 0.57 0.71 0.17 -0.20 -0.28 0.25 0.43 0.76 0.07 1-08 0.13 0.14 0.13 -0.19 0.03 -0.05 0.29 0.18 -0.22 0.74 0.35 -0.97 0.18 -0.32 -0.33 -0.40 0.33 0.47 -0.56 0.21 0.35 0.34 -0.58

4.62

COMPUTER AUTOMATED LOC P CALCULATIONS



name Multifunctional Compounds o-dimethoxybenzene m-ethoxyphenol o-ethoxyphenol p-ethoxyphenol o-methoxybenzyl alcohol p-methoxyknzyl alcohol 2-phenoxyethanol caffeine sulfanilacetamide 4-propylpyridine m-(dimethy1amino)phenol 3-(wpyridyl)propanol 3-(&pyridyl)propanoI 3-(y-pyridyl)propanoI

N,N-dimethylbenzenesulfonamide p-ethylbenzenesulfonamide 3-(a-pyridyl)propylamine 3-(@-pyridyl)propylamine 3-(y-pyridyl)propylamine 3,6-dimethoxy-1,2,4,5-tetrachlorocyclohexane barbital 4-pent ylpyrazole N-nitrosodibutylamine 6-cyanoquinoxaline 8-fluoro-4-nitroquinoline1-oxide 6-chloro-4-nitroquinoline1-oxide 4,5-dinitroquinoline 1-oxide 4,6-dinitroquinoline 1-oxide 4,8-dinitroquinoline 1-oxide 2-chloroquinoline 6-chloroquinoline 8-chloroquinoline 3-bromoquinoline 6-bromoquinoline 7- bromoquinoline 4-chloro-8-quinolinol 4-chloroquinolin 1-oxide 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol coumarin indanedione 3-nitroquinoline 44troquinoline 5-nitroquinoline 6-nitroquinoline 7-nitroquinoline 8-nitroquinoline 3-cyano-4-chlorophenoxyaceticacid 3-nitroquinoline 1-oxide 4-nitroquinoline1-oxide 5-nitroquinoline1-oxide 6-nitroquinoline1-oxide 7-nitroquinoline1-oxide 8-nitroquinoline1-oxide ninhydrin isoquinoline quinoline quinoline 1-oxide 4-hydroxyquinoline 2-quinolone 2-quinolinol 8-quinolinol 2-cyanophenyl acetate m-cyanophenylacetic acid N-methylindol-2,3-dione 3-(trifluoromethyl)phenylacetic acid p-(trifluoromethy1)phenylacetic acid m-(trifluoromethy1)phenoxyacetic acid 4-cyanophenoxyacetic acid 3-cyanophenoxyacetic acid m-(trifluoromethy1)thiophenoxyacetic acid m-(trifluoromethoxy)phenoxyacetic acid m-(trifluoromethy1)sulfonylphenoxyacetic acid 8-aminoquinoline 2-aminoquinoline 3-aminoquinoline 4-aminoquinoline 6-aminoquinoline 2-methylquinoxaline

log P."

log Pa

log Pr'

2.21 1.98 1.68 1.81 1.13 1.10 1.16 -0.07 -0.96 2.10 1.57 0.58 0.60 0.58 1.35 1.31 0.49 0.44 0.40 3.15 0.65 2.96 1.92 1.01 1.00 1.41 0.95 0.90 0.76 2.71 2.73 2.33 3.03 2.83 2.92 2.67 1.08 3.41 1.39 0.61 1.97 2.06 1.86 1.84 1.82 1.40 1.56 0.56 1.02 0.49 0.39 0.36 0.04 0.65 2.08 2.03 0.36 0.58 1.26 1.26 2.00 1.33 1.18 0.58 2.62 2.45 2.36 0.93 0.95 2.86 2.48 2.19 1.79 1.87 1.63 1.63 1.28 1.61

1.59 1.88 1.88 1.88 1.07 1.07 1.07 -0.86 -0.53 2.44 1.59 0.86 0.86 0.21 0.89 1.38 0.75 0.75 0.21 2.81 0.67 2.71 2.44 1.52 0.97 1.41 0.72 0.72 0.72 2.87 2.87 2.87 3.05 3.05 3.05 2.75 1.44 3.51 0.96 1.06 2.18 2.18 2.18 2.18 2.18 2.18 1.67 0.75 0.75 0.75 0.75 0.75 0.75 -0.07 2.21 2.21 0.78 1.11 0.83 0.96 2.10 1.25 1.16 0.27 2.58 2.58 2.44 1.02 1.02 2.92 2.04 1.62 1.56 1.56 1.56 1.56 1.56 2.24

-0.62 -0.10 0.20 0.07 -0.06 -0.03 -0.09 -0.79 0.43 0.34 0.02 0.28 0.26 -0.37 -0.46 0.07 0.26 0.31 -0.19 -0.34 0.02 -0.25 0.52 0.51 -0.03 0.00 -0.23 -0.18 -0.04 0.16 0.14

0.54 0.02 0.22 0.13 0.08 0.36 0.10 -0.43 0.45 0.21 0.12 0.32 0.34 0.36 0.78 0.1 1 0.19 -0.27 0.26 0.36 0.39 0.7 1 -0.72 0.13 0.18 0.42 0.53 -0.43 -0.30 0.10 -0.08 -0.02 -0.31

-0.04 0.13 0.08

0.09 0.07 0.06 -0.44 -0.57 -0.23 -0.3 1 -0.07 -0.07 0.28 0.63

772 J. Chem. In5 Comput. Sci., Vol. 34, No. 4, 1994

KLOPMANET AL.

Table 4 (Continued) formula 1150. C9HgN2 1151. C9HsNz 1152. C9HsN2 1153. C9HsN2S 1154. C9HsON2 1155. C9HsONz 1156. C9HsON2 1157. C9Hg02Nz 1158. C9H802N2 1159. C9H802N2 1160. C9Hs02NzS 1161. C9Hs02NSCl3 1162. C9H804 1163. C9Hg04 1164. C9H804 1165. C9H805 1166. C9H9N 1167. C9H9N 1168. C9H9N 1 169. C9H9N 1 170. C9H9NS 1 171. C9H9NS 1172. C9H90N 1173. C9H902N 1174. CgH902N3Sz 1175. C9H903N 1176. C9H903N 1177. C9H903N 1178. C9H903N 1179. C9HloN2 1180. CgHlo02 1181. CsHlo02 1182. C9Hl002 1183. C ~ H I O O ~ N ~ 1184. C9HloO3 1185. C9Hl003 1186. CsH1o03 1187. CgHlo03 1188. C9HloO3 1189. C9HloO3 1190. C9Hlo03 1191. C9HloO3 1192. CsHlo03S 1193. C9Hlo04 1194. C9Hl004 1195. C9H1004 1196. C9Hi004N2 1197. C ~ H I ~ N 1198. C ~ H I I I 1199. C9HllN3 1200. C ~ H I I N ~ 1201. CgHi 10N2C1 1202. C ~ H I I O N ~ C I 1203. C ~ H I I O N ~ B ~ 1204. C ~ H I I O Z N S 1205. C ~ H I I O ~ N S 1206. CgH1102N 1207. C ~ H I I O Z N 1208. C9Hll02N 1209. CsH1102N 1210. C9H1102N 1211. C9H1102N 1212. CsH1102N 1213. C9Hll02N 1214. C9H1102N 1215. C ~ H I I O ~ N 1216. C9Hi103N 1217. C9Hi103N 1218. C9HilOaN 1219. C9HllO3N3 1220. C9H1104N 1221, C ~ H105N2F I 1222. C ~ H I I O S N ~ B T 1223. C9H120N2 1224. C9Hl20N2 1225. C9H120N2 1226. C ~ H L Z O N ~ 1227. C9H120N2

name Multifunctional Compounds 5-methylquinoxaline 2-phenylimidazole 5-aminoquinoline

2-(methy1thio)quinoxaline 4-aminoquinoline 1-oxide 2-methoxyquinoxaline

3-methylquinazolin-4-one 4-cyanophenyl N-methylcarbamate 3-cyanophenyl N-methylcarbamate 2-cyanophenyl N-methylcarbamate 8-sulfonamidoquinoline captan m-carboxyphenylacetic acid p-formylphenoxyacetic acid acetylsalicylic acid m-carboxyphenoxyacetic acid 2-methylindole 3-methylindole 5-methylindole 8-phenylethylcyanide 2-phenethyl isothiocyanate 1-phenethyl isothiocyanate 5-methoxyindole p-acetylformanilide sulfathiazole o-(acety1amino)benzoic acid p-(acety1amino)benzoic acid 4-methoxy-b-nitrostyrene 3-methoxy-&nitrostyrene

5,6-dimethylbenzimidazole o-hydroxypropiophenone p-hydroxypropiophenone p-methoxyacetophenone p-(acet y1amino)benzamide 4-methoxyphenyl acetate m-methoxyphenylacetic acid p-methoxyphenylacetic acid m-methylphenoxyacetic acid o-methylphenoxyacetic acid p-methylphenoxyaceticacid 2-methoxyphenyl acetate p-hydroxybenzoic acid ethyl ester 3-methylthiophenoxyacetic acid 2-methoxyphenoxyacetic acid 4-methoxyphenoxyacetic acid 3-methoxyphenoxyacetic acid 3-ureidophenoxyacetic acid

1,2,3,4-tetrahydroquinoline y-phenylpropyliodine 1-propylbenzotriazole 14sopropylbenzotriazole 1,l-dimethyl-3-(m-chlorophenyl)urea 1,l-dimethyl-3-(pchlorophenyl)urea 1,l-dimethyl-3-(p-bromophcnyl)urea 4-(methy1thio)phenyl N-methylcarbamate 2-(methy1thio)phenyl N-methylcarbamate o-tolyl N-methylcarbamate p-tolyl N-methylcarbamate phenyl N,N-dimethylcarbamate p-ethoxybenzamide o-methoxylacetanilide p-methoxylacetanilide 2-methyl-4-hydroxyacetanilide 3-methyl-4-hydroxyacetanilide ethyl N-phenylcarbamate 2-ethoxy-4-aminobenzoic acid 2-methoxyphenyl N-methylcarbamate 3-methoxyphenyl N-methylcarbamate 4-methoxyphenyl N-methylcarbamate 1.1-dimethyl-3-@-nitrophenyl)urea N-maleoyl-3-aminopropionicacid ethyl ester 2'-deoxy-5-fluorouridine 2'-deoxy-5- bromouridine m-(dimethy1amino)benzamide p-(dimethy1amino)benzamide 1-phenyl-3-ethylurea 111-dimethyl-3-phenylurea 1,3-dimethyl-1-phenylurea

log Pc"

log Pcb

log PrC

2.04 1.88 1.16 2.79 0.05 2.31 0.69 0.95 0.97 0.86 0.36 2.35 1.14 0.79 1.23 1.11 2.53 2.60 2.68 1.70 3.47 3.46 2.06 0.94

2.24 2.05 1.56 2.73 0.13 1.84 0.80 0.90 0.90 0.90 1.19 2.02 1.69 1.08 1.79 1.55 2.08 2.08 2.08 2.23 3.90 3.84 1.68 0.97 0.64 1.20 1.20 2.18 2.18 2.11 2.52 1.79 1S O -0.07 1.58 1.49 1.49 1.75 1.75 1.75 1.58 1.87 2.23 1.34 1.34 1.34 0.30 1.99 3.78 1.86 1.80 2.03 2.03 2.22 2.1 1 2.1 1 1.63 1.63 1.60 0.95 0.99 0.99 0.90 0.90 2.01 0.50 1.23 1.23 1.23 1.35 0.06 -1.21 -0.67 0.66 0.66 1.41 1.38 1.38

0.20 0.17 0.40 -0.06 0.08 -0.47 0.11 -0.05 -0.07 0.04 0.83 -0.33

0.05

1.88 1.31 2.20 2.37 2.35 2.54 2.03 1.82 0.01 1.54 1.50 1.42 1.78 1.98 1.86 1.38 2.43 1.90 0.98 1.23 1.38 0.26 2.29 3.90 2.13 1.98 2.00 1.94 2.19 1.92 1.51 1.46 1.66 1.69 1.30 0.98 1.14 0.66 1.28 2.30 0.16 0.81 1.30 1.20 1.51 0.41 -1.38 -0.29 0.95 1.14 1.64 1.04 1.02

0.55

0.29 0.56 0.44 -0.45 -0.52 -0.60 0.53 0.43 0.38 -0.38 0.03 0.59 -0.68 -0.11 -0.02 -0.19 -0.24 -0.02 -0.24 -0.32 -0.08 0.04 -0.01 0.07 -0.03 -0.23 -0.1 1 0.20 -0.56 0.33 0.36 0.11 -0.04 0.04 -0.30 -0.12 -0.27 -0.18 0.03 0.09 0.03 0.19 0.60 0.17 -0.03 -0.09 -0.35 0.01 -0.15 0.24 -0.38 -0.29 0.34 0.42 -0.07 0.03 -0.16 -0.35 0.17 -0.38 -0.29 -0.48 -0.23 0.34 0.36


J. Chem. If. Comput. Sci., Vol. 34, No. 4, 1994 173


name Multifunctional Compounds y-(8-pyridy1)butanamide y-(y-pyridy1)butanamide o-isopropoxyphenol phenylglycerol 1,2,3-trimethoxybenzene 5-allyl-5-ethylbarbituricacid N-ethyl-4-sulfamylbenzamide N,N-dimethyl-o-anisidine 44a-pyridyl)butanol 4-(p-pyridyl)butanol 4-(y-pyridyl)butanol p-propylbenzenesulfonamide 4-(a-pyridyl) butylamine 4-(,8-pyridyl)butylamine 4-(y-pyridyl)butylamine probarbital N-methyl-Sbutylbarbituric acid nimorazole 3 4methylthio)-4-amino-6-isopentyl-1,2,4-triazin-5-one 3 4propylthio)-4-amino-6-isopropyl1,2,4-triazin-5-one 3 4isopropylthio)-4-amino-6-isorpopyl1,2,4-triazin-5-one 1 -(2-chloroethyl)-3-cyclohexyi-1 -nitrosourea 1 -(2-chloroethyl)-3-(4-hydroxycyhexyl)-1 -nitrosourea azelaic acid 4-tert-butyl-N-nitrosopiperidine 2,2,6,6-tetramethyl-N-nitrosopiperidine meprobamate 1,3-dibutyrylurea 2-chloro-l,4-naphthoquinone 7-(trifluoromethy1)quinoline 8 4trifluromethy1)quinoline benzal malononitrile 4-hydroxy-7-( trifluroethy1)quinoline 1,4-naphthoquinone 2-chloro-3-amino1,4-naphthoquinone 1-(2,4,5-trichlorophenylhydrazono)-l-cyanoacetic acid methyl ester 1 -(3,4,5-trichlorophenyIhydrazone)-1 -cyanoaceticacid methyl ester 2-hydroxy-1 ,rl-naphthoquinone 1 -(3,4-dichlorophenylhydrazone)-1 -cyanoacetone 1 -(3,5-dichlorophenylhydrazone)-1 -cyanoacetone 2-nitroso-1-naphthol 1-nitroso-2-naphthol 1-(3,5-dichlorophenyIhydrazone)-1-cyanoaceticacid methyl ester 1-(2,4-dinitrophenylhydrazone)- 1-cyanoacetone N-formyl-pcyanostyrlamine 1-(4-chlorophenylhydrazono)-l-cyanoacetone 1-(2-chlorophenylhydrazono)-l-cyanoacetone 1 -(3-chlorophenylhydrazono)-1 -cyanoacetone 1-( 3-chloropheny1hydrazono)-1-cyanoaceticacid methyl ester hymecromone 2-methyl-4-nitroquinoline1 -oxide 3-methyl-4-nitroquinoline1-oxide 5-methyl-4-nitroquinoline1-Oxide 6-methyl-4-nitroquinoline1 -oxide 7-methyl-4-nitroquinoline1-oxide 8-methyl-4-nitroquinoline1-ozide 8-methylquinoline 7-methylquinoline 8-methylquinoline 2-methylquinoline 6-methylquinoline 7-methoxyquinoline N-methyl-a-quinolone N-methyl-4-quinolone 4-methyl-8-quinolinol 5-methyl-8-quinolinol 2-methyl-8-quinolino1 6-methoxyquinoline 8-methoxyquinoline indole-3-aceticacid 5-methoxyl-8-quinolinol 4-methyl-5,8-dihydroxyquinoline 1-phenylhydrazono-1-cyanoaceticacid methyl ester 3-fluorobenzalmalonamide 3-cyclopropyl-2,4-benzothiadiazine 1,l-dioxide 2-N,N-dimethylamino-6-(5-NO2-2-furyl)1,3-thiazin-4-one 1 -(2-trifluoroacetamido)-2-(p-nitrophenyl)ethanol 6,7-dimethylquinoxaline

log Po"

log Pcb

log PrC

-0.08 -0.09 2.09 0.70 1.53 0.95 0.03 1.63 0.86 0.92 0.90 1.64 0.86 0.88 0.86 0.97 1.10 0.07 1.85 2.12 2.06 2.83 1.05 1.57 1.96 2.49 0.70 1.40 2.15 3.02 2.50 2.12 2.05 1.78 2.12 5.15 5.22 1.38 4.56 4.68 2.57 2.28 4.50 3.41 1.58 4.13 4.01 3.91 3.56 1.58 1.25 1.06 1.36 1.43 1.42 1.59 2.60 2.47 2.60 2.59 2.57 2.37 1.45 0.44 2.36 2.37 2.33 2.20 1.84 1.41 2.06 1.59 2.59 0.10 1.98

0.49 -0.41 2.23 0.12 1.60 0.88 0.38 1.72 1.27 1.27 0.62 1.80 1.17 1.17 0.62 1.02 0.57 0.48 1.84 1.84 1.77 2.45 1.62 1.68 1.96 2.39 1.06 2.12 1.92 3.32 3.32 2.25 2.21 1.46 1.72 4.84 4.84 1.02 4.10 4.10 2.50 2.50 4.18 2.73 1.37 3.45 3.45 3.45 3.53 1.25 1.16 1.16 1.16 1.16 1.16 1.16 2.62 2.62 2.62 2.62 2.62 2.22 1.21 1.28 2.01 2.01 2.01 2.22 2.22 1.57 1.61 1.90 2.87 0.48

0.57 -0.32 0.14 -0.58 0.07 -0.07 0.35 0.09 0.41 0.35 -0.28 0.16 0.31 0.29 -0.24

0.55

0.78 1.59 2.65

1.46 2.29

1S O

0.05

-0.53 0.41 -0.01 -0.28 -0.29 -0.38 0.57 0.11 0.00 -0.10 0.36 0.72 -0.23 0.30 0.82 0.13 0.16 -0.32 -0.40 -0.31 -0.38 -0.36 -0.46 -0.58 -0.07 0.22 -0.32 -0.68 -0.21 -0.68 -0.56 -0.46 -0.03 -0.33 -0.09 0.10 -0.20 -0.27 -0.26 -0.43 0.02 0.15 0.02 0.03 0.05

-0.15 -0.24 0.84 -0.35 -0.36 -0.32 0.02 0.38 0.16 -0.45 0.31 0.28 0.38 -0.48 0.23 0.13 0.36

KLOPMANET AL.

174 J. Chem. If. Comput. Sci., Vol. 34, No. 4, 1994 Table 4 (Continued) formula 1306.TCioHioONz 1307. CioHioONS 1308. CioHioOzNz 1309. CioHioOzNz 1310. CioHioOzN6 1311. CioHioOzN4S 1312. CioHi003N6 1313. CioHioO3N3SCl ' 1314. CioHi004 1315. CioHi004 1316. CioHioO4 1317. CloHlo04NCl 1318. CioHioOsNz 1319. CioHiiN 1320. CioHiiN 1321. CloHiiN 1322. CioHiiON 1323. CioHiiON2F3 1324. CioHii02N 1325. CioHiiOzN 1326. CioHiiO3N 1327. CioHiiOsN 1328. CioHiiO3N 1329. CioHiiOsN 1330. CioHiiO3N3S 1331. CioHii04N 1332. CioHii04N 1333. CioHiiO4N 1334. CioHi20Nz 1335. CioHi20N4 1336. CioHizOzN2 1337. CioHizOzN2 1338. CioHizOzNzS 1339. CioHizOzNCl 1340. CioHiz03 1341. CioHiz03 1342. CioHiz03 1343. CioHiz03 1344. CioH1203 1345. CioHiz03 1346. CioHi~03Nz 1347. CioH1203Nz 1348. CioHisN3 1349. CioHiiON 1350. CioHijON 1351. CioHi3ON 1352. CioHljON 1353. CioHi3ON 1354. CioHi302N 1355. CioHiaOzN 1356. CioHi302N 1357. CioHi30zN 1358. CioHi30zN 1359. CioHi3OzN 1360. CioHi30zN 1361. CioH130zN 1362. CioHi302N 1363. CioHi302N 1364. CioH1302N 1365. CioHi302N 1366. CioHi30zN 1367. CioHi30zN 1368. CioHi30zN 1369. CioH130zN 1370. CioHi30zN 1371. CioHisOzN 1372. CioHi30zN 1373. CioHi30zN 1374. CioHi30zN 1375. CioHi30zNS 1376. CioHi3OsN 1377. CioH1303N 1378. CioHipOsN 1379. CioHi303N 1380. CioH1303N 1381. C I O H I ~ O P N 1382. CioH1304NS 1383. CioHi4N~

name Multifunctional Compounds benzalcyanoacetamide 3-(methylthio)-4-amino-6-phenyl1,2,4-triazin-S-one

N,N-dimethylquinoxaline-2,3-dione benzalmalonamide azanidazole sulfadiazine DA3839 1,2,4-benzothiadiazine-1,1-0~-3-Me-6-NH 4-acetylphenoxyaceticacid 3-acetylphenoxyaceticacid 2-acetylphenoxyaceticacid 3-acetamido-4-chlorophenoxyaceticacid p-nitromethyl hippurate 1,Zdimethylindole y-phenylpropyl cyanide 1,2-dimethylindole N-methy1-a-quinoline 1,l-dimethyl-3-(m-(trifluoromethyl)phenyl)urea 2-nitro-1-butenylbenzene ðyl-P-nitrostyrene 3-allyloxy-4-aminobenzoicacid 3-acetylphenylN-methylcarbamate 4-acetylphenyl N-methylcarbamate methyl hippurate sulfamethoxazole 3-carbomethoxyphenylN-methylcarbamate 4-carbomethoxyphenylN-methylcarbamate m-acetamidophenoxyaceticacid

2-(y-hydroxylpropyl)benzimidazole 1-(3-carbamylpropy1)benzotriazole m-diacetamidobenzene 4-dimethylamino-fl-nitrost yrene 1,2,4-benzothiadiazine 2,5-dimethyl-4-chlorophenyl N-methylcarbamate 4-ethoxyphenyl acetate ethyl mandelate phydroxybenzoic acid propyl ester o-methylphenoxyaceticacid methyl ester 3-ethylphenoxyaceticacid 2-ethylphenoxyaceticacid paminohippurate diallylbarbituric acid 1-sec-butylbenzotriazole m-tolyl N-methylcarbamate o-tolyl N-methylcarbamate ptolyl N-methylcarbamate 4-phenylbut yramide N-phenylmorpholine 4-ethoxyacetanilide

N,N-dimethylphenoxyacetamide fusaric acid

m-methoxy-N,N-dimethylbenzamide o-methoxy-N.N-dimethylbenzamide pmethox y-N,N-dimethylbenzamide

2,3-dimethyl-4-hydroxyacetaniiide 2,5-dimethyl-4-hydroxyacetanilide 2,6-dimethyl-4-hydroxyacetanilide 3,5-dimethyl-4-hydroxyacetanilide 3-ethyl-4-hydroxyacetanilide 2-ethylphenyl N-methylcarbamate 2,3-dimethylphenylN-methylcarbamate 2,s-dimethylphenyl N-methylcarbamate 3-ethylphenyl N-methylcarbamate 3,4-methylphenylN-methylcarbamate 3,s-methylphenyl N-methylcarbamate 4-ethylphenyl N-methylcarbamate m-tolyl N,N-dimethylcarbamate o-tolyl N,N-dimethylcarbamate ptolyl N,N-dimethylcarbamate 3-methyl-4-methylthiophenylN-methylcarbamate 3-methoxyphenylN,N-dimethylcarbamate 4-methoxyphenyl N,N-dimethylcarbamate 2-ethoxyphenyl N-methylcarbamate 3-ethoxyphenyl N-methylcarbamate 4-ethoxyphenyl N-methylcarbamate 2-propoxy-4-aminobenzoicacid 4-sulfamonylbenzoicacid propyl ester anabasine

log Po"

log Pcb

log Pr'

1.so 1.66 0.08 -0.13 0.85 -0.08 -0.30 0.53 0.87 0.98 1.25 0.67 0.98 2.82 2.21 2.82 1.45 2.36 2.86 2.86 0.42 0.90 1.01 0.82 0.88 1.42 1.50 0.48 1.25 0.37 0.50 2.67 1.25 2.95 1.95 0.91 3.04 2.08 2.25 2.65 -0.23 1.07 2.31 1.70 1.46 1.66 1.41 1.36 1.58 0.77 -1.29 1.oo 0.71 0'96 1.06 1.09 0.80 1.60 1.79 1.93 1.95 2.03 2.20 2.09 2.23 2.23 2.05 1.86 2.03 2.47 1.60 1.53 1.24 1.75 1.63 0.70 1.75 0.97

1.12 1.61 -0.17 0.52 0.66 -0.16 0.10 0.75 1.25 1.25 1.25 1.39 0.95 1.88 2.64 2.49 1.17 2.48 2.99 3.41 0.71 1.14 1.14 0.98 0.34 1.21 1.21 0.74 1.61 0.82 0.39 2.31 1.51 2.69 2.00 1.52 2.29 2.00 2.16 2.16 0.33 1.08 2.22 1.78 1.78 1.78 1.77 1.60 1.40 1.38 -0.51 1.37 1.37 1.37 1.31 1.31 1.31 1.31 1.32 2.04 2.04 2.04 2.04 2.04 2.04 2.04 2.01 2.01 2.01 2.52 1.61 '1.61 1.64 1.64 1.64 0.92 1.38 1.59

438 -0.05 -0.25 0.65 -0.19

-0.08 0.40 0.22 0.38 0.27 0.00 0.72 -0.03 -0.94 0.43 -0.33 -0.28 0.12 0.13 0.55 0.29 0.24 0.13 0.16 -0.54 -0.21 -0.29 0.26 0.36 0.45 -0.11 -0.36 0.26 -0.26 0.05 0.61 -0.75 -0.08 -0.09 -0.49 0.56 0.01 -0.09 0.08 0.32 0.12 0.36 0.24 -0.18 0.61 0.78 0.37 0.66 0.41 0.25 0.22 0.51 5.29 447 0.11 0.09 0.01 -0.16 -0.05 -0.19 -0.19 -0.04 0.15 -0.02 0.05 0.01 0.08 0.40 -0.11

0.01 0.22 -0.37 0.62

J . Chem. In$ Comput. Sci., Vol. 34, No. 4, 1994 115

COMPUTER AUTOMATED LOG P CALCULATIONS Table 4 (Continued)

formula

name Multifunctional Compounds nicotine 1,l-dimethyl-p-tolylurea y- (a-p yridyI) pentamide a-(a-pyridyl)pentamide

6-(8-pyridy1)pentamide 6-(y-pyridy1)pentamide camphorquinone 3-(dimethy1amino)phenyl N-methylcarbamate 3,5-dimethoxy-4-bromophenethylamine 3-(2-tolyloxy)-l,2-propanediol N-isopropyl-3-(5-NO2-2-furyl)acrylamide p-oxon S-(a-pyridyl)pentanol

S-(@-pyridyl)pentanol 5-(y-pyridy1)pentanol ephedrine p- butylbenzenesulfonamide 0,OdiethylOphenyl phosphate 5-( a-pyridy1)pentylamine S-(&pyridyl)pentylamine 5-(y-pyridy1)pentylamine 3-(2-norbornyl)-l-(2-chlorocthyl)nitrosoruea

5-butyl-5-ethylbarbituricacid DA3804 l-(2-chloroethyl)-3-(4-methylcyclohexyl)-l-nitrosourea 3-morpholino-4-amino-6-isopropyl1,2,4-triazin-S-one 1-(2,6-dichloro-4-(trifluoromethyl)phenylhydrazono)- 1-cyanoaceticacid methyl ester 1-isothiocyanonaphthalene 2-isothiocyanonaphthalene 1-(2-chloro-5-(trifluoromethyl)phenylhydrazono)-l-cyanoacetone 1-(4-chloro-2-(trifluoromethyl)phenylhydrazono)- 1-cyanoaceticacid methyl ester 1-(2-chloro-5-(trifluoromethyl)phenylhydrazono)- 1-cyanoaceticacid methyl ester 1-(2-nitro-5-(trifluoromethyl)phenylhydrazono)- 1-cyanoaceticacid methyl ester 4-acetyl-7-chloroquinoline 1444trifluoromethyl)thiophenylhydrazono)-1-cyanoacetone 6-methyl1,4-naphthoquinone 1-(3-(trifluoromethyl)phenylhydrazono)-l-cyanoacetic acid methyl ester 1-(2-(trifluoromethyl)phenylhydrazono)-l-cyanoaceticacid methyl ester 1-(4-chloro-3-(difluoromethyl)phenylhydrazono)-l-cyanoaceticacid methyl ester 1-(4-(trifluoromethyl)thiophenylhydrazono)- 1-cyanoaceticacid methyl ester 1-(3,4,5-trichlorophenylhydrazono)-l-cyanoaceticacid ethyl ester 1-(2,4,5-trichlorophenylhydrazono)-l-cyanoaceticacid ethyl ester 2-methyl-3-hydroxyl-l,4-naphthoquinone 1-(4-[(trifluoromethyl)sulfonyl]pheny1hydrazono)-1-cyanoaceticacid methyl ester 4-phenylpyridine 2-phenylpyridine 1 -(3,4-dichlorophenylhydrazono)-1-cyanoaceticacid ethyl ester 1-(3,5-dichlorophenyIhydrazono)-1-cyanoaceticacid ethyl ester N-(3,5-dichloro-2-pyridyl)sulfanilamide N-(3,5-dibromo-2-pyridyl)sulfanilamide a-methylbenzalmalononitrile 1 -(4-chloro-2-methylphenylhydrazono)-1-cyanoaceticacid methyl ester 1-(3-~hlorophenylhydrazono)-1-cyanoaceticacid ethyl ester N-(3-bromo-2-pyridy1)sulfanilamide 4,5-dimethyl-8-quinolinol 4-methyl-5-methoxy-8-quinolinol sulfapyridine tribromamphenicol 7-(dimethy1amino)quinoline antipyrine 5-ethyl-5-phenylhydantoin sulfaperine sulfamerazine tryptophan indanoxylaceticacid difluoramamphenicol chloramphenicol 1-phenyl-2-acetamidocyclopropane 1-(4-carboxybutyl)benzotriazole 2-acetylphenylN,N-dimethylcarbamate 3-acetylphenylN,N-dimethylcarbamate 4-propionylphenylN-methylcarbamate 3-propionylphenylN-methylcarbamate 4-phen yl-N-nitrosopiperidine 3-methylbenzalmalonamide 3-isopropylphenoxyacetic acid 4-isopropylphenoxyacetic acid

3-propylphenoxyaceticacid

logP2

logP,b

logPr'

1.17 1.98 -0.01 0.39 0.40 0.42 1.52 1.43 2.03 1.41 1.34 1.69 1.28 1.41 1.39 1.56 2.45 1.64 1.32 1.41 1.40 2.98 1.89 -0.33 3.30 0.49 4.36 4.34 4.34

1.76 1.79 0.84 0.91 0.91 0.00 1.86 1.73 2.11 1.01 1.69 1.74 1.69 1.69 1.04 1.57 2.21 1.77 1.58 1.58 1.04 2.30 1.50 0.25 2.85 -0.03 5.29 4.09 4.09 4.55 4.63 4.63 3.95 2.78 4.38 1.87 3.98 3.98 4.36 4.46 5.25 5.25 1.43 3.16 2.97 2.97 4.60 4.60 1.90 2.27 2.34 3.94 3.94 1.43 2.92 2.52 0.59 2.61 2.35

0.59 -0.19

5.08

4.66 4.42 3.44 2.62 5.04 2.10 3.78 3.72 3.83 4.27 5.03 5.21 1.20 4.22 2.45 2.63 4.66 3.82 1.97 2.74 2.10 4.28 3.94 1.24 2.71 2.75 0.00 2.17 2.71 0.23 1.53 0.34 0.14 -1.04 2.33 0.42 1.14 1.43 0.93 0.93 1.18 1.55 1.49 2.59 0.40 2.59 2.69 2.71

0.85

1.55 0.25 0.25 -0.93 1.91 0.73 1.18 1.55

1.77 1.52 1.52 1.55 1.55 2.11 0.66 2.51 2.51 2.58

0.85

0.52 0.51 -0.42 0.34 0.30 0.08 -0.40 0.35 0.05 0.41 0.28 -0.35 0.01 -0.24 0.13 0.26 0.17 -0.36 -0.68 -0.39 0.58

-0.45 -0.52 0.93 -0.25 -0.25 -0.53 -0.03 0.21 0.51 0.16 -0.66 -0.23 0.20 0.26 0.53 0.19 0.22 0.04 0.23 -1.06 0.52

0.34 -0.06 0.78 -0.07 -0.47 0.24 -0.34 0.00 0.19 0.21 -0.23 0.59 0.44 -0.36 0.62 0.02 -0.09 0.11 0.11 -0.42 0.31 0.04

0.12 0.84 0.59 0.34 0.00 0.06 -0.48 0.26 -0.08 -0.18 -0.13

KLOPMANET AL.

176 J. Chem. Inf. Comput. Sci., Vol. 34, No.4, 1994 Table 4 (Continued) formula 1462. CiiHi403 1463. CiiHirOi 1464. CiiHi403Nz 1465. CiiHisN 1466. CiiHisN~ 1467. CiiHiSOzN 1468. CiiHisOzN 1469. CiiHisOzN 1470. CiiHi50~N 1471. CIIHISOZN 1472. CIIHISOZN 1473. CiiHisOaN 1474. CiiHis03N 1475. CiiHisOsN 1476. CiiHi603Nz 1477. CiiHi603Nz 1478. CiiHi7N 1479. CiiHiiON 1480. CiiHi702N 1481. C I I H ~ ~ O Z N 1482. CiiHi70zN 1483. CiiHi70zN 1484. CiiHi703N 1485. CiiHi803Nz 1486. CiiHia03Nz 1487. CiiHi803Nz 1488. CIZNBNZ 1489. C I ~ H ~ N ~ 1490. C I Z H ~ N Z 1491. CizHsN 1492. CizHsNS 1493. CizH90N 1494. Ci~H903N 1495. Ci~Hio02 1496. CizHioOz 1497. CizHioONz 1498. CizHioOzS 1499. CizHioO3 1500. CizHioOS 1501. CizHiiOzN 1502. CizHiiNS 1503. CizHiiON 1504. CizHiiON 1505. CizHizNz 1506. CIZHIZNZ 1507. CizHizONz 1508. CizHizOzNzS 1509. CizHi30zNS 1510. CizHi402N4S 1511. CizHi603 1512. CizHi603 1513. CizHi603 1514. Ci2Hi603 1515. CizHi607 1516. CizHi70zN 1517. CizHi70zN 1518. CizHi70zN 1519. CizH1702N 1520. CizHi70zN 1521. CizHi70zN 1522. CizHi702N 1523. CizHiiOzN 1524. C12Hi70zN 1525. CizHi70zN 1526. CizHi70zN 1527. CizHi702NS 1528. CizHi703N 1529. CizHi703N 1530. CizHi703N 1531. CizHi703N 1532. CizHi703N 1533. CizHi803NzS 1534. CizHi9N 1535. CipHsOS 1536. C13H9N 1537. C I ~ H ~ N S 1538. CisH90NS 1539. C I ~ H ~ O N S Z

name Multifunctional Compounds o-isopropylphenoxyaceticacid phydroxybenzoic acid butyl ester 3-methoxylbenzalmalonamide N-phenylpiperidine 1-pentylbenzotriazole 3-isopropyl-4-hydroxyacetanilide

2,4,5-trimethyl-N-methylphenylcarbamate 2,3,5-trimethyl-4- hydroxyacetanilide 2,3,6-trimethyl-4- hydroxyacetanilide 2-amino-5-phenylvaleric acid 4-butoxybenzamide 2-butoxy-4-aminobenzoic acid baygon 3-isopropoxyphenylN-methylcarbamate 5-allyl-5-butylbarbituric acid INPEA p hexylpyridine p-(diethy1amino)benzyI alcohol

2,3-dimethoxyamphetamine 2,4-dimethoxyamphetamine 2,5-dimethoxyamphetamine 3,4-dimethoxyamphetamine mescaline 5-amyl-5-ethylbarbituric acid amobarbital pentobarbital 1,7-phenanthroIine 4,7-phenanthroline phenazine carbazol phenothiazine 4-benzoylpyridine 2-acetamide 1,4-naphthoquinone naphthalene- 1-acetoxy 6,7-dimethyl-l ,4-naphthoquinone diphenylnitrosoamine diphenyl sulfone 2-naphthoxyacetic acid phenyl sulfoxide carbaryl 1-naphthylmethyl isothiocyanate o-phenoxyaniline p-phenoxyaniline benzidine hydrazobenzene harmalol dapsone vitavax sulfamethazine o-tert-butylphenoxyaceticacid 4-sec-butylphenoxyaceticacid o-sec-butylphenoxyaceticacid 3-butylphenoxyacetic acid arbutin 3-rert-butyl-4-hydroxyacetanilide

3,5-diethyl-4-hydroxyacetanilide 2-sec-butylphenyl N-methylcarbamate 2-rert-butylphenyl N-methylcarbamate 3-methyl-4isopropylphenyl N-methylcarbamate 3-methyl-5-isopropylphenyl N-methylcarbamate 3-methyl-64sopropylphenylN-methylcarbamate 3-rert-butylphenyl N-methylcarbamate 4-sec-butylphenyl N-methylcarbamate 4-tert-butylphenyl N-methylcarbamate 2,3,5,6-tetramethyl-4-hydroxyacetamide N-methyl-2-butylthiophenylcarbamate bufexamac 3-butoxyphenyl N-methylcarbamate 4-butoxypheny; N-methylcarbamate 2-pentoxy-4-aminobenzoicacid 2-isopentoxy-4-aminobenzoic acid butamidotolylsulfonamide p-hept ylpyridine thioxanthon acridine 4-biphenyl isothiocyanate 4-isothiocyanodiphenyl ether 4-isothiocyanodiphenyl sulfoxide

log PC"

log Pcb

log P f

2.84 3.57 0.01 2.78 3.22 2.20 2.52 1.30 1.24 -0.36 2.48 1.24 1.58 1.96 1.35 1.28 4.35 2.29 1.49 1.75 1.88 1.00 0.78 2.24 2.07 2.03 2.51 2.05 2.84 3.72 3.78 1.98 1.29 2.78 2.49 3.13 2.40 2.53 2.06 2.34 4.42 2.46 2.36 1.34 2.94 2.19 0.97 2.14 0.27 3.33 3.12 3.32 3.18 -1.35 2.85 2.36 2.78 2.65 3.11 3.10 2.84 2.93 3.20 3.06 1.44 2.98 1.47 2.96 2.86 1.55 1.47 2.34 5.00 3.99 3.40 4.66 4.75 4.40

2.51 2.70 0.26 2.10 2.69 1.67 2.45 1.72 1.72 -0.19 1.78 1.33 1.99 1.99 1.71 1.63 4.51 2.02 1.76 1.76 1.76 1.76 1.29 1.92 1.85 1.85 2.85 2.85 2.85 2.69 3.50 2.48 0.86 2.59 2.28 2.69 2.54 2.35 2.03 2.24 4.45 2.30 2.30 2.05 3.39 2.53 1.23 2.87 0.66 2.96 2.93 2.93 2.99 -0.80 2.12 2.14 2.81 2.84 2.80 2.80 2.80 2.84 2.81 2.84 2.13 3.36 1.80 2.47 2.47 1.75 1.68 1.83 4.92 3.48 3.23 4.85 4.45 3.53

-0.33 -0.87 0.25 -0.68 -0.53 -0.53 -0.07 0.42 0.48 0.17 -0.70 0.09 0.41 0.03 0.36 0.35 0.16 -0.27 0.27 0.01 -0.12 0.76 0.51 -0.32 -0.22 -0.18 0.34 0.80 0.01 -1.03 -0.28 0.50

-0.43 -0.19 -0.21 -0.44 0.14 -0.18 -0.03 -0.10 0.03 -0.16 -0.06 0.71 0.45 0.34 0.26 0.73 0.39 -0.37 -0.19 -0.39 -0.19 0.55 -0.73 -0.22 0.03 0.19 -0.31 -0.30 -0.04 -0.09 -0.39 -0.22 0.69 0.38 0.33 -0.49 -0.39 0.20 0.21 -0.51 -0.08 -0.51 -0.17 0.19 -0.30 -0.87

J. Chem. Inf. Comput. Sci., Vol. 34, No.4, 1994 I l l


name

Multifunctional Communds 4-isothiocyanodiphenylamine 1540. Ci3HioN2S 1-aminoacridine 1541. Ci3HioN2 2-aminoacridine 1542. C I ~ H I O N ~ 3-aminoacridine 1543. CisHioNz 4-aminoacridine 1544. Ci3HioN2 9-aminoacridine 1545. C I ~ H I O N ~ 1-(3,4-dichlorophenyl)-3-phenylurea 1546. Ci3HioON~C12 o-hydroxybenzophenone 1547. C13H1002 p-h ydroxybenzophenone 1548. Ci3Hio02 o-phenoxybenzoic acid 1549. Ci3Hio03 p-phenoxybenzoic acid 1550. Ci3Hio03 4-aminosalicylic acid 4-fluorophenyl ester 1551. Ci3HioOjNF 4-aminosalicylic acid 2-fluorophenyl ester 1552. CisHioOjNF 4-aminosalicylic acid 3-fluorophenyl ester 1553. CijHioOsNF 4-aminosalicylic acid 4-chlorophenyl ester 1554. CisHioO3NCl 4-aminosalicylic acid 2-chlorophenyl ester 1555. Ci3HioO3NCl 4-aminosalicylic acid 3-chlorophenyl ester 1556. CisHioO3NC1 1557. C I ~ H I O O ~ N B ~ 4-aminosalicylic acid 4-bromophenyl ester 1558. C I ~ H I O O ~ N B ~ 4-aminosalicylic acid 2-bromophenyl ester 1559. C I ~ H I O O ~ N B ~ 4-aminosalicylic acid 3-bromophenyl ester 3,6-diaminoacridine 1560. Ci3HiiN3 N-phenylanthranilicacid 1561. C13Hii02N salicylanilide 1562. Ci3Hii02N phenyl 4-aminosalicylate 1563. C13Hii03N (4,4’-dihydroxydipheny1)methane 1564. Ci3Hi202 o-phenoxyanisole 1565. C13Hi202 N’-(4-methylphenyl)sulfanilamide 1566. Ci3Hi402N2S N’-( 2-methoxyphenyl)sulfanilamide 1567. Ci3Hi403N2S N’-(4-methoxyphenyl)sulfanilamide 1568. Ci3Hi403N2S probenecid 1569. Ci3Hig04NS benzylacetoaceticacid ethyl ester 1570. C13Hi603 4-cyclopentylphenoxyaceticacid 1571. Ci4H1603 ibuprofen 1572. Ci3Hi802 2-sec-butylphenyl N,N-dimethylcarbamate 1573. Ci3Hig02N 3-methyl-4-tert-butylphenylN-methylcarbamate 1574. Ci3Hig02N 3-methyl-5-tert-butylphenylN-methylcarbamate 1575. Ci3Hig02N 3-methyl-6-tert-butylphenylN-methylcarbamate 1576. Ci3Hig02N 2-methyl-5-tert-butyl-4-hydroxyacetamide 1577. Ci3Hig02N procaine 1578. Ci3H2002N2 p-octylpyridine 1579. Ci3H2iN procainamide 1580. C I ~ H ~ I O N S timolol 1581. Ci3H2403N4S 4,4’-diisothiocyanatobiphenyl 1582. C I ~ H B N Z S ~ 4-isothiocyanobenzophenole 1583. Ci4HgONS 44sothiocyanophenyl benzoate 1584. Ci4Hg02NS benzil 1585. Ci4Hio02 N-(3-( trifluoromethy1)phenyl)anthranilic acid 1586. Ci4Hi002NF) (4-isothiocyanopheny1)phenylmethane 1587. CiiHiiNS m-phenylphenoxyacetic acid 1588. Ci4Hi203 o-phenylphenoxyacetic acid 1589. Ci4Hi203 1-cyano-3,3-dimethylacetone 1590. C I ~ H I ~ O N ~ F ~1-( C2-(trifluoromethyl)-4-chlorophenylhydrazono)~ 1-cyano-3,3-dimethylacetone 1591. C I ~ H I ~ O N ~ F ~1-( C2-chloro-5-(trifluoromethyl)phenylhydrazono)~ 4-aminosalicylic acid 2-tolyl ester 1592. Ci4Hi303N 4-aminosalicylic acid 4-tolyl ester 1593. Ci4Hi303N 4-aminosalicylic acid 3-tolyl ester 1594. Ci4Hi303N 4-aminosalicylic acid 2-methoxyphenyl ester 1595. Ci4Hi304N 4-aminosalicylic acid 4-methoxyphenyl ester 1596. Ci4Hi304N 4-aminosalicylic acid 3-methoxyphenyl ester 1597. Ci4Hi304N DA3832 1598. Ci4Hi305N3 naproxen 1599. Ci4Hi403 1-cyano-3,3-dimethylacetone 1600. C ~ ~ H I ~ O N ~ C1-(2-methyl-4-chlorophenylhydrazono)~ 4-cyclohexylphenoxyaceticacid 1601. Ci4Hi803 trimethoprim(9624) 1602. Ci4Hi803N4 pindolol 1603. Ci4H2002N2 p-hydroxybenzoic acid heptyl ester 1604. Ci4H2003 3,5-dipropyl-4-hydroxyacetanilide 1605. Ci4H~i0zN lidocaine 1606. Ci4HzzONz practolol 1607. Ci4H2203N~ atenolol 1608. Ci4HnOsNz 2-isothiocyanoanthrancene 1609. CisHgNS 2-phenylindanedione 1610. CisHioOz lorazepam 1611. CisHio02NzC12 2-phenylquinoline 1612. CISHIIN 1-methyl-4-phenyl-6-fluoroquinazolin-2-one 1613. CisHiiONzF 1-methyl-4-phenyl-7-chloroquinazolin-2-one 1614. CisHi iON2Cl 1-methyl-4-phenyl-6-chloroquinazolin-2-one 1615. CisHi iONzCl oxazepam 1616. Ci~Hii02N2CI nitrazepam 1617. Ci5HiiO3N3

log P,”

logP,b

log P,’

4.94 2.47 2.62 2.19 3.26 2.74 4.70 3.52 3.07 2.84 3.21 3.27 3.29 3.42 3.60 3.72 3.90 3.46 3.74 3.84 1.10 4.36 3.27 3.15 2.91 2.92 2.00 1.56 1.51 3.21 2.52 3.41 3.5 1 3.31 3.38 3.35 3.14 2.67 1.92 5.42 1.39 1.91 5.50 4.88 4.90 3.38 5.62 4.40 3.18 2.83 5.67 5.31 3.14 3.38 3.64 2.88 3.07 3.25 2.03 3.18 4.3 1 3.79 0.91 1.92 4.83 3.16 2.90 0.79 0.16 5.70 2.90 2.38 3.90 1.87 2.36 2.38 2.17 2.12

4.87 2.58 2.58 2.58 2.58 2.58 3.67 3.47 2.74 3.17 3.17 3.12 3.12 3.12 3.55 3.55 3.55 3.74 3.74 3.74 1.92 3.59 2.96 2.90 3.54 2.96 1.83 1.43 1.43 2.77 2.74 2.63 3.42 3.19 3.26 3.26 3.26 2.53 2.30 5.34 1.71 1.44 6.35 4.36 4.44 2.37 4.69 5.26 3.11 3.11 5.77 5.77 3.31 3.31 3.31 2.91 2.91 2.91 2.00 2.85 5.08 2.99 1.36 1.77 4.77 2.97 2.77 1.07 1.04 5.11 2.83 3.03 3.99 2.15 2.59 2.59 2.37 2.52

-0.07 0.11 -0.04 0.39 -0.68 -0.16 -1.03

-0.05 -0.33 0.33

-0.04 -0.15 -0.17 -0.30

-0.05 -0.17 -0.35 0.28 0.00 -0.10 0.82 -0.77 -0.31 -0.25 0.63 0.04 -0.17 -0.13 -0.08 -0.44 0.22 478 -0.09 -0.12 -0.12 -0.09 0.12 -0.14 0.38 -0.08 0.32 -0.47 0.85 -0.52 -0.46 -1.01 -0.93 0.86 -0.07 0.28 0.10 0.46 0.17 -0.07 -0.33 0.03 -0.16 -0.34 -0.03 -0.33 0.77 -0.80 0.45 -0.15 -0.06 -0.19 -0.13 0.28 0.88 -0.59 -0.07 0.65 0.09 0.28 0.23 0.21 0.20 0.40

KLOPMANET AL.

778 J. Chem. If. Comput. Sci., Vol. 34, No. 4, 1994 Table 4 (Continued) formula

name Multifunctional Compounds

9-carboxy-9,lO-dihydroanthracne 1-methyl-4-phenylquinazolin-2-one l-methyl-4-phenyl-6-hydroxyquinazolin-2sne 3-benzamidophenoxyactic acid

2,6-dimethyl-4-aminolicylic acid 1,l-diphenyl-3,3-dimethylurea bisphenol A( 1311) helenalin(4542) physostigmine alprenolol oxprenolol cycloheximide metoprolol diazepam medazepam tetrazepam benzyl penicillin phenoxymethyl penicillin a-hydroxybenzylpenicillin propranolol atropine 2,6-diphenylpyridine carbenicillin chlorpromazine a-phenoxyethylpenicillin methicillin diphenhydramine 1-scopolamine cocaine mepyramine atropine levbunolol desipramine acbutolol trimeprazine(9617) prazepam imipramine labetalol fenbutolol testosterone(9 109) amitriptyline(504) perazine(7 108) bevantolol progesterone(7783) pipamperone sulfinpyrazone a log

log P p

log P,b

log P$

2.67 1.79 1.72 1.99 3.38 2.80 3.32 0.87 1.58 3.10 2.37 0.55 2.34 2.66 4.05 2.76 1.83 2.09 1.40 3.14 1.76 4.82 1.13 5.35 2.28 1.30 3.40 1.24 2.09 2.85 1.79 2.40 4.90 1.77 3.44 3.72 4.62 2.51 4.15 3.32 4.92 2.90 3.00 3.87 2.40 2.30

3.05 1.94 1.82 2.1 1 3.12 3.13 4.34 1.37 1.53 2.10 2.30 1.30 2.27 3.59 4.21 3.51 1.70 1.30 0.8 1 2.69 1.77 4.15 1.13 4.92 1.65 1.30 4.03 1.48 2.29 3.67 2.13 2.51 3.74 1.82 4.62 4.17 4.17 3.42 4.15 3.79 5.23 3.93 3.53 4.53 2.75 2.43

0.38 0.15 0.10 0.12 0.34 0.33 1.02 0.50 -0.05 -0.40 -0.07 0.75 -0.07 0.93 0.16 0.75 -0.13 -0.79 -0.59 -0.45 0.01 -0.07 0.00 -0.43 -0.63 0.00 0.63 0.24 0.20 0.82 0.34 0.1 1 -1.16 0.05 1.18 0.45 -0.45 0.91 0.00 0.47 0.31 1.03 0.53 0.66 0.35 0.13

Po is the experimental value. b log Pc is the calculated value. log Pr is the estimation error.

A cross-validation test was then used to evaluate the predictive ability of our final model. Approximately 5% of the compounds were randomly selected from the original database as a test set, while the other 95% remained as the training set. A log P calculation model was then developed on the basis of the training set, and a prediction was made for the compounds in the test set. The results of 15 such crossvalidation tests are shown in Table 6. As can be seen, the r2 value and standard deviation remained almost the same for each training set. The averagepredictiver2value and standard deviation of the 15 cross-validation tests are 0.926 and 0.404, respectively. This cross-validation test demonstrates the outstanding predictive power of our log P model. It can be seen from Table 3 that the carbon fragment types, -CHs, -CH2-, and -CHC< atom is slightly hydrophilic. In our definition of basic group types, the hydrogen atom was not defined as one basic group, rather it was always expressed along with the heavy atom (C, N, 0, S,P, etc.) to which it is directly attached. However, the contributionof the hydrogen atom can be estimated from those of the basic groups 1-15 in Table 3. The calculated value is found to be about 0.18, which is the same as that

reported by Rekker,*but slightlyless than that (0.23)reported by Leo.9 The presence of fluorine, chlorine, bromine, iodine, and sulfur increases the hydrophobicity (positive contribution to the log P) of compounds, while the presence of nitrogen and oxygen groups in general decreases hydrophobicity (negative contributionto the log P). The hydrophilic characteristics of the nitrogen and oxygengroups are probably due to the strong hydration effects of these groups. It is interesting to note that, as was also observed by Rekker? some groups (-F, -OH, -COOH, -NH2, etc.) become more hydrophobic when they are directly attached to aromatic ring systems. A close examination of the correction fragments identified by the CASE program showssome analogywith the correction factors proposed by Leo" and Ghose et a1.16 Our correction fragments can be classified in several categories. (a) Tautomerization Effects. Correction factors of this type (parameters 69, 8 7 ) have often been found in pyridine analogs. In the tautomeric equilibrium shown in Figure 5 , solvation effects play an important role and subsequently determine the distribution ratio of the two tautomers. If the dominant form is not the entered structure for the calculation, the result will not be satisfactory. Some fragments related

J. Chem. Inf. Comput. Sci., Vol. 34, No. 4, 1994 779

COMPUTER AUTOMATED LOG P CALCULATIONS Table 5. List of Compounds with Large Estimation log P Error formula

name 9-fluorenone cyclohexylamine Ado Guo dGuo dDAPR adenine, 8Aza purine acetaldoxime 2-fluoroethanol 1-methyl-1-hydroxyurea 2,4,5-tribromoimidazole thiazole pyrazine pyrimidine

2,3,4,5,6-pentachloropyridine pyridine 1-oxide 2-methylpyrazine 6-aminonicotinamide isoniazid y -pyridylmethylamine 4,6-dimethylpyrimidine m-aminobenzenesulfonamide zoxazolamide trifluoromethoxybenzene phenyl-trifluoromethyl sulfone o-phenylenethiourea p-( fluorcwulfony1)toluene

1-(methy1thio)pentachlorocyclohexane 2-(a-pyridyl)ethanol 2-(&pyridiyl)ethanol 2-(y-pyridyl)ethanol 2-(a-pyridyl)ethylamine 2-(&pyridyl)ethylamine 2-(y-pyridyl)ethylamine 4,5,6,7-tetrachloro-2-(trifluoromethy1)benzimidazole 4,5,6,7-tetrabromo-2-(trifluoromethy1)benzimidazole 4,5,6-tribromo-2-( trifluoromethy1)benzimidazole 4,7-dichloro-2-trifluoromethylbenzimidazole p-trifluoroacetamide bromobenzene quinazoline-2,3-dione p-( fluorosulfony1)phenoxyaceticacid p-aminophenylacetate N-phenylglycine 8-sulfonamidoquinoline 8-trifluoromethylquinoline N-methyl-4-quinolone 1,2-dimethylindole y-(a-pyridy1)pentamide 1-(2,6-dichloro-4-(trifluoromethyl)phenylhydrazono)- 1-cyanoacetic acid methyl ester 144-[(trifluoromethyl)sulfonyl]pheny1hydrazono)-1-cyanoaceticacid methyl ester 1-(4-carboxybutyl)benzotriazole p-hydroxybenzoic acid butyl ester 4,7-phenanthroline carbazol (4-isothiocyanophenyl) phenyl sulfoxide 1-(3,4-dichlorophenyl)-3-phenylurea 3,6-diaminoacridine

4,4'-diisothiocyanatebiphenyl benzil

N-(3-(trifluoromethyl)phenyl)anthranilic acid (4-isothiocyanopheny1)phenylmethane 4-cyclohexylphenoxyaceticacid atenolol bisphenol A(1311) diazepam mepyramine desipramine trimeprazine (9617) labetalol perazine (7108)

10gPp"

logP2

logP,c

3.58 1.49 -1.23 -1.89 -1.30 -0.52 -0.96 -0.37 -0.12 -0.92 -0.46 1.96 0.44 -0.22 -0.40 3.53 -1.30 0.23 0.70 -1.14 -0.38 0.62 -1.20 2.46 3.17 2.68 1.66 2.74 3.75 0.12 0.12 0.10 0.08 0.00 -0.01 3.97 4.81 4.08 2.87 3.34 0.20 1.84 -0.16 0.62 0.36 2.50 0.44 2.82 -0.01 4.36 4.22 0.93 3.57 2.05 3.72 4.40 4.70 1.10 5.50 3.38 5.62 4.40 3.79 0.16 3.32 2.66 2.85 4.90 3.44 2.51 2.90

2.66

-0.92 -1 .os -0.90 -1.20 -0.96 -0.86 0.85 0.90 0.94 0.85 -0.83 0.83 0.81 1.04 1.22 0.94 1.07 1.oo -1.20 1.13 0.85 1.02 1.10 -0.90 -0.89 -0.82 -0.95 -1.34 0.88 0.97 0.97 0.99 0.80 0.88 0.89 1.04 0.94 0.83 0.83 -0.83 0.87 -0.94 1.08 -0.97 0.83 0.82 0.84 -0.94 0.85 0.93 -1.06 0.84 -0.87 0.80 -1.03 -0.87 -1.03 0.82 0.85 -1.01 -0.93 0.86 480 0.88 1.02 0.93 0.82 -1.16 1.18 0.91 1.03

0.44 -2.13 -3.09 -2.26 -1.38 -0.11 0.53 0.82 -0.07 -1.29 2.79 1.25 0.82 0.82 4.47 -0.23 1.23 -0.50 -0.01 0.47 1.64 -0.10 1.56 2.28 1.86 0.7 1 1.40 4.63 1.09 1.09 1.09 0.88 0.88 0.88 5.01 5.75 4.91 3.70 2.51 1.07 0.90 0.92 -0.35 1.19 3.32 1.28 1.88 0.84 5.29 3.16 1.77 2.70 2.85 2.69 3.53 3.67 1.92 6.35 2.37 4.69 5.26 2.99 1.04 4.34 3.59 3.67 3.14 4.62 3.42 3.93

*

log Pe is the experimental value. log Po is the calculated value. log P, is the estimation error.

to the tautomerization effect have been identified and are included in our log P calculation model. (b) Dipolarlon Effect (ZwitterionEffect). The log Pvalues for compoundssuch as amino acids are largely underestimated

by the model using group contribution alone. This is because a large fraction of these compounds in water is not in a neutral form, but rather exists in a dipolar ion form. This dipolar ion effect has been identified by the CASE program (parameters

KLOPMANET AL.


Table 7. Experimental (LOGP) and Calculated log P Values Using Four Methods

Table 6. Cross-ValidationTest Results for a Database of 1624 Comuounds test set learning set no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

mean

no.ofcompds

9

SD

1592 1585 1578 1590 1582 1575 1584 1590 1601 1580 1593 1595 1573 1598 1580 1586

0.929 0.929 0.930 0.929 0.929 0.929 0.929 0.928 0.929 0.929 0.930 0.929 0.929 0.929 0.929 0.929

0.380 0.382 0.381 0.391 0.383 0.383 0.381 0.384 0.382 0.383 0.380 0.382 0.381 0.382 0.381

no.ofcompds 71 78 85 73 81 88 89 71 62 83 70 68 90 65 73

0.383

87

r2

0.914 0.927 0.912 0.924 0.903 0.919 0.931 0.946 0.933 0.928 0.908 0.906 0.926 0.925 0.924

SD 0.430

0.406 0.414 0.419 0.382 0.381 0.419 0.350

0.409 0.374 0.434 0.412 0.413 0.399 0.419

0.926 0.404

70, 81, and 90) and was included in our log P model. (c) Proximity Effecr. In aromatic systems, the interactions between two polar substituents ortho to each other were found to have a large effect on the log P values. For instance, in salicylic acid, the interaction between COOH and OH groups (the proximity effect) was found to be an important factor for the evaluationof its partition coefficient. Therefore,this effect should be included in an accurate log P model. Parameters 79 and 80 were identified by the CASE program to represent this effect. These parameters reflect the intramolecular hydrogen bonding between two polar ortho substituents. In aliphaticsystems,compoundswith structures such as X-CH2CH2Y also show a proximityeffect, when X and Y have strong intermolecularinteraction. Parameter 85 has been identified to represent this effect. (d) Conjugated Multiheteroatomic Effect. The CASE program has identified somesignificantcorrectioneffects such as parameters 71,78,82,83,88,and 89 related to conjugated multi-heteroatomic interaction. In our study, we found that a large systematic error for the hydrocarbon compounds arises when group contributionsare used alone. This is probably due to the flexibilityof the carbon chain in alkanes. We found, however, that the molecular weight (parameter 97)is a very effectivecorrection factor for alkanes. Finally, an indicator parameter (parameter 98)was used to correct for the systematic error observed for the unsaturated hydrocarbons. Using the group contribution alone, log P values were overestimated for compounds with structure such as CHa(CH2).X and pyridins-(CHz),X, where X is a polar group (X = OH, NH2, COOH, CONH2, F, etc.) and n 1 2. We found that this overestimation is probably caused by a folding effect;13i.e. when a molecule with this type of structure folds, the polar group at the end of the side chain interacts with the P cloud of the atomatic ring. A molecular dipole (AP+XC) is developed which may reduce the lipophilicityof the molecule. Thus, we included parameters 94-96 in our log P estimation model to account for this folding effect. Two examples are shown below to illustrate the calculation procedure. The log P values calculated by using CLOGP, developed by Leo et al.," are also listed for comparison. Example 1. 6-Valerolactone C5HsO2

Fo

u

log P = YPa.11) r-0.14

+ (Pa.&) - 0.703

measured I-0.35; calculated by CLOGP = 0.66

no.

name

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43

Ado dAdo ddAdo ddeAdo EddAdo Guo dGuo ddGuo ddeGuo dDAPR ddDAPR FddDAPR Urd dUrd ddUrd ddeUrd FddUrd dThd ddThd ddeThd FddThd CYd dCyd ddCyd ddeCyd FddCyd F6ddP F62AddP Br6ddP Br62AddP C16ddP C162AddP I6ddP I62AddP ddI uracil adenine, 8Aza guanine, 8Aza cytocine adenine thioguanine adenine, 9-1 uracil, 6Aza guanine thymine hypoxanthine purine

44 45 46 47

LOGP KLOGP ALOGP CLOGP BLOGP -1.23 -2.13 -1.240 -2.941 0.182 -0.630 -2.531 -0.54 -1.29 0.356 -0.190 -1.116 -0.21 0.406 -0.46 0.040 -1.600 -0.35 -0.42 0.379 0.08 -0.020 -0.23 -1.273 0.522 -1.89 -1.630 -0.210 -3.923 -3.09 -0.013 -1.30 -1.010 -2.26 -3.338 -1.00 0.177 -0.580 -1.923 -1.43 0.115 -1.21 -0.350 -2.407 -1.39 -0.52 -0.910 -2.592 -0.101 -1.38 -0.55 0.067 -0.46 -0,470 0.067 -0.32 -0.300 -1.333 0.05 0.249 -1.71 -2.28 -2.560 -1.590 0.085 -1.50 -1.44 -0.980 -2.090 0.456 -0.88 -0.61 -0.540 -0.675 0.667 -1.07 -0.57 0.645 -0.320 -1.159 -0.48 -0.38 -0,370 -0.832 0.912 0.817 -1.17 -1.03 -0.820 -1.591 -0.20 -0.63 -0.390 -0.176 1.042 0.999 -0.16 -0.8 1 -0.160 -0.660 -0.220 -0.333 1.269 -0.27 0.03 -3.111 -2.5 1 -2.86 -1.420 0.113 -1.77 -2.03 -0.810 -2.549 0.478 -1.30 -1.20 -0.370 -1.133 0.619 -1.42 -1.16 -0.140 -1.617 0.571 -0.91 -0.97 -0.200 -1.290 0.775 0.00 0.28 0.490 -0.906 0.247 -0.1 1 -0.05 0.210 -0.970 0.375 0.8 1 0.35 1.080 -0.356 0.798 0.42 0.33 0.800 -0.420 0.765 0.50 0.23 0.780 -0.386 0.489 0.1 1 0.545 0.21 0.500 -0.450 0.074 1.00 1.011 0.52 1.OS0 0.010 0.61 0.996 0.52 0.800 -0.950 -1.755 4.335 -1.24 -1.55 -0.720 -1.060 -0.86 4,585 -1.07 -0.1 1 -0.670 -0.063 -0.034 4.96 -1.060 -1.14 -1.004 4.836 -0.71 -1.73 -0.550 -1.45 -1.846 -0.769 -0.09 -0.360 0.036 0.23 -0.426 -0.07 -0.020 0.308 -1.824 -0.37 0.690 0.437 0.74 1.327 0.50 -0.490 -0.593 -1.013 -0.59 -0.91 -0.750 -1.264 4.91 -0.891 -1.17 -0.560 -0.557 -0.130 -0.62 -0.45 -1.1 1 -0.89 -0.873 -0.880 -1.260 -0.280 -0.290 -0.139 -0.37 0.53

Figure 5. Equilibrium of tautomerization.

Example 2. Oxazepam C15HllClN202

+ +

log P = (Pa12) e(Pa.14) (Pa.18) (Pa25) (Pan) 0.7W = 227

-

measured = 2.17

+ 5(Pa.15) + + (Pa.37) +

~alarlatedby CLOGP = 3.33

(3)Comparison. Viswanadhan et al. have publisheda paper recently,in which they systematicallyevaluatedthree methods for their ability to accurately predict the log Pfor n~cleosides.2~ The three methods used in their report are (1) the atomic constant approach of Viswanadhanand co-workers(ALOGP), (2) the molecular orbital approach of Bodor and co-workers (BLOGP), and (3) the fragmental constant approach of Leo and co-workers (CLOGP). A set of 47 nucleosides and nucleobaseshave been chosen for the comparison. It includes 35 nucleosides and analogsand 12 nucleobasesand derivatives.

COMPUTER AUTOMATED LOG P CALCULATIONS Table 8. Statistical Results Using ALOGP, BLOGP, CLOGP, and KLOGP Methods r (SD)) method'

all

nucleosides

bases

KLOGP BLOGP CLOGP ALOGP

0.89 (0.46) 0.40 (1.20) 0.71 (0.93) 0.84 (0.51)

0.91 (0.47)

0.77 (0.46) 0.81 (0.53)

0.43 (1.37) 0.75 (1.02) 0.87 (0.55)

0.60 (0.63)

0.80 (0.42)

The abbreviations used here are explained in the method. r is the correlation coefficient; SD is the standard deviation.

In this study, we calculate the log P values for the same 47 compounds using our final model (KLOGP). Table 7 lists the experimental and calculated log P values using four different methods. As can be seen in Table 8, the overall correlation ( r ) of 0.89 with standard deviation (SD) of 0.46 calculated by KLOGP is the best among the four methods. For nucleosides only, it yields also the best correlation of 0.91 with SD = 0.47. However, for nucleobases, ALOGP has a better correlation of 0.80with SD = 0.42compared to KLOGP with a correlationof 0.77 and SD = 0.46. A close examination of these nucleobasesreveals that the relatively large deviation calculated by using KLOGP was caused by only one compound, purine. This comparison shows that KLOGP is a better method than the other methods for this special class of compounds. CONCLUSION We have successfullycombined the group contribution and the CASE methodologyto develop a reliable and accurate log P estimation model (n = 1663, 9 = 0.93, SD = 0.38). The CASE program has been shown to be a very useful tool in identifying the correction factors for log P calculations. The cross-validationexperimentsdemonstrated that our model can give accurate log P predictions for complex compounds as well as for simplemolecules. For nucleosidesand nucleobases, our model has a better prediction ability than the other methods. In the future, by updating the learning database, the CASE program should be able to identify new correction factors to improvethe predictive power of our log Pestimation model even more. REFERENCES AND NOTES (1) Leo,A. The Octanol-Water Partition Coefficient of Aromatic Solutes: the Effect of Electronic Interactions, Alkyl Chains, Hydrogen Bonds, and ortho-Substitution, J. Chem. SOC.,Perkin Trans. 1983, 2, 825. (2) Takacs-Novak, K.;Jozan, M.; Hermecz, I.; Szasz, G. Lipophilicity of Antibacterial Fluoroquinolones. In?. J. Pharm. 1992, 3, 89. (3) Klopman, G.; Srivastava, S.Computer-Automated StructureEvahation of Gastric Antiulcer Compounds: Study of Cytoprotective and Antisecretory Imidazo[ 1,2-a]Pyridines and -Pyrazines. Mol. Pharmacol. 1990,37, 958. 14) . , Hansch. C.: Biorkroth.J. P.:Leo. A. HvdroDhobicitvand Central Nervous SystemAgents: the Principleof Min&al Hydrophibicity in Drug Design. J. Pharm. Sci. 1987, 76, 663.

J. Chem. Znf. Comput. Sci., Vol. 34, No. 4, 1994 781 Hansch, C.; Muir, R. M. Correlation of Biological Activity of Phenoxyacetic Acids with Hamment Substituent Constants and Partition Coefficients. Nature 1962, 194, 178. Watanabe, T.; Matsuhashi, K.; Takayama, S. Placental and BloodBrain Barrier Transfer following Prenatal and Postnatal Exposure to Neuroactive Drugs: Relationship with Partition Coefficient and Behavioral Teratogenesis. Appl. Pharm. 1990, 105, 66. Leo, A. Calculating log Pa from Structure. Chem. Rev. 1993, 30, 1283. Rekker, R. F. The Hydrophobic Fragmental Constant; Elsevier: New York, 1977. Hansch, C.; Leo, A. J. Substituent Constants for Correlation Analysis in Chemistry and Biology; Wiley: New York, 1979. Leo, A.; Hansch, C.; Elkins, D. Partition Coefficients and Their Uses. Chem. Rev.1971, 71, 533. Leo, A. J. In Comprehensive Medicinal Chemistry; Ramsden, C. A., Ed.; Pergamon: Oxford, U.K., 1990; Vol. 4, p 295. Calvino, R.; G a m , A.; Leo, A. An Analysis of the Lipophilicity of Furazan and Furoxan Derivatives Using the CLOGP Algorithm. J. Chem. Soc., Perkin Trans. 1992, 2, 1643. Klopman, G.; Namboordiri, K.;Schochet, M. Simple Method of Computing the Partition Coefficient. J . Comput. Chem. 1985,6, 28. Klopman, G.; Wang, S.A Computer Automated Structure Evaluation (CASE) Approach to Calculation of Partition Coefficient. J . Comput. Chem. 1991,8, 1025. Ghose, A. K.; Crippen, G. M. Atomic PhysicochemicalParameters for Three-DimensionalStructure-Directed Quantitative Structure-Activity Relationship I. Partition Coefficientsas a Measure of Hydrophobicity. J. Comput. Chem. 1986, 7, 565. Ghose, A. K.; Pritchett, A,; Crippen, G. M. Atomic Physicochemical Parameters for Three Dimensional Structure Directed Quantitative Structure-Activity Relationships 111. Modeling Hydrophobic Interactions. J . Comput. Chem. 1988,9, 180. Klopman, G.; Iroff, L. Calculationof Partition Coefficientsby thecharge Density Method. J. Comput. Chem. 1981, 2, 157. Bodor, N.; Gabanyi, Z.; Wong, C.-K. ANew Method for the Estimation of Partition Coefficient. J. Am. Chem. SOC.1989, 111, 3783. An Extended Version of a Novel Method for Bodor, N.; Huang, M.-J. the Estimation of Partition Coefficient. J . Pharm. Sci. 1992, 81, 272. Dunn, W. J., 111; Nagy, P. I.; Collantes, E. R. A Computer-Assisted Method for Estimation of the Partition Coefficient. Monte Carlo SimulationsoftheChloroform/Water log Pfor Methylamine,Methanol, and Acetonitrile. J . Am. Chem. Sci. 1991, 113, 7898. Dunn, W. J., 111;Nagy, P. I. Relative Log P and Solution Structure for Small Organic Solutes in the Chloroform/ Water System Using Monte Carlo Methods. J. Comput. Chem. 1992, 13, 468. Jorgensen, W. L.; Briggs, J. M.; Contreras, M. L. Relative Partition Coefficientsfor OrganicSolutes from Fluid Simulations. J . Phys. Chem. 1990,94, 1683. Klopman, G. Artificial Intelligence Approach to Structure-Activity Studies. Computer Automated Structure Evaluation of Biological Activity of Organic Molecules. J. Am. Chem. SOC.1984, 106, 7315. Klopman, G. MULTICASE 1. A hierarchical Computer Automated Structure Evaluation Program. Quant. Struct.-Act. Relat. 1992, 1 1, 176. Suzulri, T.; Kudo, Y. Automated Log P Estimation Based on Combined Additive Modelling Methods. J . Comput.-Aided Mol. Des. 1990, 4, 155. Klopman, G.; McGonigal, M. Computer Simulation of PhysicalChemical Properties of Organic Molecules. 1. Molecular System Identification. J . Chem. Inf. Comnut. Sci. 1981. 21. 48. Dimayuga, M. Structure Activity 'Relationship Studies of Biological Activitiesof Chemicals. DoctoralDissertation,Case Western University, Cleveland, OH, 1991; pp 132-144. (28) Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R.; Robins, R. K. Atomic PhysicochemicalParameters for Three-Dimensional Structure Directed QuantitativeStructure-Activity Relationships. 4. Additional Parameters for Hydrophobic and Dispersive Interactions and Their Application for an Automated Superposition of Certain Naturally Occurring Nucleoside Antibiotics. J . Chem. InJ Compur. Sci. 1989, 29, 163. (29) Viswanadhan, V. N.; Reddy, M. R.; Baquet, R. J.; Erion, M. D. Assessmentof Methods Used for Predicting Lipophilicity: Application to Nucleosides and Nucleoside Bases. J. Comput. Chem. 1993, 14, 1019.

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