Quantitative structure-activity relation of antimalarial and dihydrofolate

96 cJournal of Medicinal Chemistr), 1977, Vol. 20, 30.1

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for each titration. A magnetic stirrer was used for mixing and nitrogen was bubbled through the test solution. Both the stirring and nitrogen flow were stopped to permit pH readings to stabilize after each aliquot of 0.25ml of titrant was added. The electrode was cleaned periodically by alternate soaking in dilute NaOH and dilute HC1 for 5-10-min periods followed by thorough rinsing with distilled water. To titrate the acidic function, 0.02N KOH was used, and for the basic function, 0.02N HC1 was used. Distilled, deionized water was boiled and used for all dilutions. The use of 10-ml burets permitted aliquots of 0.25 ml of titrant to be added accurately and the KOH buret was fitted with a Ca(OH)? tube to eliminate Con. Between five and ten pK, readings were used to obtain the average ionization constant. All values determined in ethanol were normalized to 100% aqueous solutions.

Acknowledgment. The authors wish to express their gratitude to the University of Kansas for support of the computing required in this study. Research support from the University of Kansas General Research Fund is gratefully acknowledged. The authors express their appreciation to Professor Corwin Hansch (Pomona College) for helpful comments and suggestions throughout the course of this work. References and Notes (1) C. Hansch in “Drug Design”, Vol. I, E. J. Ariens, Ed., Academic Press, New York, N.Y., 1971,p 271.

Hansch et al.

(2) S.M. Free, Jr., and J. W. Wilson, J . Med. Chem., 7,395 (1964). (3) A. Cammarata, A n n u . Rep. Med. Chem., 1970,245 (1971). (4) J. K. Seydel, H. Ahrens, and W. Losert, J . Med. Chem., 18, 234 (1975). (5) V. D. Warner, D. B. Mirth, M. P. Pastore, S.S. Turesky, I. G l i c h a n , and B. Soloway, J. Periodontol., 45,564(1974). (6) V. D. Warner, J. N. Sane, D. B. Mirth, S.S.Turesky, and B. Soloway, J . Med. Chem., 19,167 (1976). ( 7 ) V. D.Warner, J. D. Musto, S.S.Turesky, and B. Soloway, J . Pharm. Sci., 64,1563 (1975). (8) A. Albert and D. Magrath, Biochem. J., 41, 534 (1947). (9) A. Albert, M. I. Gibson, and S.D. Rubbo, Br. J . Exp. Puthol., 34,119 (1953). (10) C.Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, and E. J. Lien, J . Med. Chem., 16, 1207 (1973). (11) C. Silipo and C. Hansch, J. Am. Chem. Soc., 97,6849(1975). (12) C. Silipo and C. Hansch, J . Med. Chem., 19, 62 (1976). (13) M. Yoshimoto and C. Hansch, J. Med. Chem., 19,71(1976). (14) P. N. Craig, J . Med. Chem., 14,680 (1971). (15) J. G.Topliss and M. D. Yudis, J. Med. Chem., 15,400 (1972). (16) A. Leo, C. Hansch, and D. Elkins, Chem. Reu., 71,525(1971). (17) A. Leo, P. Y. C. Jow, C. Silipo, and C. Hansch, J . Med. Chem., 18,865 (1975). (18) A. F. Yopel, Adu. Chem. Ser., No. 114,189 (1972). (19) A. Albert and B. P. Serjeant, “Ionization Constants of Acids and Bases”, Wiley, New York, N.Y., 1962,p 16.

Quantitative Structure-Activity Relationships of Antimalarial and Dihydrofolate Reductase Inhibition by Quinazolines and 5-Substituted Benzyl-2,4-diaminopyrimidinesl Corwin Hansch,* James Y. Fukunaga, Priscilla Y. C. Jow, Department of Chemistr), Pomona College, Claremont, C’alifornia 9171 I

and John B. Hynes Department o f Pharmaceutical Chemistrj, College of Pharmac?, Medical L‘niLersit) of South Carolina, Charleston, S o u t h Carolina 29401 Receiced June 1. 1976

A quantitative structure-activity relationship (QSAR) for the inhibition of dihydrofolate reductase from S. faecium by quinazolines has been formulated. This is compared with a QSAR for inhibition of E. coli dihydrofolate reductase by 2,4-diamino-5-benzylpyrimidines. The QSAR for inhibition of bacterial enzyme is compared with QSAR for mammalian enzyme inhibition. A QSAR has also been formulated for the antimalarial zction of quinazolines against P. herghei in mice. The antimalarial QSAR is consistent with that of the in vitro bacterial study.

We have been interested in the quantitative structure-activity relationships (QSAR) of enzyme inhibitors and their use as starting points in drug development.2-6 Dihydrofolate reductase inhibition is of particular interest since such inhibitors have already proved to be of value as antibacterial, antimalarial, and antitumor agents. The success of dihydrofolate reductase inhibitors as antimicrobial agents depends on the great differences in this enzyme from mammalian and microbial sources.’ We are concerned in the present report with the comparative QSAR of quinazolines (I) and benzylpyrimidines (11)acting as inhibitors of mammalian and bacterial dihydrofolate hH*13k,Sbi

I

R-?

I1

reductase. The QSAR of the isolated enzymes is compared

Figure 1.

with the antimalarial action of the quinazolines. Using the results of Hynes et al., the QSAR of eq 1 was obtained for enzyme from rat liver.6 We have now formulated eq 2 for bacterial (Streptococcusfuecium) enzyme from other data from the laboratories of Freisheim and Hynes.sc Equation 3, based on data for antimalarial activity, is from the work of Elslager et al.9 The necessary biological activity and physicochemical parameters are given in the section on Method. Method. x and MR constants were taken from our were compilationlo or calculated as b e f ~ r e . T~ ,constants ~ determined for seven new groups by measuring the following log P values.

Q S A R of Antimalarial and Dihydrofolate Reductase Inhibition

log P N =O I

Journal of Medicinal Chemistry, 1977, Vol. 20, No. 1 97 sterically sensitive

‘7XU

I

3.38

Ph-NCH2C6H5

N

CHO

II

I

2.62

Ph-NCH&H5

0.49 H2N

CH3

4.22

2.09

P h - N a

2.78

0.65

P h -N

3.13

1.00

3.08

0.95

2.59

0.46

H C H2C6H5

P h - N a


a

h

C

N

n x = log (Ph-X) - 2.13.

Only a for the circumscribed substituent was used for examples of the type NH,

An indicator variable was used with such tetrahydro derivatives to see if they differed in activity from the completely aromatic congeners; no difference was found. In the particular case shown above, a of 4-methylpyridyl was taken as Kpyridine since we have found that T C H ~between an aromatic ring and an electronegative atom is near zero. T o calculate R of 4-phenylpiperidine, we have added apiperidyl a p h e n y ] (0.84 1.96). TOcalculate a of 1,2,3,4-tetrahydro-2-isoquinolyl, we have used Tpiperidyl + a n - b u t y l (0.84 + 1.32). Compound 29 of Table IV has an extra nitrogen in the ring. The a value for this compound was adjusted by -1.48 which is the difference between log P of benzene and log P of pyridine.

+

10-

open t o solvent

-

unknown

Figure 2.

I

Ph -hCH2C6H5

P

-

c - hydrophobic?

1.25

+

Results Equation 1correlates the molar concentration of quin-

log 1 j C = 0.81 (MR-6) - 0.064 (MR-6)’ + 0.78 ( n - 5 )- 0.73 (1-1)- 2.14 (1-2) - 0.54 (1-3) - 1 . 3 9 (I-4) + 0.78 (I-6)- 0.20 (MR-6.I-1) + 4.92 (1) n = 101; r = 0.961; s = 0.441 azoline causing 50 % inhibition of mammalian dihydrofolate reductase.6 In eq 1, n refers to the number of data points, r is the correlation coefficient, s is the standard deviation, and MR-6 and a-5refer to the molar refractivity of substituents in position 6 and the hydrophobicity of 5-substituents. The indicator variable I-1is given a value of 1for 2-OH or 2-SH, 1-2 takes the value of 1for 2-H, and I-3 assumes the value of 1 for 4-OH or SH. The negative coefficients with these three variables show that replacement of 2- or 4-”2 by H, OH, or SH results in much lower activity. I-4 is a more ambivalent variable and is given the value of 1 for the following bridges between position 5 and an aryl group: -S-, -SO-, - S o y , -CH2S-, -CH=CH-.

Because of the bulky character of the aryl group and the relatively small bridges involved, there is high collinearity between I-4 and MR-5. The negative coefficient suggests a sterically unfavorable interaction between large groups off position 5 and some feature in the enzyme. A comparable steric effect has been found with triazine inhibitors.3 1-6 takes the value of 1 for 6-SOzAr where Ar = 2naphthyl in all cases but one (3,4-dichlorophenyl). Its positive coefficient might be associated with the production of a conformation perturbation in the enzyme. Another explanation is that sulfur is large enough and the bond angle favorable enough so that part of Ar can reach a hydrophobic pocket (see Figure 1). The cross-product term MR-6.I-1 shows a negative synergistic effect between a 2-OH or SH group and a large group in position 6. Since 2-SH or 2-OH quinazolines are poor inhibitors, it is assumed that they bind poorly to the enzyme. If these congeners are less firmly anchored, large 6-substituents might not be able to produce their maximum conformational change in the enzyme. Figure l is a crude map of the inferences from eq 1. Equation 2 has been derived from the bacterial data in Table I. The 5-substituents show properties similar to

log 1 j C = 1 . 1 2 5 (k0.35) (71-5) - 1 . 1 0 3 (k0.25) (MR-5) - 2.385 (k0.59) (1-1) - 4.092 ( i 0 . 8 2 ) (1-2) - 2.368 (k0.37) (1-3) + 8.255 (k0.27) (2) n = 67; r = 0.926; s = 0.672 those of eq 1 and Figure 1. The positive slope with a-5 suggests hydrophobic space off the 5 position and the negative coefficient with MR-5 suggests steric sensitivity in this region. In fact, I-4 in eq 1 can be replaced with MR-5 to obtain an equation with almost as good a correlation as eq 1but with the characteristics of eq 2. This would seem to be a better way to handle the QSAR of eq 1 than our earlier idea.6 I-1,I-2, and I-3 have the same meaning as in eq 1; however, the coefficients are much more negative in eq 2, indicating that the amino group plays a more important role in bacterial than in mammalian enzyme. Note that no term in MR-6 or a-6 appears in eq 2 which points up the fact that the region adjacent to position 6 must be open to solvent. The large intercept with eq 2 suggests that the present substitution pattern has gained little in activity over that of the parent molecule (2,4-diaminoquinazoline). Since it is impossible to design a group with high a and low MR, not much can be gained by placing substituents in position 5 unless a flexible group such as propyl or butyl would be able to reach hydrophobic space without running into the sterically sensitive zone. It would also be of interest to explore substituent space off of positions 7 and 8 with groups such as -(CH2),C&. The location of a hydrophobic pocket in this region would offer the possibility of increased activity as well as increased selectivity. The results of eq 2 are summarized in Figure 2.

Hansch et al.

98 Journal of Medicinal Chemistry, 1977, Vol. 20, No. 1 Table I. Inhibition Constants and Physicochemical Parameters for Inhibition of S. faecium Dihydrofolate Reductase by Quinazolines Grouo

No. 1 2 3 4 5 6

7 8


9 10 11 12 13 14 15 16 17 18 19 20 21

22 23 24 2 5' 26 27 28 29 30 31 32

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68

I A log Obsd Calcd 1 / C l n-5

3 . 5 1 4.05 2-H, 4-NH,; 6-S0,-2-CioH, 3.65 3.39 2,4-SH, 6-S-2-Cl0H. 3.85 3.39 2-SH, 4-OH; 6-S-2-CloH. 4.05 4.68 2,4-NH,, 5-SO,-2-ClOH4.07 4.05 2-H, 4-NH,; 6-S-2-CloH4.07 5.89 2-NH,, 4-OH; 5-CH3; 6-NHCH2CbH,-4-C0,H 4.24 3.39 2-OH, 4-SH; 6-S-2-Cl,H. 4.32 3.39 2,4-OH, 6-S-2-C1,H, 4.34 5.76 2-OH, 4-NH,; 6-S-2-Cl0H, 4.36 4.28 2,4-NH2,5-SO-2-CioHq 4.52 5.89 2-NH2,4-OH; 5-CH3;6-NHCH,CbH,-4-C0,Et 4.55 5.78 2-NH2,4-OH; 6-NHCH,C,H,-4-C02Et 4.58 4.05 2-H, 4-NH,; 6-SO-2-Cl0H.. 4.65 4.99 2,4-NH,, 5-SOC,H3-3,4-C1, 4.68 4.50 2-NH,, 4-OH; 5-S-2-CioH, 4.69 5.76 2-SH, 4-NH,; 6-S-2-Cl,H, 5.11 5.78 2-NH,, 4-OH; 6-CH,NHCbH,-4-CONHCH(C0,C,H5). CH,CH,CO,C,H 5.17 5.78 2-NH,, 4-SH; 6-S0,-2-CloH, 5.28 5.78 2-NH,, 4-OH; 6-SO-2-CI,H. 5.30 5.78 2-NH,, 4-OH; 6-S0,C,H3-3,4-C1, 2-NH,, 4-OH; 6-CH2N(CH3)CbH,-4-CONHCH(C0,C,H5)-5.35 5.78 CH,CH,CO,C,H, 5.57 5.78 2-NH,. 4-OH ; 6-NHCH .C, H - 4 - C 0 ,E t 5.74 5.78 2-NH;; 4-OH; 6-CH2NHC,H;-4-CO;H 5.80 5.78 2-NH,, 4-OH; 6-CH2NHC6H,-4-CONHCH(C0,H)CH,CHzC0,H 5.85 2.31 2-NH,. 4-OH: 5-S0,-2-C,,Hq 5.85 5.39 5.92 5.78 2 :N H ,, 4 - 0H ; 6-S-C; Hi - 3,4 k 1 6.09 6.02 2-NH2,4-OH; 5-Cl; 6-NHCH2CbH,-4-C0,Et 6.10 5.78 2-NH,. 4-SH; 6-S-2-C,,Hm 6.30 5.78 2-NH;; 4-OH; 6 - S O , - Z k l 0 H , 6.37 5.78 2-NH,, 4-OH; 6-CH,N(CH,)C6H,-4CONHCH(CO,H)CH,CH,CO,H 6.52 5.78 2-NH,, 4-OH ; 6-CH2N(CHO )C, H, -4CONHCH(CO,H)CH,CH,CO,H 6.54 7.58 2,4-NH 2 , 5-SC H3-3,4-C11 6.74 5.78 2-NH,, 4-OH; 6-S-2-CioH, 7.07 5.78 2-NH,, 4-OH; 6-CH,NHC,H,-4-CO2Et 7.12 7.40 2,4-NHZ,5-trans-CH=CH-2-CloH, 7.24 7.18 2,4-NH,, 5-CH ,SC6H,-4-Cl 7.25 6.87 2,4-NH2,5-S-2-Ci,H, 7.34 8.14 2,4-NH,, 6-NHCH,CbH,-4-C0,Et 7.43 7.40 2,4-NH ,, 5-cis-CH=CH-2-C 7.52 8.14 2,4-NH2, 6-CH,NHC6H,-4-C0,-n-Bu 7.55 7.10 2,4-NH2, 5-CH,S-2-CioH, 7.68 8.14 2,4-NH2, 6-CH,NHC6H,-4-C0,Et 7.68 8.39 2,4-NH,, 5-C1; 6-CH,NHC6H,-4-C0,-n-Bu 7.70 8.14 2,4-NH2, 6-CH,NHC6H,-4-CONHCH(CO~CzHs)(CH~)2CO~CzHj 2,4-NH2, 6-CH,NHC,H,-4-CONHCH(CO~C2H5)CH,C0,C,H, 7.77 8.14 7.96 8.26 2,4-NH2, 5-CH3;6-CH,NHC6H,-4-C0,H 8.00 7.21 2.4-NH.. 5-CH,CH,-2-C,"H." 8.15 8.14 2;4-NH 6-S-2:C loH7 8.15 8.26 2,4-NH,, 5-CH3;6-CH,NHC6H,-4-C0,-n-Bu 8.20 8 . 3 9 2 .4-NH1, 5-Cl; 6-NHCH .C,H, -4420, E t 8.21 8.14 2;4-NH;; 6-CH,NHCbH,~4~CONHCH(C0,H)CH,C0,H 8.24 8.14 2,4-NH I , 6-S-C6H,-3,4-Cl , 8.24 8 . 2 6 2,4-NH2, 5-CH3;6-CH,NHCbH,-4-CONHCH(C0,CzH5)CH2CO,C,HS 8.27 8.39 2,4-NH,, 5-Cl; 6-CH2NHC,H,-4-C0,H 8.29 8.26 2,4-NH,, 5-CH3;6-CH,NHC6H,-4-C0,Et 8.40 8.14 2,4-NHZ,6-S02-2-C,,H, 2,4-NH2, 5 4 1 ; 6-CH,NHC6H,-4-CONHCH(C0 ,C,H ,)CH,CO ,- 8.42 8.39 C,H, 2,4-NH2, 5421; 6-CH,NHCbH,-4-CONHCH(C0,H)CH,C0,H 8.55 8.39 8.60 8.19 2,4-NH2, 5-CH3; 6-CH,NHC,H,-4-CONHCH(CO,H)CH2CO2H 8.64 8.39 2,4-NH,, 5-Cl; 6-CH2NHC,H,-4-C0,Et 8.70 8.14 2,4-NH,, 6-SO-2-Cl0H, 2,4-NH,, 6-CH2NHC,H,-4-C02H 8.80 8.14 2,4-NH,, 5-CH3;6-NHCH,C6H,-4-CO,Et 8.85 8.26 8.85 8.14 2,4-NH >, 6-CH,NHC,H,-4 -CONHCH(CO,H)CH ,CH ,CO ,H 9.00 8.14 2,4-NH2, 6-CH2N(CHO)C6H,-4-CONHCH(CO,H)CH,CH,CO,H 9.15 8.14 2,4-NHZ,6-SC,H,-3-CF3 9.15 8.14 2,4-NH2, 6-SO,-CbH,-3,4-C1,

;;

I

0.54 0.26 0.46 0.63 0.02 1.82 0.85 0.93 1.42 0.08 1.37 1.23 0.53 0.34 0.18 1.07 0.67

0.00 0.00 0.00 1.59 0.00 0.56 0.00 0.00 0.00 1.25 0.56 0.00 0.00 1.35 3.64 0.00 0.00

0.61 0.00 0.50 0.00 0.48 0.00 0.43 0.00

MR-5 1-1 I-2 1-3 Ref 0.10 0.0 1.0 0.0 8a 0.10 1.0 0.0 1.0 8a 0.10 1.0 0.0 1.0 8a 4.86 0.0 0.0 0.0 8a 0.10 0.0 1.0 0.0 8a 0.57 0.0 0.0 1.0 8 b 0.10 1.0 0.0 1.0 8a 0.10 1.0 0.0 1.0 8a 0.10 1.0 0.0 0.0 8a 4.88 0.0 0.0 0.0 8a 0.57 0.0 0.0 1.0 8 b 0.10 0.0 0.0 1.0 8 b 0.10 0.0 1.0 0.0 8a 4.34 0.0 0.0 0.0 8a 4.97 0.0 0.0 1.0 8a 0.10 1.0 0.0 0.0 8a 0.10 0.0 0.0 1.0 8c 0.10 0.10 0.10

0.10

0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0

1.0 8a 1.0 8a 1.0 8a 1.0 8c

1.0 8 b 1.0 8 b 1.0 8c 0.10 0.0 1.0 8a 4.86 0.0 0.0 8a 4.32 0.0 1.0 8a 0.10 0.0 0.60 0.0 1.0 8 b 0.10 0.0 0.0 1.0 8a 0.10 0.0 0.0 1.0 8a 0.10 0.0 0.0 1.0 8c

0.21 0.04 0.02 3.54 0.46 0.14 0.07 0.32 0.52 0.59

0.00 0.00 0.00 1.59 1.69 0.00 0.71 0.00 0.00 0.00

0.74

0.00 0.10 0.0 0.0 1.0 8c

1.04 0.96 1.29 0.28 0.06 0.38 0.80 0.03 0.62 0.45 0.46 0.71 0.44 0.37 0.30 0.79 0.01

4.43

0.19 0.07 0.10 0.02

3.74 0.00 0.00 4.10 3.25 3.64 0.00 4.10 0.00 4.20 0.00 0.71 0.00 0.00 0.56 3.98 0.00 0.56 0.71 0.00 0.00 0.56

0.12 0.03 0.26 0.03

0.71 0.56 0.00 0.71

0.60 0.57 0.10 0.60

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 8 b 0.0 8 b 0.0 8a 0.0 8 c

0.71 0.50 0.71 0.00 0.00 0.56 0.00 0.00 1.01 0.00 1.01 0.00

0.60 0.57 0.60 0.10

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 8c 0.0 8 C 0.0 8 b 0.0 8a 0.0 8 b 0.0 8 b 0.0 8c 0.0 8c 0.0 8a 0.0 8a

0.11

0.16 0.41 0.25 0.56 0.66 0.59 0.71 0.86

0.10 0.10

0.10 0.10

0.0 0.0

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

4.96 4.29 4.97 0.10 4.96 0.10 5.33 0.10 0.60 0.10 0.0 0.10 0.0 0.57 0.0 5 . 0 1 0.0 0.10 0.0 0.57 0.0 0.60 0.0 0.10 0.0 0.10 0.0 0.57 0.0

0.10

0.57 0.10

0.10 0.10 0.10

0.0

0.0 0.0 0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0 0.0 0.0

8a 8a 8b 8a 8a 8a 8b 8a 8b 8a 8b 8b 8c 8c 8b 8a 8a 8b 8b

0.0

8c

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 1.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0

0.0 0.0 8a 0.0 0.0 8c

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

a This congener, which is mispredicted by more than five times the standard deviation, was omitted in deriving eq 2. It is assumed to be operating via a different mechanism or it is possible that an experimental error is involved.

Q S A R of Antimalarial and Dihydrofolate Reductase Inhibition Table 11. Development of E q 2 Constant I-2 I- 3 7.34 7.59 7.10 8.30 8.26 8.19 a

Fi,bo:

oi

-1.20 - 2.24 -2.07 - 2.40 -2.37 -2.38 O.WI

I- 4

-3.54 -3.04 -4.20 -4.09 -4.38

= 1 1 . 9 7 ; Fi.60;CY

0.05

MR-5

-0.38 - 1.10 -1.08

0.14 =


n-5

r

s

1.13 1.12

0.563 0.705 0.767 0.873 0.926 0.927

1.42 1.23 1.12 0.861 0.672 0.675

- 2.48

-2.38 -2.32

Fl

,xa

30.1 22.9 14.0 40.8 4.60

4.00.

n-5

MR-5

I-1

1-2

I- 3

1.00

0.86

0.03 0.03 1.00

0.08 0.08 0.04 1.00

0.01 0.01 0.00 0.03 1.00

1.00

I- 1

1.09

Table 111. Squared Correlation Matrix for Variables of Eq 2 n-5 MR-5 I- 1 I- 2 I-3

Journal of Medicinal Chemistry, 1977, Vol. 20, No. 1 99

Table I1 shows the development of eq 2 and Table I11 the degree of independence of the variables of eq 2. Except for MR-5 and a-5, which unfortunately are highly collinear, the rest are reasonably orthogonal. Quinazolines of type I have been tested against malaria (Plasmodium berghei) in mice.g Equation 3 has been log 1 j C = 0.877 (k0.28) (n-sum) - 0.155 (k0.05) (71-sum)’ - 0.679 (k0.46) (I-6) + 0.373 (k0.32) (1-8)+ 1 . 5 2 6 (k0.29) (1-9) + 1.185 (20.40) (1-10) + 3.272 (20.40) (3)

n = 60; r = 0.906; s = 0.427; n o = 2.82 (2.5-3.2) formulated from the data of Table IV. C in log 1 / C in this equation is the molar concentration (mol/kg) of orally given drug producing 90% suppression of malaria and a-sum refers to all of the substituents in the 5 , 6, and 8 positions. Turning to the development of eq 3 (Table V), it is seen that 1-9 and I-10 are the two most important variables which assume the value of 1 for 25 congeners having the groups 6-N(X)CHzAr (1-9) and 6-CHzNHAr (1-10). All of the most active congeners have such structural features. It is surprising that with a large variation in X (I-9), no special account is needed of steric and electronic characteristics of X. It was considered that the N(X)CHz or CHzN bridges might possibly allow a hydrophobic or steric interaction of the R or Ar moiety in receptor space off the 6 or even the 5 position; evidence for this rationale could not be found. Hence it would seem that it is the CHzNH or NCHz unit per se which produces this effect. This is not entirely surprising when one considers the structure of the normal substrate folic acid. 4

OH

even though the two examples of the latter are poorly predicted, and still retain high activity. It may be possible that the -N=O and CHO groups are removed metabolically in the mouse. The next most interesting information of eq 3 is that contained in the a-sum terms; a0 is calculated from this to be 2.8. Since log P for the unsubstituted 2,4-diaminoquinazoline is 1.2, log Po for this set of congeners is 4. This is a most important limit to work with in the design of new derivatives. 1-8, which assumes the value of 1.00 for 5-Me (nine cases) and 5-C1 (one case), makes a positive contribution. Since a for Me and C1 is so close in value (0.56 and 0.71), a single indicator variable has been used. Equation 2 suggests that 5-substituents contact hydrophobic space on the enzyme so it is not surprising to find a positive coefficient with I-8 for small substituents. However, the negative MR-5 term in eq 2 shows that large groups in this position will not yield high activity unless they are flexible enough to get around the sterically sensitive site or can be moved away from this sterically sensitive zone (for example, the 3 position on the N-phenyl moiety of triazene V). Since there are only four examples where alkyl groups have been placed on the essential 2,4-diamino groups, I-6 is not an important term. Its negative coefficient does remind one that such a structural feature has a depressing effect on inhibitory power. Table VI shows that the variables of eq 3 are reasonably orthogonal. Only one congener of Table IV contains an &substituent (24). Since it is well predicted by eq 3, there would appear to be no special interaction not covered by Ea. However, an 8-substituted derivative (8-NHCHzCsH5) has been reportedga with log 1 / C < 3.25, while eq 3 estimates log 1/C should be about 4.64. These meager data leave us in an ambivalent position about position 8. More explanation is needed. Only one 7-substituent (7-NHCH2CsH3-3’,4’4%) was tested; it was found to be inactive. A set of 2,4-diamino-5-(X-benzyl)pyrimidines (11)has been tested against dihydrofolate reductase from rat liver and Escherichia coli.’l Equations 4 and 5 log 1 / C = - 1.443 (k0.48) C U’ + 5.865 (k0.38)

(4)

n = 10; r = 0.926; s = 0.418 W

I

COOH

I11

The I-9 and I-10 characterized bridges of Table IV are analogous to the 9,lO bridge in isofolic and folic acid, respectively. What is surprising is that the unnatural bridge (1-9) produces better binding than the natural bridge (1-10). More than simple length of the bridge is important since the examples where OCH2 is used do not take these variables. It is the nitrogen atom which seems to be important; strangely, however, it can carry such strongly electron-attracting groups as -N=O and CHO,

log 1 / C = - 1 . 1 2 5 (k0.15) CUR’ + 5.538 (k0.19) n = 10; r = 0.986; s = 0.182

(5)

have been formulated from the data in Table VI1 for E . coli enzyme. Attempts to improve eq 4 or 5 by addition of terms in a or MR were unsuccessful. C in these equations is the molar concentration causing 50% inhibition, u+ is Brown’s parameter,12 and UR+ is Taft’s resonance parameter.13 The u constant in each equation has been selected with respect to the ortho position of the -CHr bridge. Utilizing u with respect to the bridge results in a much poorer correlation. The fact that the electronic

Hansch

100 Journal of Medicinul ('hemisti-), 1977, Vol. 20, No. 1

Pt

al.

Table IV. Activity and Physicochemical Parameters for Suppression of P. berghei in Mice by Quinazolines _-____ __-_ __I__--

No. 1 2a 3

4 5b

6 7 8b 96


10 11 126 13 14 15 16 17 18b 19 20 21 22 23 24 25b 26b 27 28 29 30 31 32 33 34 35 36a 37 38b 39 40 41 42 43 44 45 46 47 48 49

50 51' 52 53 54 55 56 5'1 Ma

59 60

61 62 63

64

____________

LOgl'c Obsd Calcd

Group

__________

2.4 -NH,. 6-NHCH.C, H ,-2-NH, 2,4-NHZ, 6-OCH2C,H, 2,4-NH,, 6-NHCH,C6H,-2-N0, 2,4-Et,N, 6-NHCH,CbH,-3,4-C1. 2,4-NH2, 6-CH2-4-C,H,N 2,4-BuNH, 6-NHCHIC,H,-3,4-C1, 2,4-NH,, 6-0-1-C,,H,-4-C1 2,4-NH2,6-CH,C,H, 2,4-NH,, 6-CH2C,H,-2-CI 2-(CH,\,N, 4-NH2;6-NHCH,C H , 2,4-NH2,6-NHCH2-2-C,H,S 2,4-NH,, 6-CH,-3-C5H,N 2,4-NH , 6-0-2-C,,H,-1,6-Br7 2,4-NHJ, 6-OCH2C,H,-4-C1 . 2,4-NH2,6-N(octyl)CHLC,>H,-4 C1 2,4-NH,, 6-0-2-C,,H,-6-Br 2,4-NH i, 6-OC6H;:3 ,5-C!12 2,4-NH,, 6-CH,C6H,-4-CI 2,4-NH2,6-NHCH,C,H,-3-OCH3 2,4-(CH,)>N,B-NHCH,C €1,-3,4-C12.4-NH,. B-NHCII,CH . C H* -4-C1 214-NHi; 6-(NC,HI) 2,4-NH2,6-N(C ,H,-Q-C,H,) 2,4 -NH,, 6 , s -bis-N(C H ,- 2,5 -Me) 2,4-NH2,6-CH,Ci.H7-2,6-CI, 2,4-NH2,6-CH2C,H,-2,4-C1, 2,4-NH2,6-OC6H, 2,4-NH,, 6-OC,H3-3,5-CF 2,4-NH,, 8-aza; 6-N(NO)CH2Ph-3,4-C1, 2,4-NH,, 6-NHCII,-2-C,H,S-5-C1 2,4 -NH ,, 6 -0C H .,-3,4 -C1: 2,4-NH,, 6-OC,HZ-2,4,5-C1 2,4-NH,, 6-NHCH,C,,IIi-3,4-CI: 2,4-NH,, 6-NHCH,-2-Cl,Y,-l-C1 2,4-NH2,6-NHCH(CH3)C,H,-3,4-C12 2,4-NH1, 6-2'-(1,2,3,4-H4-isoquinoline) 2,4-NH ? , 5-Me; 6-NHCH ,Pli-3,4-C1, 2,4-NH2,6-CH,C,,H3-3,4-C1, 2,4-NH,, 6-N(buty1)CH zPh-3,4-C1 2,4-NH2,5-Me; 6-N(NO)CH,Ph-3,4-CI2 2,4-NH2,5-Me; 6-N(Et)CH2Ph-3,4-C12 2,4-NH,, 6-CH,NHC6H,-4-C1 2.4 -NH 2, 6-N(C H 0 )C H ,C H - 3,4-C1 2,4-NH2,5-Me; 6-NHCH,C,Hj 2,4-NH z, 5 -Me; 6-N(Pr )CH ,Ph-3,4-C1, 2,4-NH2,5-Me; 6-CII,N(NO)Ph-3,4-Cl, 2,4-NH2,6-CH2NHC,H,-3,4-C1, 2,4 -NH ,, 6 -NMeCHMeC,H, -3,4-C1 2,4-NH,, 5-Me: 6-N(CHO)CH2Ph3,4-Cl; 2,4-NH Z , 5-CI; 6-NHCH ,Pl1-3,4-Cl2 2,4- NH ,, 6 - NHC H ,C H - 3 Br 2,4-NH,, 6-N(C,H7-2-C,H;) 2,4-NH2,6-N(Et)CH,-1-Cl,,II, 2,4-NH,, 6-N(Et)CH,P:1-3,4-CI2 2,4-NII !, 5-Me; 6-CH2NHPh-3,4-CI, 2,4-NH,, 6-N(Pr)CH,C,>H;.3,4-Cl2 2,4-NH,, 6-CH2N(NO)C,H;-3,4-Cl2 2,4-NH i, 6-N(NO )CH ,C,.H ;3,4 -C1, 2,4-NH,, 6-N(Me)CH,C6H, 2,4-NH2,6-N(Pr)CH,C,H4-4-C1 2,4-NH2,6-N(Me)CHIC,.H,-3,4-C1: 2,4-NH2,6-N(Et)CH,C6H,-4-Cl 2,4-NH,, 5-Me; 6-CH,NHC,H4-4-C1 2,4-NH,, 6-N(i-Pr)CH2C6H,-4-C1 ~

~

3.07 3.18 3.26 3.31 3.31 3.47 3.57 3.65 3.73 3.75 3.82 3.88 4.05 4.06 4.08 1.09 4.11

3.06 4.30 3.82 3.81 3.64 3.81 4.26 4.41 4.51 3.32 3.78 3.64 3.70 4.48 4.18 '1.20

4.48 4.49 1.52 4.57 4.59 4.59 4.60 4.80 4.83 4.92 5.06 5.1 5 5.20 5.20 5.24 5.33 5.36 5.52 5.56 5.60 5.69

1.44 4.51 3.98 3.81 4.45 3.97 4.51 4.25 1.46 1.46 4.43 4.36 4.10 4.18 4.44 4.22 4.49 -1.51 4.51 5.93 4.88 4.46 5.31 4.86 5.95 5.50 5.91 4.64 5.64 6.04 5.67 5.83 6.39

5.72 5.93 5.94 5.97 6.00 6.02 6.10 6.16 6.13 6.15 6.30 6.34 6.40 6.55 6.76

4.87 4.37 5.98 5.86 5.83 6.07 5.60 5.70 4.51 5.96 5.89 5.97 6.01 6.02 5.90

4.14

4.15 4.21 4.24 4.29 4.30 4.34 4.36 4.40 *.43 4.44

log l/Cl

IA

0.01 1.12 0.56 0.50 0.33 0.34 0.69 0.76 0.78 0.44 0.04 0.24 0.35 0.42 0.10 0.11 0.34 0.37 0.17 0.40 0.21 0.32 0.21 0.09 0.10 0.06 0.00 0.08 0.38 0.31

0.08 0.35 0.10 0.08 0.09 1.12 0.05 0.46 0.25 0.29 0.75 0.30 0.67 0.69 0.28 0.52 0.11 0.23 0.70 0.85 1.56 0.04 0.11 0.17 0.05 0.50 0.46 1.62 0.20 0.41

0.37 0.39 0.53 0.86

n-sum _ _ 1-6 I-8 __ --

0.23 1.66 0.72 2.42 0.46 2.42 4.11 2.01 2.72

1.00 0.65 0.46 5.12 2.37 6.30 4.26 3.50 2.72 0.98 2.42 2.21 0.95 2.80 4.14 3.43 3.43 2.08 3.84 1.19 1.36 3.50 1.21 2.42 3.03 2.92 1.97 2.98 3.43 5.01 3.23 4.57 1.71 1.91 1.56 5.07 3.23 2.42 4.01 2.47 3.13 1.86 2.42 3.91 4.01 2.98 4.51 2.67 2.67 2.09 3.80 3.51 3.30 2.27 3.80

0.0 0.0 0.0 1.0 0.0 1.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0 0.0 0.0 0.0

1.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

0.0 0.0 0.0 0.0 0.0

0.0 1.0 0.0 0.0 1.0 1.0

0.0 0.0 1.0 1.0 1.0 0.0 0.0 1.0

1.0 0.0

1-9

1-10

Ref ___

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0 1.0 0.0 i.0 0.0 1.0 0.0 1.0 0.0 0.0 1.0 1.0

0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 1.0 1.0 0.0 0.0

9a 9d 9a 9a 9e 9a 9d 9e 9e 9a 9a 9e 9d 9d 9g 9d 9d 9e 9a 9a 9a 91 9b 9b 9e 9e 9d 9d 9c 9a 9d 9d 9d 9a 9a 9b 9a 9e 9g 91 9g 91 91 9g 9g 91 91 9g 91

0.0 0.0 1.0 1.0 1.0 0.0 1.0 0.0 0.0 1.0 1.0 1.0 1.0 0.0 1.0

0.0 0.0 0.0 0.0 0.0 1.0 0.0

9a 9a 9b 9g 9g 91 9% 91 9b 9g 9g 9g 9g

~

10 0.0 0.0 0.0 0.0 0.0 1.0

91

0.0

9g

These congeners, which are mispredicted b y about three standard deviations, have been omitted in deriving eq 3. Including these four points, the following equation is obtained: log l / C = 0.93 (-i.0.36)(n-sum) - 0.16 ( f 0 . 0 6 ) (n-sum)' - 0.73 (20.58) (1-6) 0.36 ( k 0 . 4 0 ) (1-8)4 1 . 3 8 (i0.35)(1-9) A 1.13 (10.51) (1-10) + 3.23 (-i.0.50)( n = 6 4 ; r = 0 . 8 4 6 ; s = 0.546). a

~,.. b

These compounds are

\;*Y,+\N--*

.

~~, L.J~ A ,

Quantitative structure-activity relation of antimalarial and dihydrofolate

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