Article pubs.acs.org/jced
New Bicyclic 1,3-Selenazine Derivatives: Distribution in Model Biological Media and Membrane Permeability Svetlana V. Blokhina,*,† Tatyana V. Volkova,† Marina V. Ol’khovich,† Angelica V. Sharapova,† Alexey N. Proshin,‡ and German L. Perlovich†,‡ †
Institute of Solution Chemistry, Russian Academy of Sciences, 1 Akademicheskaya Street, 153045, Ivanovo, Russia Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia
‡
ABSTRACT: 2-Amino-1,3-selenazine template derivatives in the form of hydrobromides were synthesized. Phenyl, paraisopropylphenyl, and para-fluorophenyl were used as substituents. The distribution coefficients of the compounds in two-component systems modeling biological membranes, pH 2.0 and 7.4 buffer solution−organic solvent, were determined by a shake-flask method within the temperature range of 293 K to 313 K. Influences of the molecular structure, pKa, and pH of the buffer solutions, temperature, and solvent chemical nature on the distribution processes were investigated. Distribution thermodynamic functions were calculated for the selenazines under 298 K. It was established that the selenazines studied are substances with high membrane permeability.
1. INTRODUCTION The most significant structures among drug substances have been assigned on the basis of the analysis of the obtained results on a vast array of chemical structures. 1 Heterocyclic compounds structurally similar to natural objects with high biological activity belong to the above-mentioned structures.2 Compounds containing nitrogen, sulfur, and oxygen atoms are often used in pharmaceutical chemistry. The insertion of a selenium atom in a heterocycle fragment is aimed to give antioxidant activity for neurodegenerative, cancer, and cardiovascular diseases therapy.3 Lipophilicity is a most significant physicochemical parameter connected with bioavailability and their pharmacokinetic behavior.4 The approach to determine the lipophilicity based on the distribution coefficient in the water−octanol system is widely spread.5 Besides fundamental importance in view of the solution theory, this system appeared to be rather useful for predicting the biological properties of new compounds.6 The maximum number of investigations of the correlation between the distribution constant and the structure of the molecules is devoted to the octanol−water system.7 To estimate the contribution of the specific interactions to the distribution processes, the system hexane−water is often used where hexane plays the role of a solvent which can interact with a solute molecule only by means of van der Waals forces. The efficiency of compound distribution from water to organic solvent depends on the chemical nature of the solvent, molecular structure, dissociation constants, pH of the aqueous solution, and temperature. The information on the regularities of the distribution between different phases is collected in refs 8 and 9. Another important stage of drug design is the ability of the molecules to penetrate across the cellular semipermeable phospholipide membranes. The search of a relationship © 2015 American Chemical Society
between the structure and lipophilicity/membrane permeability of a substance opens an opportunity to rational new drugs synthesis. Earlier it was revealed that new bicyclic nonaromatic derivatives of a 2-amino-1,3-selenazine template have neuroprotective and antioxidant properties.10 The aim of the present study is the synthesis of these compounds and investigation of the correlation between molecular structure and the parameters of the distribution process in model biological systems and permeability across artificial phospholipid membranes. The present study is a continuation of our previous investigations on the solubility of the bicyclic nonaromatic derivatives of the 2-amino-1,3-selenazine template.11
2. EXPERIMENTAL SECTION 2.1. Materials. A synthetic approach to spiro-derivatives of 1,3-selenazine 5 is based on intramolecular cyclization of selenoureas 3 containing a γ,σ-unsaturated fragment (Scheme 1). Reactions of isoselenocyanates 1 with 2-(cyclohex-1enyl)ethylamine 2 (a γ,σ-unsaturated amine) afford 1-aryl-3(2-cyclohex-1-enylethyl)selenoureas 3. They were hydrobrominated at the double bond of the cyclohexene ring in boiling 48 % aqueous HBr to give 1-aryl-3-[2-(1-bromocyclohexyl)ethyl]selenoureas 4, which promptly underwent intramolecular Sealkylation and cyclization into the corresponding N-substituted 1-selena-3-azaspiro[5.5]undec-2-en-2-ylamines 5 in total yields of 60 % to 80 %. 1 H NMR spectra were recorded on Bruker CXP-200 instrument (Germany) in CDCl3, the chemical shifts are Received: December 5, 2014 Accepted: March 9, 2015 Published: March 17, 2015 1146
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Scheme 1
Table 1. Source, Purification, and Analysis Details of the Compounds Studied N I II III a
chemical name N-(1-selena-3-azaspiro[5.5]undec-2-en-2-yl)aniline hydrobromide N-(1-selena-3-azaspiro[5.5]undec-2-en-2-yl)-4isopropylaniline hydrobromide N-(1-selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-fluoroaniline hydrobromide
source
initial mole fraction puritya
method purification
final mole fraction purity
analysis method
synthesis
nd
recrystallization
0.98
NMR
synthesis
nd
recrystallization
0.98
NMR
synthesis
nd
recrystallization
0.98
NMR
nd = not determined.
USA). Phosphate buffer (0.06 M, pH 7.4) was prepared combining the K2HPO4 (9.1 g in 1 L) and NaH2PO4·12H2O (23.6 g in 1 L) salts. Salts K2HPO4 and NaH2PO4·12H2O were supplied by Merck (99 % purity). Ionic strength was adjusted by adding potassium chloride. All chemicals were of AR grade. The pH values were measured by using an electroanalytical analyzer, type OP-300, Radelkis, Budapest, standardized with pH 1.68, 6.86, and 9.22 solutions. 2.2. Apparatus and Procedure. The experiments for the determination of partition coefficients buffer/octanol were carried out by the isothermal saturation method at five temperatures: (293.15, 298.15, 303.15, 308.15, 313.15) K. The procedure was as follows: to a defined volume of a buffer saturated octanol solution, an identical volume of octanol saturated buffer of defined compound concentration was added in an ampule placed in a thermostat. The resulting solution was equilibrated for 2 days with continuous shaking. The drug concentrations in the both phases were determined by means of a spectrophotometer, Cary-50 (USA), in the UV spectral region (λ = 190 nm to 400 nm) with an accuracy of 2 % to 4 %. The reported experimental values represent the average of at least three replicated experiments. The octanol/aqueous buffer partition coefficients DO/B were calculated as the ratio of equilibrium concentrations in the organic and aqueous phases:
given in the d scale relative to Me4Si. The solvents were removed using a rotary evaporator under a water pump vacuum. N-(1-Selena-3-azaspiro[5.5]undec-2-en-2-yl)aniline hydrobromide (I). Yield 79 %, light brown crystals, mp 149.9 °C. Found (%): C, 46.41; H, 5.45; N, 7.22. C15H21N2SeBr. Calculated (%): C, 46.22; H, 5.33; N, 7.31. 1H NMR, δ: 1.37 (m, 3 H,C(9)H2, C(10)HH); 1.69 (m, 5 H, C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.14 (m, 4 H, C(11)HH, C(7) HH, C(5)H2); 3.71 (m, 2 H, C(4)H2); 7.28 (m, 2 H, Harom); 7.40 (m, 3 H, Harom); 10.92 (s, 1 H, NH); 11.26 (s, 1 H, NH). N-(1-Selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-isopropylaniline hydrobromide (II). Yield 75 %, light cream-colored crystals, mp 163.9 °C. Found (%): C, 50.24; H, 6.32; N, 6.51. C18H27N2SeBr. Calculated (%): C, 50.02; H, 6.22; N, 6.64. 1H NMR, δ: 1.25 (d, 6 H, CH(CH3)2, J = 6.8 Hz); 1.43 (m, 3 H, C(9)H2, C(10)HH); 1.68 (m, 5 H, C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.08 (m, 4 H, C(11)HH, C(7)HH, C(5)H2); 2.93 (m, 1 H, CHMe2); 3.69 (m, 2 H, C(4)H2); 7.17 (d, 2 H, Harom, J = 8.6 Hz); 7.26 (d, 2 H, Harom, J = 8.6 Hz); 10.83 (s, 1 H, NH); 11.09 (s, 1 H, NH). N-(1-Selena-3-azaspiro[5.5]undec-2-en-2-yl)-4-fluoroaniline hydrobromide (III). Yield 80 %, light cream-colored crystals, mp 200.5 °C. Found (%): C, 44.35; H, 4.96; N, 6.90. C15H20N2FSeBr. Calculated (%): C, 44.51; H, 4.82; N, 6.81. 1H NMR, δ: 1.32 (m, 3 H, C(9)H2, C(10)HH); 1.62 (m, 5 H, C(11)HH, C(10)HH, C(8)H2, C(7)HH); 2.06 (m, 4 H, C(11)HH, C(7)HH, C(5)H2); 3.63 (m, 2 H, C(4)H2); 7.04 (m, 2 H, Harom); 7.20 (m, 2 H, Harom); 10.88 (s, 1 H, NH); 11.17 (s, 1 H, NH). The origin, purification method, purity, and method of purity determination of all samples are presented in Table 1. n-Octanol was obtained from Sigma Chemical Co. (USA). Hexane (99 % purity) was received from Aldrich (St. Louis,
DO/B = xO/x B
(1)
where xO and xB are the mole fraction solubilities of a compound in the octanol and buffer phases, respectively. The standard Gibbs energy of transfer ΔtrGo from buffer to organic systems was calculated thus: Δtr Go = −RT ln(DO/B) 1147
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the buffer solutions agree with the biological liquids of gastrointestine and blood flow media and allow an investigation of the influence of the ionization processes on hydrophobic properties of the substances. The molecules of the investigated compounds contain an H-acceptor fragment (basic N atom in the heterocycle) and H-donor one (acidic secondary aminogroup) and, consequently, can be ionized in aqueous solution. At that, a ratio between the concentrations of uncharged and ionized forms of the molecules depends on the acidity constants and pH. The calculated pKa (SciFinder database) of the selenazines are given in Table 1. The data show the substances to be weak bases. A ratio between ionized and unionized forms of the molecules was determined using pKa values by the Henderson−Hasselbach equation:12
The temperature dependence of partitioning (van’t Hoff method) was employed to obtain the enthalpy of transfer ΔtrHo: d(ln(DO/B)) dT
=
Δtr H o RT 2
(3)
The entropy of transfer ΔtrS can be calculated from o
Δtr S o = (Δtr H o − Δtr Go)/T
(4)
The partition coefficient of the compounds studied in the hexane−buffer phase (KH/B) was determined in a similar manner.
3. RESULTS AND DISCUSSION 2-Amino-1,3-selenazine template derivatives were synthesized, and the molecular structure of the central fragment is represented in Figure 1. The structures of the substituents
log
[N ] = pH − pK a [NH +]
(5)
+
where N and NH are heterocyclic N atoms of the neutral and protonated molecular forms correspondently. Figure 2 shows the molecules to be fully protonated under pH 2.0. In pH 7.4 medium the decrease of the molecular ionized forms content was observed. The selenazines molecules are neutral when pH > 10. The data in Tables 4 and 5 indicate a shift of the equilibrium in the octanol pH 2.0−buffer system in the organic phase (DO/B > 1), and in hexane pH 2.0−buffer system in the aqueous phase (DH/B < 1). Hansh13 suggested a special hydrophobicity parameter, π, for aromatic compounds in the octanol−water system for an organic substituent, x, determined by the following equation:
Figure 1. Molecular structure of the studied 1,3-selenazine bicyclic derivatives.
phenyl (I), para-isopropylphenyl (II), and para-fluorophenyl (III) are represented in Table 2. The investigated compounds were obtained in the form of hydrobromic salts to increase the stability in the crystalline state and solubility. The distribution coefficients of the selenazines were obtained in octanol−buffer and hexane−buffer systems in the temperature range of 298.15 K to 318.15 K includes standard temperature 298.15 K and body temperature 310.15 K. The experimental log D values are represented in Tables 3 and 4. A sufficiently high substance concentration revealed in the octanol phase can be a reason for the deviation from an ideal solution. To prove this supposal, the concentration dependence of the distribution coefficients in the investigated systems was obtained. No log D values dependence on the concentration was revealed that indicates the absence of associative processes. A pH 2.0 hydrochloric buffer solution (I = 0.076 mol/L) and a pH 7.4 phosphate buffer (I = 0.039) were used. pH-values of
πx = log Dx − log D0
(6)
where Dx and D0 are the distribution coefficients between organic and aqueous phases of substituted and unsubstituted compounds correspondently. The temperature dependences of the πx parameter for the investigated compounds in the octanol−buffer pH 2.0 and hexane−buffer pH 2.0 systems are represented in Figure 3. Positive πx values mean that the introduction of isopropyl and fluoro substituents in the paraposition of the benzene ring of compound I promotes compounds II and III distribution in the organic phase. The obtained results are in accordance with the literature data on the hydrophobic action of the alkyl and halogen substituents in the structure of the molecules.14 The substituent influence on
Table 2. Structural Formula of the Substituents (R-), CAS Number, Constant of Dissociation (pKa), and Apparent Permeability Coefficient (Papp) for the Compounds Studied
a
Calculated Using Advanced Chemistry Development (ACD/Laboratories) Software V11.02. 1148
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Table 3. Experimental Solubility and Partition Coefficients for Compounds Studied in the Octanol/Buffer System (xO, Mole Fraction in Octanol; xB, Mole Fraction in pH 2.0 Buffer) at Temperature Ta I T/K
xO·104
293.15 298.15 303.15 308.15 313.15 Ab Bb Rc σd
1.23 1.26 1.28 1.30 1.32
xB·106 3.58 3.30 3.06 2.81 2.64 4.06 ± 0.05 −739.7 ± 15.3 −0.9992 0.003
II log DO/B
xO·105
1.54 1.58 1.62 1.66 1.70
2.45 2.47 2.49 2.50 2.51
III
xB·107 1.36 1.31 1.27 1.23 1.20 3.32 ± 0.02 −279.4 ± 7.9 −0.9995 0.001
log DO/B
xO·104
2.26 2.28 2.29 2.31 2.32
1.28 1.29 1.33 1.35 1.39
xB·106
log DO/B
3.18 2.98 2.89 2.79 2.69 3.27 ± 0.04 −490.0 ± 11.3 −0.9994 0.002
1.60 1.63 1.66 1.69 1.71
Standard uncertainties are u(T) = 0.05 K, ur(x) = 0.04, u(p) = 101.33 kPa ± 0.03 kPa. bParameters of the correlation equation: log DO/B = A − B/ T. cR = pair correlation coefficient. dσ = standard deviation. a
Table 4. Experimental Solubility and Partition Coefficients for Compound Studied in System Hexane/Buffer (xH, Mole Fraction in Hexane; xB, Mole Fraction in Buffer) at Temperature Ta hexane/buffer pH 2.0 I T/K
xH·106
293.15 298.15 303.15 308.15 313.15 Ab Bb Rc σd
4.78 4.10 3.65 2.97 2.34
xB·105 1.74 1.76 1.77 1.78 1.79 −5.53 ± 0.28 1461 ± 85.2 0.9996 0.007
hexane/buffer pH 7.4
II log DH/B
xH·106
−0.56 −0.63 −0.69 −0.78 −0.89
8.77 8.03 7.17 6.59 6.02
xB·105 3.33 3.34 3.36 3.37 3.39 −3.32 ± 0.04 803.6 ± 13.8 0.9995 0.003
III log DH/B
xH·106
−0.58 −0.62 −0.67 −0.71 −0.75
8.82 7.52 6.66 5.59 5.05
xB·105 1.71 1.74 1.76 1.78 1.79 −4.39 ± 0.10 1203.0 ± 32.4 0.9998 0.007
II log DH/B
xH·106
xB·107
logDH/B
−0.29 −0.36 −0.42 −0.50 −0.55
2.94 3.11 3.20 3.36 3.51
4.77 4.41 4.22 3.89 3.59 3.84 ± 0,16 −893.6 ± 49.2 −0.9969 0.008
0.79 0.85 0.88 0.93 0.99
a Standard uncertainties are u(T) = 0.05 K, ur(x) = 0.04, u(p) = 101.33 kPa ± 0.03 kPa. bParameters of the correlation equation: log DH/B = A − B/ T. cR = pair correlation coefficient. dσ = standard deviation.
permeability. The distribution coefficients in the octanol− buffer pH 2.0 system decrease in the order II > III > I, and in the hexane−buffer 2.0 system the order is III > II > I. It is interesting to note that Compound II with the isopropylsubstituent has high log DO/B values. This fact can be explained by the molecular hydrophobicity increase when an substituent with electron-donated ability is introduced in the benzene ring; and also by the creation of the intermolecular hydrogen bonds of the distributed substance with octanol. In the buffer-hexane system the described effect disappears because the interaction of the organic solvent with the solute molecules occurs by means of weak van der Waals forces only. The fluoro-derivative has the maximal log DH/B value among the investigated compounds. The molecule association occurs easily when a certain amount of a solvent in which the compound is poorly soluble is added to the solvent in which a high concentration of the substance can be achieved without association. A similar association phenomenon was observed for selenazines when the buffer solution pH 7.4 is added to the octanol solution of the investigated compounds. It was proven by the shifts in the absorption spectra of the compounds. In this connection it was impossible to determine the concentration in the octanol phase and calculate the distribution coefficients in the octanol−buffer pH 7.4 system. The investigated temperatures and correspondent distribution coefficients of compound II in the hexane−buffer pH 7.4
Figure 2. Dependence of content of the ionized forms of the compounds studied on the pH of buffer solution at 298 K.
the shift of the equilibrium from buffer pH 2.0 to octanol increases, whereas from buffer pH 2.0 to hexane, the substituent influence decreases with temperature rising. Comparison of the investigated selenazines structures and the distribution constants revealed a number of regularities. log DO/B values are changed in the range from 1.5 to 3.4, which corresponds to the optimal lipophilicity of the substances for pharmaceutical use.15 On the basis of the lipophilicity data the investigated substances should have high absorption due to the optimal balance between the solubility and passive diffusion 1149
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Table 5. Thermodynamics Functions of Distribution at 298.15 K ΔGotr com pound
a
B/Sol
D
−1
kJ·mol
I II III
38.2 188.7 43.1
−9.0 −13.0 −9.3
I II III
0.2 0.2 0.4
3.6 3.5 2.1
II
7.05
−4.8
ΔH0tr
T·ΔS0tr
−1
−1
kJ·mol
kJ·mol
Octanol/Buffer 2.0 14.2 23.2 5.35 18.3 9.38 18.7 Hexane/Buffer 2.0 −27.8 −31.5 −15.2 −18.7 −23.2 −25.3 Hexane/Buffer 7.4 17.1 21.9
ΔS0tr
ςHtra
ςTStrb
%
%
77.7 61.5 62.7
37.9 22.6 33.4
62.1 77.4 66.6
−105.7 −62.7 −84.8
47.0 44.8 47.8
53.0 55.2 52.2
73.5
43.8
56.2
−1
−1
J·mol ·K
%ςHtr = (ΔH0tr/(ΔH0tr + T·ΔS0tr))·100. b%ςTStr = (T·ΔS0tr/(ΔH0tr + T·ΔS0tr))·100.
Figure 4. Relationship between the entalpic and entropic terms of energy Gibbs of transfer compounds studied in octanol/buffer and hexane/buffer. Figure 3. Temperature dependences of the πx parameter of the compounds II and III in the systems octanol−buffer pH 2.0 (●) and hexane−buffer pH 2.0 (⧫).
aqueous solution to the octanol phase is thermodynamically favorable, endothermic, and entropy driven. The endothermic character of the resolvation process allows the proposition that selenazine molecules will interact with solvate shell more strongly in the aqueous phase in comparison with the organic one. The disorder of the system and appearance of the growth of flexability of the molecules appears when the energy of the interaction between the substance molecules and octanol decreases. According to the experimental data, the entropy essentially determines the octanol system distribution. The pH values of the aqueous solutions influence the selenazines hexane−buffer system distribution processes. At that, the entropy term contributes in Gibbs energy increasingly. In contrast to the water−octanol system the distribution of the protonated molecules from buffer pH 2.0 to hexane is not favorable (ΔtrGo > 0) due to high negative entropy values. The process of distribution in this system is enthalpy driven. Appearance of the un-ionized molecules in the buffer solution pH 7.4 shifts the equilibrium to the organic phase and the distribution process becomes energetically efficient (ΔtrGo < 0). The observed dependence of the thermodynamic distribution functions on the buffer solution pH value is due to the ability of the selenazines to form hydrogen bonds with water molecules. It is well-known that a marked correlation between the distribution Gibbs energy in the octanol−water system and biological activity of the organic compounds is often
system are represented in Table 4. It was revealed that the distribution from hexane to buffer does not occur for compounds I and III. It should be mentioned that in the buffer solution pH 7.4 the formation of un-ionized forms of the molecules takes place and the equilibrium is shifted from the aqueous to the organic phase. Thus, a comparatively high log DH/B value of the isopropyl derivative is explained by a low buffer solubility of the molecular forms of the compounds. The higher the temperature, the more shift to the hexane phase is observed. It is interesting that the log DH/B value for isopropyl substituted thiazine of the same molecular structure16 is higher than that of compound II. On the basis of the temperature dependences of the distribution coefficients the thermodynamic distribution parameters of the investigated substances have been calculated at 298 K, and represented in Table 5. A diagram approach was applied to analyze the experimental data (Figure 4). The transfer process from aqueous solution to octanol characterizes the distribution of the substance between hydrophilic and lipophilic phases. The standard Gibbs energy values for the substances in the octanol−buffer pH 2.0 system are negative, whereas the enthalpy and entropy values are positive. This fact indicates that the distribution of the protonated ions from the 1150
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observed.13 Meanwhile, a hypothesis of the physical correspondence between the octanol−water system and a cellular membrane was proven to be inaccurate.17 In this connection we tried to estimate the correlation between the structure of the selenazines and their ability to penetrate across biological membranes. An artificial phospholipid membrane based on liposome bilayer modeling the in vivo absorption was used to measure the passive diffusion permeability of the compounds.18 The permeability of the selenazines membrane was investigated in the buffer solution (pH 7.4) at 25 °C. The pH 7.4 buffer solution was used because it can model the pH of the blood and the permeability processes in the intestine epithelium membranes. The apparent values of the permeability coefficients for substances I to III are given in Table 2. According to the Biopharmaceutical Classification System19 all the investigated selenazines are highly permeable (Papp > 0.9· 10−6 cm/s) and correspondingly would reveal good oral absorption. The isopropyl (II) and fluoro (III) substituents in the selenazine molecules appeared to increase the permeability in comparison with the nonsubstituted phenyl group. A number of fundamentals form the basis of the permeability enhancing strategy: reduce ionizability, increase lipophilicity, reduce polarity, or reduce hydrogen-bond donors or acceptors.20 Thus, a possible reason for permeability increasing as III > II > I is the increase of the content of molecular forms in buffer at pH 7.4 from ∼8 to 30% in the same order (Figure 2). The comparative analysis of tiazines and selenazines of a similar structure21 show very close permeability values for the derivatives with a nonsubstituted phenyl fragment. Alternately, a considerable decrease of the permeability of the selenazines of the isopropyl-substituted compounds in comparison with thiazines was observed.
the protonated molecules from buffer pH 2.0 to hexane is not spontaneous and is determined by negative entropy values. The formation of the neutral forms of the molecules in pH 7.4 buffer solution shifts the equilibrium to the organic phase, and the distribution process to the hexane phase becomes energyoptimal. The permeability of the studied compounds was studied using an artificial phospholipid membrane. According to the apparent permeability coefficient values the investigated selenazines belong to highly permeable compounds.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel.: 7 (4932)351545. Fax: 7(4932) 336246 . Funding
This work was supported by the grant of Russian Foundation of Basic Research (No. 13-03-00348-a). Notes
The authors declare no competing financial interest.
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REFERENCES
(1) Nadendla, R. R. Principles of Organic Medicinal Chemistry; New Age International Ltd.: New Delhi, India, 2005. (2) Bioactive Heterocyle I. In Topics in Heterocyclic Chemistry; Eguchi, I. S., Ed.; Springer-Verlag: Berlin, 2006. (3) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Organoselenium and organotellurium compounds: Toxicology and pharmacology. Chem. Rev. 2004, 104, 6255−6286. (4) Pliska. V. Lipophilicity in Drug Action and Toxicology; John Wiley & Sons: Chichester, 2008. (5) Sangster, J. Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry; John Wiley & Sons: Chichester, 1997. (6) Hansch, C. Chem-Bioinformatics: Comparative QSAR at the Interface between Chemistry and Biology. Chem. Rev. 2002, 102, 783− 812. (7) Sangster, J. LOGKOW A databank of evaluated octanol−water partition coefficients (LogP) Sangster Research Laboratories. http:// logkow.cisti.nrc.ca/logkow/. (8) Avdeef, A. Solubility of sparingly-soluble ionizable drugs. Adv. Drug Delivery Rev. 2007, 59, 568−590. (9) Pharmacokinetics and Metabolism in Drug Design; Smith, D. A.; van de Waterbeemd, H.; Walker, D. K.; Eds.; Wiley-VCH: Verlag GmbH: 2001. (10) Proshin, A. N.; Serkov, I. V.; A.S. Lermontov, E. F.; Shvetsova, M. E.; Neganova, L. N.; Bachurin, S. O. Novel bicyclic derivatives of 1,3-selenazine. Russ. Chem. Bull. 2013, 1, 142−146. (11) Blokhina, S. V.; Volkova, T. V.; Ol’khovich, M. V.; Sharapova, A. V.; Proshin, A. N.; Perlovich, G. L. Solubility and solution thermodynamics of novel bicyclic derivatives of 1,3-selenazine in biological relevant solvents. J. Chem. Eng. Data 2014, 59, 2298−2304. (12) Po, H. N.; Senozan, N. M. Henderson−Hasselbalch equation: Its history and limitations. J. Chem. Educ. 2001, 78, 1499−1503. (13) Hansch, C.; Leo, A. Substituent Constants for Correlation Analysis in Chemistry and Biology; John Wiley: New York, 1979. (14) Korenman, I. M. Extraction in the Analysis of Organic Substances; Khimiya: Moscow, 1977. (15) Comer, J. E. High throughput measurement of logD and pKa. In Artursson, P.; Lennernas, H.;. van de Waterbeemd, H., Eds.; Methods and Principles in Medicinal Chemistry; Wiley-VCH: Weinheim, Germany, 2003; pp 21−45. (16) Blokhina, S. V.; Ol’khovich, M. V.; Sharapova, A. V.; Proshin, A. N.; Perlovich, G. L. Thermodynamics of solubility processes of novel drug-like spiro-derivatives in model biological solutions. J. Chem. Eng. Data 2012, 57, 1996−2003.
4. CONCLUSIONS Amino-1,3-selenazine template derivatives in the form of hydrobromic salts were synthesized. Phenyl, para-isopropylphenyl, and para-fluorophenyl were used as substituents. The compounds studied are the most promising as a nitric oxide antagonist and agents for the treatment of neurodegenerative diseases. The distribution coefficients of the compounds in twocomponent systems: buffer solution (pH 2.0 and 7.4)−organic solvent have been determined within the temperature range of 293 to 313 K. Using the pKa values, the content of the ionized and neutral forms of the molecules was calculated depending on the pH of the aqueous solution. It was estimated that in the buffer solution pH 2.0−octanol system the distribution of the substances to the octanol phase takes place, whereas in the water−hexane system the distribution is in water. Change of the molecular structure of the substances by the insertion of isopropyl and fluorophenyl substituents in the para position of the benzene ring promotes the distribution into the organic phase. The pH transition from 2.0 to 7.4 leads to a shift of the isopropyl derivative distribution from the aqueous phase to hexane that can be explained by the poor buffer solubility of the molecular forms of the compound. The phenyl- and fluorophenyl-substituted selenazines practically totally remain in the hexane phase. The analysis of the calculated thermodynamic parameters of the distribution process showed that in the buffer 2.0−octanol system the distribution is controlled mainly by the entropy effects. The selenazine distribution processes in the hexane− buffer systems depend on the pH values of the aqueous solutions. In contrast to the octanol−water system transferring 1151
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DOI: 10.1021/je501101f J. Chem. Eng. Data 2015, 60, 1146−1152
