Aqueous Solubilities, Infinite Dilution Activity ...

Journal of Solution Chemistry, Vol. 28, No. 6, 1999

Aqueous Solubilities, Infinite Dilution Activity Coefficients and Octanol-Water Partition Coefficients of Tricyclic Analogs of Acyclovir* W. Zielenkiewicz1,* B. Golankiewicz,2 G. L. Perlovich,2,3 and M. Kozbiat1 Received June 15, 1998; revised March 10, 1999 Solubilities of tricyclic analogs of acyclovir have been determined in water at 25, 35, and 45°C and in octanol, water-saturated octanol, and octanol-saturated water at 25°C. Octanol-water partition coefficients were determined at 25°C. Melting temperatures and molar enthalpies of fusion were measured. Activity coefficients in water, octanol, and in aqueous octanol solutions were determined and are discussed. The effect of hydrophilic and hydrophobic substituents in the tricyclic analogs on their thermodynamic properties are discussed. The standard Gibbs energy of transfer between the saturated phases were found to correlate with known values of the melting point of the solvents and the solubilities of the solute. For a number of the compounds examined, correlations between the minimum inhibitory concentration against the herpes simplex virus type 1 (HSV1) and type 2 (HSV-2), varicella-zoster virus (VZV), thymidine kmase-deficient (TK - ) strains of VZV and AG0-0; AC0 were established. Detailed conclusions have been derived concerning the relationships between the structure and the thermodynamic parameters of the compounds examined. KEY WORDS: Tricyclic analogs of Acyclovir; octanol, water; infinite dilution activity coefficient; solubility; partition coefficient.

1

Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. 2 Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61704 Poznan, Poland. 3 Permanent address: Institute of Solution Chemistry, Russian Academy of Sciences, 153045 Ivanovo, Russia. t We dedicate this paper to the memory of Kenneth S. Pitzer in recognition of his many invaluable contributions to solution chemistry.

731 0095-9782/99/0600-073l$16.00/0 © 1999 Plenum Publishing Corporation

732

Zienlenkiewicz Golankiewicz, Perlovich, and Koibiat

1. INTRODUCTION It is well known that hydrophobic, electronic, and steric factors are three major factors governing drug actions. Among these factors, hydrophobicity is related to the transportation of drugs across multiple lipophase-water interfaces and is usually symbolized by the logarithm of the partition coefficient In P, in the octanol-water system. The success of octanol as a model solvent for simulation of the partition phenomena occurring in the biophase has been attributed to its lipophilic-hydrophilic balance, which results from the octyl chains, the hydrogen bonding ability of the hydroxy group, and to the relatively high water content at saturation. 1 - 3) In order to predict biological activity properties of new drugs, correlation equations, which include In P and the solubilities in water and octanol as independent variables are used.(4-6) This method employs thermodynamic parameters that are sensitive to the structure of the investigated compounds and to structuring of the water-octanol phase. In this article, we attempt to analyze the influence of the structure of a dissolved molecule on the thermodynamic state of the solution and to find correlations between the thermodynamic functions and the biological activity of the compounds studied. We report here solubilities, infinite dilution activity coefficients, and partition coefficients (octanol-water) at temperatures 25, 35, and 45°C for a series of nine tricyclic analogs of acyclovir, a potent and selective antiherpetic drug, together with data for the parent compound and two derivatives of different type. Tricyclic modification has been found to be a way to shape the physicochemical and biological properties of the parent compound.(7) Recently, a tricyclic analog has been used as a substrate in the first [1H] NMR NOE study of the Herpes Simplex Virus thymidine kinase (HSV1 TK)-substrate complex in solution.(8)

2. MATERIALS AND METHODS The compounds investigated in this work (with identifying numbers) are: 1, acyclovir, 9-[(2-hydroxyethoxy)methyl] guanine (ACV). 2, 8-bromo9-[(2-hydroxyethoxy)methyl] guanine (8-Br-ACV); 12, ganciclovir, 9-[(1,3dihydroxy-2-propoxy)methyl]guanine (GCV); 3 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazol[1 ,2-a]purine (TRIC-ACV); and its substituted derivatives, 4, 6-methyl (6-Me-TRIC-ACV); 5, 6-phenyl (6-Ph-TRICACV); 6, 6-(4-biphenylyl) (6-Ph-Ph-TRIC-ACV); 7, 6-tert-butyl (6-r-BuTRIC-ACV); 8, 2-bromo-6-methyl (2-Br-6-Me-TRIC-ACV); 9, 6-(4-bromophenyl) 6-[(4-BrPh)-TRIC-ACV]; 10, 6-(2-naphthyl) [(6-(2-napht)-TRIC-

Tricyclic Analogs of Acyclovir

733

ACV], 11, 6-(4-methoxyphenyl), [6-(4-MeOPh)-TRIC-ACV]. The structures of these compounds is given in Fig. 1. All the compounds, synthesized in the Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Poznan, Poland as described earlier,(7,9-11) were crystalline and homogenous according to TLC in three solvent systems and [1H] NMR.

Fig. 1. Structural formulas of the compounds

1-12.

734

Zienlenkiewicz Golankiewicz, Perlovich, and Kozbiat

The substances used for the investigations were predried, desorbed, and desolvated. Their TG and DSC thermograms showed no change in weight with temperature and no irregular courses, respectively. A Du Pont Instruments model 9900A Thermal Analyzer equipped with a model 910 DSC cell was used for these investigations. Enthalpies of fusion were determined. Prior to the actual measurements, the DSC instrument was calibrated against a high-purity indium with a precisely known enthalpy of fusion. Each thermal analytical measurement was carried out at a heating rate of 10 K-min-1 in a dynamic argon atmosphere (100 mL-min -1 ). Sample weights ranged from 5 to 10 mg. The melting temperatures were determined by two methods: DSC (onset temperature) and on a Koffler hot-stage instrument. The data obtained were interconsistent. Except for Compound 9 none of the substance tested revealed any signs of thermal decomposition over the experimental range from room to the melting point temperature. Saturated solution was obtained in an apparatus holding glass ampules of about 15 cm3 which could be rotated by 180°. This equipment was immersed in a thermostat. Temperature in the thermostat was measured with a HewlettPackard model 2801A quartz thermometer and controlled with a PID (type 650 operated with a type 651 power unit, UNIPAN, Warsaw, Poland) temperature controller to ±0.001°C. The substance examined was placed in a glass ampule and weighed. Double-distilled, deionized water (Millipore, Elix 5 purifier), and Pure anhydrous octanol (Sigma 99%) was used for the experiments. A glass ball was placed inside the ampule, which was somewhat smaller in diameter than the ampule. To attain thermodynamic equilibrium, the solute and the solvent were mixed continuously for minimum of 4 days at a speed of 25 rpm. The time and speed of rotation were established in preliminary experiments covering time spans of 24 to 144 h and swinging speeds of 25 to 60 rpm. After the experiment was completed, the sample was centrifuged at 40,000 rpm for 40 min at 25±0.1°C, the supernatant liquid collected, diluted, and its concentration determined with a UV-VIS (Varian Carry IE) spectrophotometer. The photometric accuracy was 0.005 A and the wavelength measurement accuracy was 0.2 nm. The experiments were repeated at least three times for each solubility. The equipment described was also used for the determination of the partition coefficients P. The procedure was as follows: an aqueous solution at a concentration one half the solubility of the substance examined was prepared. The solution was placed in an ampule and an identical volume of octanol added; a glass ball was placed inside the ampule which was sealed and placed in a thermostat. The measurement took 2 days with continuous stirring. The initial concentration in the aqueous solution and the final concen-


735

tration of the substance after each measurement were determined by spectrophotometry. The partition coefficient was evaluated as

where Cow and Cwo are the molar concentrations of the solute in the mutually saturated phases of octanol and water, respectively. The correctness of the P value was verified by checking the mass balance of the starting amount of the substance "i" and the total amount of the substance partitioned between the two phases,

where mi = Ci Vi is the starting mass (in moles) of the substance, mow = CowVowis the mass of the substance dissolved in the water-saturated octanol phase, and mwo = CWOVWO is the mass of the substance dissolved in the octanol-saturated water phase. Each experiment was repeated three times. It can be noted that the value of partition coefficients does not depend on the initial concentration of aqueous solutions studied. This statement results from preliminary experiments made with various concentrations of initial aqueous solutions. They correspond to the concentrations two to five times smaller than the concentration of saturated solution. The infinite dilution activity coefficient -y2 was of interest. For a sparingly soluble solid dissolved in a liquid, the equation relating the solubility (as mole fraction x2) of the pure unsolvated solute in a solvent with the molar enthalpy of fusion A fus H m and the melting point temperature Tm is(12,l3)

where R is the universal gas constant, ACP is the heat capacity difference between the liquid and solid phases, and T is the system temperature. Assuming the heat capacity difference ACP to be small enough to make the last term in Eq. (3) negligible and the solubility to be low enough to write C2 = x2IV1, where C2 is the molar solubility of the solute and V1 is the molar volume of the solvent, Eq. (3) can be rearranged to

Hence, the infinite dilution activity coefficient can be calculated using the

736

Zienlenkiewicz Golankiewicz, Perlovich, and Kozbial

values of the melting temperature the enthalpy of fusion, and the molar solubility of the solute and the volume of the solvent. The phase i -> j transfer standard Gibbs energy was determined from the equation

3. RESULTS AND DISCUSSION The molar extinction coefficients are listed in Table I. The solubilities of the substances measured in water Cw, octanol C0, octanol-saturated water Cwo and water-saturated octanol Cow at 25°C are listed in Table II and presented graphically in Fig. 2. The partition coefficients and the solubility ratio evaluated from the data listed in Table I are listed in Table III. The melting points Table I.

Molar Extinction Coefficients E and Wavelength Amax for Compounds 1-12 in Water and Octanol Octanol

Water Compoundb

1 2 3

4 5 6 7 8 9

10 11 12 a

Amax

e

251 259 226 285 230 284 249 306 249 306 230 284 235 284 256 309 254 315 259 306 251

1.34 1.49 3.21 1.10 2.57 0.865 1.79 0.553 2.08 0.647 3.62 1.17 3.27 1.31 2.94 0.977 3.13 0.760 2.95 1.20 1.20

Units: e, (L-mol -1 -cm -1 ) X 10-4; Amax, nm, For explanation of compound numbers, see Section 2.

b

Amax

e

257 257

0.689 0.299

284 261 283 254 309 254 309 283

0.690 0.654 0.734 1.69 0.507 1.57 0.518 1.39

285 232 260 316 258 322 264 309 254

1.51 2.83 4.07 1.26 5.83 1.41 1.03 0.436 0.379


737

Table II. Solubilities of Compounds 1-12 in Water, Water Saturated with Octanol, Octanol, and Octanol Saturated with Water at 25°Ca

Cw

cwo

Co

Cow

80.7+1.6 10.3 ±0.8 30.7 ±0.6 187±3.7 2.38+0.15 2.29±0.16 30.8+0.3 21.1+0.4 3.64+0.18 1.66+0.05 0.529+0.021 123±1

74.4+1.5 8.59+0.30 27.2±0.8 131+2 3.34+0.32 5.83±0.01 37.8+1.1 10.51+0.05 4.12+0.12 1.91+0.04 1.35+0.10 110+3

2.12+0.18 4.43+0.27 1.40+0.03 32.4+1.3 67.8+3.2 20.4+1.3 159±2 2.27±0.10 7.80±0.08 7.25+0.32 4.03+0.06 1.66+0.06

3.53+0.04 6.89+0.40 4.27+0.14 35.9±0.71 17.91+0.27 18.1 ±0.70 99.2+4.9 8.58 ±0.25 6.81 ±0.20 6.84±0.20 3.74±0.07 3.83 ±0.36

Compound*

1 2 3 4 5 6 7 8 9 10 11 12 aUnits: bSee

(mol-L-1)X 104. footnote, Table I.

Fig. 2. The solubilities of the compounds 1-12.

738

Zienlenkiewicz Golankiewicz, Perlovich, and Kozbiat Table III.

Octanol-Water Partition Coefficient P and Solubility Ratio at 25°C for Compounds 1-12

Compound"

Co/Cw

Cow/Cwo

P

1 2 3 4 5 6 7 8 9 10 11 12

0.026 0.430 0.046 0.173 28.4 8.90 5.16 0.108 2.14 4.37 7.62 0.013

0.048 0.802 0.157 0.274 5.36 3.10 2.62 0.816 1.65 3.58 2.84 0.035

0.0363 ±0.0009 0.544±0.087 0.138 ±0.001 0.205 ±0.005 3.51+0.29 3.10±0.08 4.13 ±0.04 0.780±0.009 3.54+0.17 3.54 ±0.01 2.43 ±0.22 0.0173 ±0.0004

"See footnote, Table I.

Tm, enthalpies of fusion AfusHm, fugacity ratios f2/f2. and the activity coefficients -Go, Gow, Gw, and Gwo at 25°C are listed in Table IV. The solubilities in water, f 2 f 2 . and Gw at 35 and 45°C are listed in Table V. The values used to calculate G2 were: Vw = 0.018 L-mol -1 ; Vo = 0.157 L-mol -1 ; Vow = 0.121 L-mol -1 , and Vwo = VW.(14) Table VI gives the standard transfer Gibbs energies related to the transfer from the solute-saturated water to the solute-saturated octanol solution Table IV. Melting Temperature, Enthalpy of Fusion, Fugacity Ratio, and Activity Coefficients y at 25°C for Compounds 1-12" Compound*

Tm

A fus H m

(f 2 /f 2 )10 4

To

1 2 3 4 5 6 7 8 9c 10 11 12

248.7 179.7 247.4 192.2 212.6 211.3 205.3 201.1

26.86 36.44 43.33 36.06 63.78 45.43 37.95 50.44

96.1 65.9 5.71 53.72 0.484 8.70 31.2 5.23

288.79 94.80 25.90 10.56 0.045 2.71 1.25 14.68

225.04 79.08 11.09 12.37 0.223 3.97 2.60 5.04

66.17 355.64 10.34 15.96 11.29 210.94 56.32 13.78

71.78 426.43 11.67 22.78 8.05 82.86 45.90 26.66

220.2 234.1 236.0

37.64 48.41 37.88

24.60 3.19 17.77

21.61 5.04 68.20

29.72 7.05 38.35

823.21 335,09 8.03

715.46 131.31 8.98

a

Units: Tm °C; A fus H m , KJ-mol-1. See footnote, Table I. c Thermal decomposition. b

Gow

Yw

Gwo

739


Table V. Solubilities in Water, Fugacity Ratios, and Activity Coefficients yw at 35 and 45°C for Compounds 1-12" 35°C

45°C

Gw

Compound

Cw

(f 2 /f o 2 )10 4

1 2 3 4 5 6 7 8 9 10 11 12

162±8 19.0±1.1 59.1 ±2.9 266±IO 5.17±0.26 5.54±0.23 204±3 23.6±0.5 8.98 ±0.27 2.56±0.04 1.44±0.07 218+2

142.41 106.24 10.07 86.12 1.11 15.76 51.32 10.13

48.84 310.65 9.47 17.99 11.98 158.04 13.98 23.84

40.26 6.01 29.18

873.72 232.00 7.43

a

Cw 197±4 24.9 ±1.2 67.5±3.3 324±12 7.28±0.32 6.58 ±0.30 319±5 25.9±0.7 12.8±0.33 2.65±0.03 4.65 ±0.23 229 ±3

(f2/fo2)104

Gw

200.50 166.13 17.14 134.05 2.44 27.51 81.75 18.80

56.54 370.65 14.11 22.99 18.60 232.33 14.24 40.33

63.89 10.89 46.45

1339.40 130.11 11.27

Unit: C w (mol-L- 1 ) X 104. See footnote, Table 1.

b

Table VI. Standard Transfer Gibbs Energy at 25°C for Compounds 1-12" Compoundb -In(C w ) --In (Co) -In (Cwo) -In (Cow)

1 2 3 4 5 6 7 8 9 10 11 12

4.81 6.88 5.78 3.98 8.34 8.38 5.78 6.16 7.92 8.70 9.85 4.40

8.46 7.72 8.87 5.73 5.00 6.19 4.14 8.39 7.16 7.23 7.82 8.70

aUnits, kJ-mol- 1 . *See footnote, Table I cAGo-o= -RTIn(CJC w ). d AGoo-ow = -RT In (C ow /C wo ). e AGo= -RT In P.

4.90 7.06 5.91 4.34 8.00 7.45 5.57 6.86 7.79 8.56 8.91 4.51

7.95 7.28 7.76 5.63 6.32 6.31 4.61 7.06 7.29 7.29 7.89 7.87

AGw-o

9.04 2.09 7.63 4.35 -8.29 -5.42 -4.07 5.51 -1.88 -3.65 -5.03 10.76

a

AGwo-ow

7.52 0.55 4.59 3.21 -4.16 -2.80 -2.39 0.50 -1.24 -3.16 -2.59 8.31

AGoe

8.22 1.51 4.91 3.93 -3.11 -2.80 -3.51 0.62 -3.13 -3.13 -2.20 10.05

740

Zienlenkiewicz Golankiewicz, Perlovich, and Kozbial

AGo-o = —RT In(Co/Cw), from the octanol-saturated water to the watersaturated octanol solution AGw 0 -ow = -RT In(Cow/Cwo); and from the water phase to the octanol phase in the water-octanol system AGtr = — RTln P. In terms of the solubilities in water and in octanol (Table II), the compounds can be divided into two groups. Group one includes compounds 1, 2, 3, 4, 8, and 12 which are more soluble in water than in octanol, CwCo > 1. In addition, for these substances Cw > Cwo, GO > Gow, and Gw < Gwo (Tables II and IV). Group two includes compounds 5, 6, 7, 9, 10 and 11 for which, characteristically, C0 > Cow and Cw < Cwo as well as Gw > Gwo and Go < Gow A correlation of the type AGoo-ow vs. AGo-o was developed for each group. For compounds 1, 2, 3, 4, and 12 (Group one) it was,

with r = 0.978, a = 0.76, and n = 5 where r is the correlation coefficient, a is the standard deviation, and n is the number of compounds. For compounds 2, 5, 6, 7, 9, and 11 (Group two), it was

with r = 0.998, or = 0.09, and n = 6. Equations (6, 7) show that the compounds of Group one are more sensitive to the mutual solvation of the solvents and thus also to the lipophilichydrophilic balance. The DGoW->o and AGowo->ow values for compound 2 (Fig. 3) occur in the vicinity of the point of intersection of the straight lines described by Eqs. (6 and 7). Except for compounds 2, 7, and 9, the discussed analogs of acyclovir comply with the following correlations AG°r = f(Tm, Cw) and AGor = f(Tm, Cwo)

with r = 0.980, rd = 0.977, S = 1.03, F = 70.83, and Ftab = 5.60 and

with r = 0.976, rd = 0.973, S = 1.10, F = 61.79, and Ftab = 5.60, where r is the multiple correlation coefficient, rd is the multiple correlation coefficient adjusted to the number of degree of freedom, a is standard deviation, F is the calculated Fisher distribution value, and Ftab is the F-distribution tabulated value.(16) The fractional coefficients of correlation between the independent variables Tm vs. ln Cw and Tm vs. ln Cwo in Eqs. (8 and 9) are 0.0498 and 0.0027, respectively. These correlations may help qualitatively predict the partition coefficients for compounds of a given group in the octanol-water system. As


741

Fig. 3. A relationship DG°wo->ow =f(AG 0 w->o ).

evident from the relationships given, AGor varies as much with ln Cwo as it does with ln Cw. The present result may be due to the low number of compounds on which the correlation was based. The substances examined are inhibitors against a wide variety of herpes viruses. It is, therefore, of interest to find a correlation between the minimum inhibitory concentration C* (concentration required to reduce virus-induced cytopathicity or plaque formation by 50%) and the thermodynamic parameters. Table VII lists the values of ln C* for compounds 1, 4-8, and 12:(7) the herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), and thymidine kinase-deficient (TK - ) strains of VZV. The values of AGor and AGow->o were used to develop the correlation; they are expected to correctly reflect energy conditions of the substances examined in the tissues of living organisms. The correlation developed is as follows:

742

Zienlenkiewicz Golankiewicz, Perlovich, and Kozbiat Table VII. Activity of Compounds 1, 4-8, and 12 Against Human Herpes Viruses Minimum inhibitory concentration, ln C*a Virus (strain)

1

4

5

6

7

8

12*

1 HSV-1 (KOS) 2 HSV-1 (F) 3HSV-1(McIntyre) 4 HSV-2 (G) 5 HSV-2 (196) 6 HSV-2 (Lyons) 7 VZV (YS) 8 VZV (OKA) 9 TK-VZV (YS-R) 10 TK- VZV (07/1)

-3.91 -5.52 -2.66 -2.41 -4.61 -4.71 -0.97 -1.71 1.55 2.62

-0.22 -0.54 0.00 1.10 0.41 0.00 2.24 1.53 4.25 3.91

-0.92 -0.36 -1.61 0.26 -1.61 -0.36 0.34 0.26 4.20 4.20

0.26 0.69 -0.36 1.95 0.69 0.69 3.69 4.17 4.61 4.61

1.50 1.39 0.69 2.56 1.95 3.00 0.79 0.00 4.84 3.69

4.55 5.01 5.01 5.86 4.25 5.01 5.39 5.37 5.22 5.19

-5.81 -5.52 -5.52 -3.91 -3.22 -5.52 0.34 -0.69 0.34 0.41

a

Unit C*, ug-mL-1. Ref. (7).

b

where a0, a1, and a2 correlation coefficients. The data obtained (Table VIII) appear to be of interest even if no correlation of this type could be established for VZV(YS), VZV(OKA), and TK-(VZV07/1) viruses. The results demonstrate the practical value of the thermodynamically derived parameters. The activity coefficients of the compounds examined (Table IV) vary over the broad range of 0.043 to 802. None of the compounds examined ideally dissolves in any solvent phase. Among substances whose properties are close to those of ideal solutions, with activity coefficients close to 1, Table VIII. Parameters of a0, a1, and a2 in Eq. (10) Virus (strain)

a0

a1

a2

ra

rab

SC

Fd

1 HSV-1 (KOS) 2 HSV-1 (F) 3HSV-1(McIntyre) 4 HSV-2 (G) 5 HSV-2(196) 6 HSV-2 (Lyons) 7 VZV (YS) 8 VZV (OKA) 9 TK - VZV (YS-R) 10 TKT-VZV (07/1)

0.75 ±0.70 0.84+1.00 0.60±0.94 2.09±0.72 0.89+0.96 1.31+0.65 2.34 ±1.42 2.06+1.76 4.29 ±0.60 4.07±0.80

0.80±0.37 0.80+0.49 0.88+0.47 0.78 ±0.36 0.77+0.47 0.83+0.32 0.52+0.70 0.53 ±0.87 0.24+0.30 0.20 ±0.40

-1.4±0.5 -1.5±0.7 -1.4+0.6 -1.4+0.5 -1.3+0.6 -1.6+0.4 -0.8±0.9 -0.9+1.2 -0.6±0.4 -0.5+0.5

0.975 0.965 0.954 0.975 0.950 0.986 0.768 0.738 0.946 0.858

0.970 0.958 0.945 0.970 0.940 0.983 0.713 0.674 0.935 0.826

0.753 0.99 0.97 0.72 0.96 0.65 1.42 1.76 0.60 0.81

39.20 27.23 20.29 38.40 18.41 67.34 2.87 2.40 16.96 5.57

a

Multiple correlation coefficient. Multiple correlation coefficient adjusted to the degrees of freedom. c Standard deviation. d Criterion of Fisher (the table value is Ftab = 9.197 for n = 7 number of data). b


743

compound 5 in octanol and in water-saturated octanol, and compound 7 in octanol should be mentioned. The observed activity coefficients allow us to evaluate the molecular interactions prevailing in the solutions examined. (12,15) The type and value of these interactions appear to be of considerable interest. These interactions may be estimated using the following equation

where W11, w22, and w12 represent the solvent-solvent, solute-solute, and solvent-solute interactions, respectively, V2 is the molar volume of the subcooled liquid solute, and P1 is the volume fraction of the solvent. Each type of interaction appeared significantly to contribute to the value of the activity coefficient. Various forms of octanol autoassociates are known to occur in water, viz., linear and cyclic multimers, (17) aggregates forming roughly spherical clusters (18) and cyclic tetramers.(19) Similarly, in octanol-water solutions, the molecules of water are known to form tetramers,(17,20) various clusters tied up with octanol molecules,(21) clusters with coordinated hydroxyl groups, and the hydrocarbon chains pointing outward. These facts confirm the significance of solute-solvent and solvent-solvent interactions as determined by Eq. (11) in the solutions of compound 8 in which the activity coefficients in water and in the alcohol are identical. To evaluate these coefficients, we may assume that in Eq. (11) the expression V 2 P 2 /RT can be represented by a constant value A. The equation then becomes

and, if we assume A1 = A2, then

As evident from Eq. (13), the difference between the interaction energies in the aqueous and octanolic solutions equals half the difference between the interaction energies of the water-water and octanol-octanol interactions. This fact confirms the suggestion that molecular interactions are different, which may be of consequence in the studies of the relationship between the solubility of a compound and some important parameters for modeling biological membranes and predicting the transport and distribution of drugs in the organism.(1,2.22) With the various substances examined, the activity coefficients are observed to follow different courses in relation to increased temperature. For substances 3, 5, 8, 10, and 12 the values are increasing and for the 4, 7, and 11 they are decreasing; for substances 1 and 2 they are constant. For compound 6, the activity coefficient was found to follow a complicated course and to

744

Zienlenkiewicz Golankiewicz, Perlovich, and Kozbiat

attain its minimum at a temperature of 35°C. On the other hand, the solubility of each compound invariably increases with the increasing temperature. The present data also provide a number of detailed conclusions. For example, a methyl group in position 6 in the compound TRIC-ACV increased the partition coefficient P; however, this value was still less than unity (compounds 3 and 4). A tert-butyl group attached to the skeleton of the molecule results in a considerably higher partition coefficient, higher than unity (compounds 3 and 7), whereas addition of a CH2OH group giving rise to hydrogen-bonding possibilities, results in a decreased partition coefficient (compounds 1 and 12). No general relationships were found to occur between C0/CW and the partition coefficient, nor between COW/CWO and P. The COW/CWO values could be correlated with P (within the limits of experimental error) only for compounds 6, 8, 10, and 11. The data (Table III) permits a number of conclusions concerning the effect of the substitutent on the partition coefficient. Distinctly different is the effect of the position of substitution of a -Br group on the partition coefficient. The Br atom at position 8 increases the partition coefficient (cf. compound 1 and 2, 4, and 8). In position para in the phenyl ring, the Br atom fails to affect the partition coefficient (cf. 5 and 9). Similarly, diphenyl and naphthyl ring substituents introduced at position 6 in compound 3 fails to affect the partition coefficient (cf. compounds 5, 6, and 10). On the other hand, an introduction of a OCH3 group at the phenyl ring results in a decrease of partition coefficient (cf. 5 and 11). A general relationship has been reported to occur between the solubility of acyclovir analog and the melting temperature.(14,23) This relationship is believed to be due to the considerable structural similarity of the compounds examined. No such relationship has been found to occur for the presently investigated compounds. Only for two compounds was a lower solubility found to correspond with increased melting temperature, viz., Tm (8) > Tm (4), which may be associated with the stabilization of the crystal lattice. In a similar way, the increased solubility of compound 4 as compared with the solubility of compound 1, Tm (1) > Tm (4), may well be due to the dilation of the crystal lattice.

ACKNOWLEDGMENT This work was supported by the State Committee for Scientific Research under Project KBN 3 T09A 05611.


745

REFERENCES 1. C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (Wiley, New York, 1979). 2. F. G. Topliss, Quantitative Structure Activity Relationships of Drugs (Academic Press, New York, 1983). 3. A. Leo, C. Hansch, and D. Elkins, Chem. Rev. 71, 525 1971. 4. H. Fujiwara, Yong-Zhong Da, K. Ito, T. Takagi, and Y. Nishioka, Bull. Chem. Soc. Jpn. 64, 3770(1991). 5. C. Yamagami, K. Iwasaki, and A. Ishikawa, Chem. Pharm. Bull. 45, 1653 (1997). 6. Yong-Zhong Da, K. Ito, and H. Fujiwara, J. Med. Chem. 35, 3382 (1992). 7. B. Golankiewicz, T. Ostrowski, G. Andrei, R. Snoeck, and E. De Clercq, J. Med. Chem. 37, 3187(1994). 8. J. Czaplicki, T. Bohner, A.-K. Habermann, G. Folkers, and A. Milon, J. Biomol. NMR 8, 261 (1996). 9. J. Boryski and B. Golankiewicz, Nucleosides, Nucleotides 8, 529 (1989). 10. J. Boryski, B. Golankiewicz, and E. De Clercq, J. Med. Chem. 31, 1351 (1988). 11. J. Boryski, B. Golankiewicz, and E. De Clercq, J. Med. Chem. 34, 2380 (1991). 12. S. I. Sandier, Chemical and Engineering Thermodynamics, 2nd ed. (Wiley New York, 1989), p. 408 . 13. J. M. Prausnitz, R. N. Lichenthaler, and E. G. de Azevedo, Molecular Thermodynamics of Fluid-Phase Equilibria (Prentice-Hall, Englewood Cliffs, New Jersey 1986). 14. A. Kristl and G. Vesnaver, J. Chem. Soc. Faraday Trans. 91, 995 (1995). 15. J. H. Hildebrand and R. L. Scott, Regular Solutions, (Prentice-Hall, Englewood Cliffs, New Jersey, 1962). 16. N. R. Draper, H. Smith, Applied Regression Analysis (Wiley, New York, 1973), p. 459. 17. J. H. Smith, C. Hansch, and M. M. Ames, J. Pharm. Sci. 64, 599 (1975). 18. N. P. Franks, M. N. Abraham, and W. R. Lieb, J. Pharm. Sci. 82, 466 (1993). 19. M. Iwahashi, Y. Hayashi, N. Hachiya, H. Matsuzawa, and H. Kobayashi, J. Chem. Soc. Faraday Trans. 89, 707 (1993). 20. B. C. Lippold and M. S. Adel, Arch. Pharm. 305, 417 (1972). 21. A. J. Dallas and P. W. Carr, J. Chem. Soc. Perkin Trans. 2, 2155 (1992). 22. S. H. Yalkowsky and S. Banerjee, Aqueous Solubility (Marcel Dekker, New York, 1992). 23. A. Kristl, J. Chem. Soc. Faraday Trans. 92, 1721 (1996).