Thus, the organotellurium compounds I, III, and VI tested have a pronounced parasiticidal action during intestinal development of Trichinella in experimental trichinosis of white mice and they have low acute toxicity (LDs0).

LITERATURE CITED

i. A. A. Aldashev and I. Ao Rakhimova, Anthelminthics [in Russian], Frunze (1983), pp. 99- 105.

2. V. A. Britov and V. A. Figurnov, Trichinosis in Man and Animals in the Soviet Far East (preprint) [in Russian], Vladivostok (1984), pp. 20-36.

3. A. I. Krotov, Fundamentals of Experimental Helminth Therapy [in Russian], Moscow (1973), pp. 204-210, 220-222.

4. M. N. Lebedeva, V. F. Gladnikh, and N. D. Lychko, Med. Parazitolo, No. 3, 296-304 (1974). 5. Clinical, Diagnostic, Treatment, and Prophylactic Methods for Trichinosis [in Russian],

Moscow (1984), pp. 15-19. 6. I. D. Sadekov, G. M~ Abakarov, V. B. Panov, et al.; Khim. Geterotsikl. Soedin., No. 6,

757-768 (1985). 7. Yu. S. Tsizin and A. M. Bronshtein, Khim.-farm. Zh., Noo i0, 1171-1190 (1986).

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS IN SUBSTITUTED

ORTHOAMINOMETHYLPHENOLS

S. M. Gorbunov, Sh. M. Yakubov, Zh. V. Molodykh, L. A. Kudryavtseva, and I. S. Ryzhkina

UDC 615.281:547.562.2].074

Phenols and their derivatives are widely used as disinfectants, antimicrobials, and anti- fungal agents. Quantitative structure-activity relationships have been found for substituted phenols [15, 16, 22]. The effects of structure in o-aminomethylphenols (AP) on their bacte- rio- and fungistatic activity have been examined [8]. The object of the present study was to establish quantitative structure-activity relationships in p-substituted AP (I-X):

h R = H ; lh R =CHa; III: R = C~Hs; IV: R = C~H,-/;

V: R -- C~Hg-i; Vh R =C1; VII: R = B r ; VIII: R=NO2; IX:R----OCHs; X:R----F.

Data on the biological activity of the AP is given in Table io In order to establish the relationship between the types of activity studied and the structure of the AP, the ex- perimental data were analyzed by computer. According to some reports [4, 13, 17], the bio- logical activity of a compound may be represented in the general case as a linear combination of physicochemical parameters:

tog ( l ien)=~ + kx~ +k2c+~Es, (1)

where C R is the equiactive concentration in moles, ~, o, and E s are constants characterizing the hydrophobic, electronic, and steric properties of the substituents relative to the un- substituted basic structure, and k i the regression parameters. The latter were determined by least squares multistage regression analysis [9].

In the present study, in a search for the optimum equations best describing the experi- mental data, in addition to the general relationship (i), more specific models with a smaller

A. E. Arbuzov ]institute of Organic and Physical Chemistry, Kazan. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 22, No. 9, pp. 1101-1104, September, 1988. Original article submitted March 17, 1987.

0091-150X/88/2209-0705512.50 �9 1989 Plenum Publishing Corporation 705

TABLE i. Bacterio- and Fungistatic Activity (minimum, concen- trations, M) and Physicochemical Parameters of o-Aminomethyl- phenols (I-X)

Compound

I II

I l l IV V

VI VII

VIII IX X

102 -'C, M

St. au- I reus E. col!

3,31 3,31 1,51 1,51 0,56 0,56 0,24 0,24 0,12 0,24 0,67 0,67 1,09 1,09 5,10 5,10 0,82 0,82 0,74 0,74

C. albi- ca~s

1,65 0,76 0,70 0,48 0,24 1,34 1,09 5,10 1,38 1,48

T. menta- grophY tee

0,66 0,60 0,56 0,12 0,12 0,54 0,43 5,10 0,55 0,59

0 0,56 1,02 1,98 2,13 0,71 0,86

--0,28 --0,02

0,14

O.O

0 --0,I0 --0,14 --0,13 --0,I I --0.23 --0,19

0,15 --0,43 --0,34

PKa, I PKa, 2 [2

8.51 8,65 8,60 8,51 8,45 7,93 7,66 5,60 8,80 8,21

11,20 I 1,30

I 1,40

I0,80 I0,70

I 1,40

number of independent variables were examined. Models were considered having a nonlinear re- lationship of biological activity to physicochemical properties, namely parabolic [5, 14, 18]:

and bilinear [20]:

log (I/CR) = k, + k1~ + k2n 2 ( 2 )

log (11Ca)=~+k1=+~ Mg (~=+ I). (3)

The constants describing the hydrophobic, electronic, and steric properties of the sub- stituents were obtained from [9]. The physicochemical constants used in the mathematical analysis included also the ionization constants pK=I, found experimentally by us (Table i), and the dipole moments B [21]. Studies of the relationship of structure to biological ac- tivity in AP have shown it to bedependent on the hydrophobic properties of the substituents (~). This property is not, however, the sole factor determining the bacterio- and fungistat- ic activity of AP. For example, examination of bacteriostatic activity (E. coli, Staph. aureus) in ten AP showed a correlation coefficient iog (I/C R) = f(~) of 0.874, and in the case of fungistatic activity 0.897 (C. albicans) and 0.847 (T. menta~rophytes). In order to im- prove the correlational characteristics of these relationships, additional parameters were considered, namely the Hammer constants o, the dipole moments, D, the inductive constants o0, and the Taft steric constants Es, which were checked for orthogonality. This showed that in a series of AP there was a significant relationship between the pK= values and ~ (r = 0.96) and ~ (r = 0.88, and hence in the subsequent search for better models of structure-biological activity the pKa value only was used as being universal.

Studies of bacteriostatic activity (E. coli, Staph. aureus) showed that the electronic properties of the substituents had a considerable effect on activity, which was even greater than that of hydrophobic interactions, the equation taking the form:

log (I/CR) ---- 0.508 (::k0.12) ~ - - 1.237 (-4-0.63) a ~ -F 1.523 (:/:0.52);

n = I0; r=O.968;S=O.134;F = 5 6 . 1 . (4)

In contrast, examination of the relationship between structure and bacteriostatic activ- ity (Staph. aureus) in ten analogous p-substituted phenols (Table 2) gave the equation:

log (IICR) ----- 0.793 (-4-0.12) n - - 0.347 (-4-0. I0) pKa -{- 4.901 (-4-0.97);

n = I0; t = 0.981; S ----- 0.129; F = 94. I , (5)

in which the main contribution is made by the hydrophobic properties of the substituents, in accordance with a literature report [15], in which a good correlation (r = 0.956) was found between the bacteriostatic activity (Staph. aureus) and lipophilicity in 26 phenols substi- tuted in various positions in the benzene ring~ Phenolic compounds probably modify the per- meability of the cytoplasmic membrane of the bacterial cell, disrupting the function of the latter as an efficient metabolic entity [7]. It is also possible, however, that the effects of different types of phenols could differ, and therefore the differences in the values of the regression coefficients in equations (4) and (5) and the appearance of new variables could be explained by thespecific behavior of the aminophenols.

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TABLE 2. Bacterio- and Fungistatic Activity (minimum concentrations, M) and Ionization Constants of para-Sub- stituted Phenols

Subst i tuent in the pa ra -pos i f ion

10 2 "C, M

IT. mentag- St. aureus ropbYtes pg a [I i j

H CH3

4Hg-t C4Hg-i C! Br NO= CH30 F

5,3 2,3 0,52 0,17 0,085 0,49 0,36 0,72 4,0 2,2

0,66 0,463 0,13 0,0348 0,0167 0,121 0,0289 0,018 0,504 0,446

I0,04 I0,24 l 0,2 l l 0,23 I0,25 9,38 9,36 7,15

I0,24 9,90

Studies of structure-fungistatic activity relationships (C. albicans) showed that the best equation for AP is also one with a linear dependence on hydrophobic properties and the pK a values:

n = i0; r = 0.976; S =- 0.0087; F ----- 74.9, (6)

in which the dominant factor, in contrast to Eqo (4), is hydrophobicity. A significant con- tribution to Eq. (6) is also made from the acid-base properties of the aminoethyl group (PKa,,). It is likely that a similar relationship will exist between the pK a value of the phenolic group (PKa,2, Table 2), since there is a correlation between pKa, I and PKa, 2 (r = 0.94).

Examination of the dependence of fungistatic activity (T. mentagrophytes) and structure in the AP showed that the best equation is:

log ( I /CR) = 0.362 (4-0.13) ~ -~- 0~ (4-0. l I) PKa, I -~ 0.138 (4-0. I0);

n = I0; r = 0 . 9 6 7 ; S = 0 . 1 4 1 ; F = 45.7, (7)

in which the contribution of the hydrophobic factor and the acid-base properties are similar to those found from Eq. (6) for C. albicans. The same factors also characterize the depen- dence of fungistatic activity (T. menta~rophytes) on structure in the corresponding phenols (Table 2).

log (I/C•) = 0.737 (0~ 14) n - - 0~ (4-0.12] PKa -{- 8.164 (4-I .26);

n = 10; r = 0.975; S = 0.158; F = 71,6. (8)

It is noteworthy that in this series of p-substituted o-aminomethylphenols and phenols, the introduction of steric constants for the substituents does not result in a significant improvement of correlation.

As will be seen from Tables I and 2, AP are less active biologically than the correspond- ing phenols~ The nitrogen of the aminomethyl group in the AP is capable of forming an intra- molecular hydrogen bond with the phenolic hydroxyl, so that in strongly polar media zwitter- ions may be formed, the pK a values of which will be much lower than those of the neutral and phenoxide forms of the AP [12]. In the pH region 7.0-9.0, the AP exist predominantly as the zwitterions, which are more hydrophilic than the neutral forms of the molecule, and should be less active biologically. For example, in the case of aminomethyl phosphonates, it has been shown that the zwitterionic forms display reduced bacteriostatic and especially fungi- static activity, while simultaneously showing lower surface activity [3].

EXPERIMENTAL

The test organisms used in examining antimicrobial activity were Trichophyton mentogro- phytes 1773, Candida albicans 622, Escherichia coli BKMB-125, and Staphylcoccus aureus. The fungistatic activity of the compounds against T. mentagrophytes was measured using the

707

method described in [6], using a 2-week culture of the organism. Fungistatic activity against C. albicans and bacteriostatic activity were determined by serial dilution on a liquid nutri- ent medium, as described in [i]o

The AP were obtained by the Mannich condensation of the appropriate phenol, formaldehyde, and dimethylamine in ethanol or benzene [23], or by reacting bisdimethylaminomethane with the phenol as described in [i0]. The ionization constants PK:al of the AP were determined by po- tentiometric titration in aqueous solution at a concentration of AP of 4"10 -s M (25~ with a pH-340 apparatus. Table 1 shows the mean pK= values from 3-4 measurements.

LITERATURE CITED

I. E. A. Ved'mina and N. M. Furer, Manual of the Microbiology, Clinical Treatment, and Epidemiology of Infectious Diseases [in Russian], Moscow (1964), Vol. i, p. 670.

2. B. R. Gasanov, M. M. Nasirov, and Ya. P. Stradyn', Zh. Obshch. Khim., 54, No. 9, 2075- 2082 (1984).

3. A. M. Zotova, Zh. V. Molodykh, L. A. Kudryavtseva, et al., Khim.-farm. Zh., No. Ii, 1324-1327 (1986).

4. A. S. Komskii, ibid., No. 5, 69-74 (1976). 5. M. A. Landau, Molecular Mechanisms of the Effects of Physiologically Active Compounds

[in Russian], Moscow (1981). 6. S. N. Milovanova and Z. G. Stepanishcheva, Methods of Experimental Chemotherapy [in Rus-

sian], Moscow (1971) p. 318. 7. Molecular Basis of the Activity of Antibiotics, E. Gale, E. Candliff, P. Reynolds,

et al. (eds.), [Russian translation], Moscow (1975). 8. Zh. V. Molodykh, L. A. Kudryavtseva, R. A. Shagidullina, et al., Khim.-farm. Zh., No. 2,

186-190 (1987). 9. V. N. Peregudov, The Least Squares Method and Its Research Applications [in Russian],

Moscow (1965). 10. E. G. Rukhadze, S. F. Zapuskalova, and A. P. Terent'ev, Topics in Organic Synthesis

[in Russian], Leningrad (1965). ii. Table of Rate and Equilibrium Constants for Heterolytic Organic Reactions [in Russian],

Vol. i, part i, 1975. 12. A. B. Teitel'baum, K. A. Derstuganova, N. A. Shishkina, et al., Ivz. Akad. Nauk SSSR,

Set. Khim., No. 4, 803-808 (1980). 13. C. Hansch, Khim.-farm. Zh., No. i0, 15-30 (1980). 14. P. H. Bell and R. O. ~ Roblin, J. Am. Chem. Soc., 64, 2905-2917 (1942). 15. G. L. Biagi, O. Gandolfi, and M. C. Guerra, J. Med. Chem., 18, 868-872 (1975). 16. C. Grieco, C. Silipo, and A. Vittoria, Farm. Edo Sci., 34, 433-464 (1979)o 17. C. Hansch, P. P~ Maloney, T. Fujita, and Ro M. Mair, Nature, 194, 178-180 (1962). 18. C. Hansch and J. M. Clayton, J. Pharm. Sci., 62, 1-21 (1973). 19. C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and

Biology, New York (1979). 20. H. Kubinyi, Arzneim.-Forsch., 29, 1067-1080 (1979). 21. Eric J. Lien, Guo Long-Ru, Li Ren-Li, and SuChing-Tang, J. Pharm. Sci., 71,641-655 (1982~. 22~ M. Polster, B. Rittich, and R. Zaludova, Coll. Czech. Chem. Commun., 51, 241-248 (1986). 23. B. Reichert, Die Mannich-Reaction, Berlin (1959).

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