Quantitative structure-activity relationships of ortho-aminomethylphenols and their derivatives
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QUANTITATIVE STRUCTURE- -ACT IV ITY RELATIONSHIPS OF
ORTHO-AMINOMETHYLPHENOLS AND THEIR DERIVATIVES*
L. A. Kudryavtseva, A. B. Mirgorodskaya, Zh. V. Molodykh, S. M. Gorbunov, R. A. Shagidull ina, and Sh. M. Yakubov
It is known that the activity of mediators and coenzymes is determined by their chemical structure, small variations of which may lead to a serious change of biological effect . The analogous dependence of biological action on the structure of fragments in the molecule of compounds is also found in synthetic preparations. Therefore, the establishment of simple quantitative associations between structure and biological properties assists in the search for chemical groups responsible for
the given type of activity. Phenols and their derivatives are known widely as antimicrobial and antifungal agents. A series of quantitative
relationships for structure--biological activity was established for substituted phenols [4, 12, 14, 17], also including substituted ortho-aminomethylphenols (APs) .
In the present paper, we continued the investigation into the dependence of biological activity on the structure of APs and their derivatives and synthesized a series of quaternary ammonium salts of ortho-aminomethylphenols (QAPs) of the general
_ 3 1 7 " ,
where R: Ia: H; 11o: 4-C1; Ic: 4-F; Id: 4-Br; Ie: 4-NO2; Ig: 4-CH3; Ih: 4-n-C4H9; Ii: 4-t-C4H9; Ij:
4-n-CsH17; Ik: 2-CH3; I/: 2,3 (CH3) 2.
Data on the biological activity of the compounds (I) toward St. aureus and C. albicans are presented in Table 1. The dipole moments (DMs) were determined in hexane at 25~ for a series of APs, including those which we
previously studied, of the general formula (II) 
where R: IIa: H; l/b: 4-Cl, IIc: 4-F; lid: 4-Br; IIe: 4-NO2; IIf: 4-CH3; IIg: 4-C2H5; llh: 4-n-C4H9; IIi: 4-t-C4H9; lIj: 4-n-C8H17; IN: 2-CH3; IIl: 2,3 (CH3)2; llm: 2,3,5 (CH3)3; lIn: 4-CH30; IIo: 2,4-Br2; IIp: 3,5 C12.
Since the DMs are a quantitative measure of the charge distribution in the molecule and may determine the electrostatic interactions of the substance with the receptor, there is interest in showing the influence of the polarity of the APs on their
*Communication 2. For Communication 1, cf. .
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan' Scientific Center, Academy of Sciences (AN) of the RF. Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 27, No. 8, pp. 27-30, August, 1993. Original article submitted June 24, 1991.
566 0091-150X/93/2708-0566512.50 9 Plenum Publishing Corporation
TABLE 1. Bacteriostatic and Fungistatic Activity (minimal concentration, M) of the Compounds of the Formula (Ia-m) and
the Physicochemical Parameters of the Substituents*
1 , pound st. aureus C. albicans I a 3,4 l 3,41 164 8,60 0 0 Ib 1,53 1,53 218--219 8,10 0,7l --0,97 I c 6,43 12,85 207--209 8.62 O, 14 --0,46 I d 1,34 t .34 209--212 8, l 0 0,86 -- I, t 6 I e -- 7,94 255 5,80 --0,28 -- I f 1,63 1.63 114--115 9,19 0,56 --[,24 I g 1,56 1,56 120 9,10 1,02 - - 1,31 I h O, 179 0,090 125 9,00 2,13 -- 1,63 I i 0,143 0,090 210 (w i th decomp. ) 8,99 1,98 --2,78 I j 0,0012 0,0025 128 8,90 4.13 -- 1,57 I k 3,26 3,26 200 (with decomp. ) 8,83 0,56 --l,24 [ .~ 1,56 0,78 180-- 182 8,94 I, 12 --2,48 Im 1,49 1,49 200 (with decomp.) 9,20 1,68 --3,72
O, 103 0,603 0,092 0.888 0,736 0.565 1,030 1,959 1,959 3,82
*Here and in Table 2, physicochemical parameters are taken from .
**All compounds were recrystallized from ethanol.
biological activity. Data on the bacteriostatic and fungistatic action of the compounds (II) and the values of the DMs are
presented in Table 2. Computer analysis of the experimental data was performed in order to calculate the association between the structure
of the APs synthesized and their derivatives and the types of activity studied, since it is considered that the biological activity
of the compounds may be presented in the form of linear combinations of physicochemical parameters - - the principle of the
quantitative structure--activity relationship (QSAR) [7, 16]. Multiple regression analysis applied to the experimental data 
allowed verification of the possible association between the activity and different parameters of the substituents including those
such as the hydrophobicity constants (70, the steric Taft constants (Es), and electrostatic properties which are expressed by the
pK a values. These factors were considered to be the main ones responsible for the biological action of the compounds .
It can be seen from the data in Table 3 that the activity toward St. aureus and C. albicans for the QAPs with para
substituents in the benzene ring is associated with the factor 7r by linear dependences with the correlation coefficients r =
0,982-0.986 (cf. Table 3, equations 1 and 2), which also remain practically high for a wider series of QAPs with substituents
at different positions of the benzene ring (equations 3 and 4). On the basis of this, it can be assumed that the penetration to
the primary sections of action is determining for the biological activity of the compounds of the formula (I). Moreover, the
good correlation between the biological activity toward St. aureus and the molecular refraction (MR) (equation 5) indicates that
this form of activity is associated with the polarizability of the QAPs. Since the coefficients a and b in the equations 1 and 5
are virtually the same, the equation obtained with the application of the MR instead of a- gives the analogous correlation
qualitatively. This is determined by the fact that the 7r and the MR are almost collinear in the series of compounds studied.
At the same time, there is virtually no correlation between log 1/C (St. aureus and C. albicans) and the E s for the QAPs (r <
0.4). For the APs, the bacteriostatic and fungistatic activity also show good correlation with the hydrophobic properties of
the substituents in the benzene ring, but the r = 0.916-0.974 (cf. Table 3, equations 6-9), i.e., it is somewhat lower than for
the QAPs. No dependence of these types of activity on the steric constants of the substituents E s (r < 0.4) is observed for the
compounds of the formula (II). Since the E s and the 7r have low correlation (cf. Table 2, r = 0.528), the steric constants of
the substituents were utilized as a second descriptor or to obtain the two-parameter equations 11 and 12 with higher correlation
coefficients than those in the equations 6 and 7.
St. aureus: log 1/C=0,740(-4-0,14):~4_0,15( s 4- 4-1,743(+_0,270) (n= 13, r=0,959, s=0,251, F2,~o=57), (11)
C. albicans: logl/C=O.707(+O,15)n4-O,196(+_O,17)E~4- 4-1,809(_+0,30) (n= 13, r=0,942, s=0,281, F2.m=39,5). (12)
However, as can be seen from these equations, the most significant influence on the value of the activity is shown by the hydrophobic properties of the substituents in the benzene ring of the APs.
The utilization of the DM as a second parameter in the dependence of the bacteriostatic activity of the compounds of
the formula (II) on the ~r (equation 6) is statistically insignificant. However, the inclusion of the DM in the equation 7 (for C.
TABLE 2. Bacteriostatic and Fungistatic Activity (Minimal
Concentration, M) for the Compounds of the Formula (II)
and the Physicochemical Parameters of the Substituents*
Com- i02.C, M pound (exp.) ~ .~ a E,
aureus r cans f~,~
l la 3,30 1,66 11,20 8,51 0 0 2,56 l ib 0,676 1,35 10,80 7,93 0,71 --0,97 3,24 l l c 0,741 1,48 - - 8,21 0,14 --0,36 3,12 l id 1,10 1,10 I0,70 7,66 0,86 --1,16 3,19 lie** 5,01 5,01 - - 5,60 --0,28 - - - - [ I f 1,51 0,759 11,30 8,65 0,56 --1,24 2,93 I lg 0,562 0,708 11,30 8,60 1,02 --1,31 2,92 l lh 0,120 0,240 - - 8,45 2,13 --1,63 - - l I i 0,240 0,479 11,40 8,51 1,98 --2,78 - - I l j 0,0019 0,0019 - - 8,60 4,13 --1,57 2,95 l lk 1,82 0,607 - - 8,07 0,56 --1,24 2,45 It ~ 0,562 0,282 - - 8,18 1,12 --2,48 2,31 Ilm 0,240 0,479 - - - - 1,68 --3,72 - - l ln 0,832 1,38 11,40 8,80 --0,02 --0,55 2,76 llo** 0,0204 0,0204 - - 5,82 1,72 --2,32 - - liP** 0,0575 0,115 6,90 1,42 --1,94 - -
Note. **Not utilized in the correlations.
albicans) is statistically justified (F 1,8 = 5.24 -- the partial criterion of Fisher for the inclusion of the DM in the equation)
and leads to an increase in the correlation coefficient
log !/C=0,73( (177 (13) (n=10, r=0,985, s=O,171, F2,7=115,7 )
The descriptors of hydrophobicity ~r and the DM for the series of APs considered are thereby mutually independent. Although the main contribution to the equation 13 is introduced by the hydr0Phobicity of the substituents, the influence of the polarity of the APs on their activity is present. The equation 13 describes 97 % of the dispersion of the fungistatic activity of the APs.
Therefore, for the compounds studied in the given work and for substituted phenols , the biological action is determined practically by the hydrophobicity of the substituents in the benzene ring. There are close observed linear dependences for log 1/C = f(Tr) for the same values of the 7r for the APs and their quaternary ammonium salts (QAPs) in
relation to St. aureus and C. albicans (cf. Table 3). It is interesting to note that the absence of the association of the biological activity with the pK a of the phenolic
hydroxyl of the investigated compounds is probably observed due to the fact that the content of the phenolate form at neutral pH values is insignificant, judging from the pK a values (cf. Tables 1