Effect of Substitution on the Antimycobacterial Activity of 2-(Substituted benzyl)sulfanyl Benzimidazoles, Benzoxazoles, and Benzothiazoles—A Quantitative Structure–Activity Relationship Study
Chemical and pharmaceutical bulletin
Experimental Chemistry The synthesis and structural features of 2-(subst. benzyl)sulfanyl benzimidazole (BIM), 5) 5-methylbenzimidazole (5-Me-BIM), 6) benzoxazole (BOZ), 7) and some benzothiazole (BTZ) 8 ) derivatives (benzazoles) have already been published. Biology The antimycobacterial activity of the model compounds was evaluated in vitro against Mycobacterium tuberculosis CNCTC My 331/88, Mycobacterium kansasii CNCTC My 235/80, Mycobacterium kansasii 6509/96 and Mycobacterium avium CNCTC
... erium avium CNCTC My 330/88 using the mi- A set of 1160 minimum inhibitory concentration (MIC) values evaluating effect of substitution on the antimycobacterial activity of the previously published 2-(substituted benzyl)sulfanyl benzimidazoles, benzoxazoles, and benzothiazoles has been analyzed by the methods of multidimensional analysis (exploratory analysis, 2Dnonlinear mapping (NLM), principal component analysis (PCA), factor analysis (FA), multiple linear regression (MLR)). The antimycobacterial activity of 2-(subst. benzyl)sulfanyl derivatives of benzimidazole (BIM), 5methylbenzimidazole (5-Me-BIM), benzoxazole (BOZ), and benzothiazole (BTZ) increased in the order of BTZϽBOZϳBIMϽ5-Me-BIM. The sensitivity of particular strains towards these compounds decreased in the order of Mycobacterium kansasii 6509/96, M. avium My 330/88, M. kansasii My 235/80, and M. tuberculosis My 331/88. In general, derivatives with 3-CSNH 2 , 2,4-(NO 2 ) 2 , 4-CSNH 2 , 3,5-(NO 2 ), and partially 4-NO 2 substituents possess the highest antimycobacterial activity. The effect of substitution was also described quantitatively with good correlation factor R of 0.79-0.88. The log MIC values depended with a negative slope on the Hammett substituent constants s s or molar refractions MR and, for the given set of substituents, were dominantly raised with increasing log P value and partially lowered with (log P) 2 or s s؋D D log P. The derivatives featuring high polarizability, low lipophilicity and electron-withdrawing subtituents showed the highest antimycobacterial activity. The dependence on the steric substituent constant v was not statistically significant and, therefore, the ortho effect was most probably not important.