QSAR analysis of some benzimidazole derivatives based on their antituberculotic activity

Věra Klimešová (klimeso@faf.cuni.cz), Karel Palát jr. (palat@faf.cuni.cz)

Department of Inorganic and Organic Chemistry, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Czech Republic

Summary

The antituberculotic activity of 29 benzimidazole derivatives against M. tuberculosis CNCTC My 331/88 were correlated to their electronic, hydrophobic, and steric parameters. The antituberculotic activity of benzimidazole derivatives is mainly related to the electronic parameters σ and to the quantum-chemical parameters ε_HOMO. The activity increases with electron withdrawing substituents in the benzyl moiety of studied compounds. The significance of HOMO orbital, revealed in QSAR analysis, can be concluded with mechanism of action. HOMO orbital can play an important role for the interaction of the molecule with the receptor. HOMO orbital is located on sulfur in the sulfanyl group and on the benzimidazole moiety. Atoms with the highest density of this orbital could be the location of the highest reactivity and could react as a nucleophilic reagent. This reasoning confirms earlier pronounced hypothesis about the sulfanyl group as a pharmacophore of the antituberculotic activity.