Application of quantitative structure-activity relationships to the modeling of antitubercular compounds. 1. The hydrazide family

Abstract

A QSAR/QSPR methodology was used to analyze a set of 173 hydrazides, a great part of which are isoniazid (INH) derivatives. Nineteen molecular descriptors of various types (physicochemical, steric, geometrical, and electronic) have been systematically tested through a careful application of MLR. The analysis revealed that the biological activity of these compounds against M. tuberculosis does not depend on lipophilicity, as measured by log P. Properties that account for the biological response of isoniazid and related compounds, consistent with a mechanism involving the formation of radical species, were identified. The role of substituents in the stabilization of the intermediate species that gives rise to the active agent, the acyl radical, is discussed. It is postulated that the activation of INH derivatives' prodrugs (hydrazines and hydrazones) occurs near the surface of M. tuberculosis.