Insights on the Mechanism of Action of INH-C as an Antitubercular Prodrug.

Tuberculosis remains one of the top causes of death worldwide, and combating its spread has been severely complicated by the emergence of drug-resistance mutations, highlighting the need for more effective drugs. Despite the resistance to isoniazid (INH) arising from mutations in the katG gene encoding the catalase-peroxidase KatG, most notably the S315T mutation, this compound is still one of the most powerful first-line antitubercular drugs, suggesting further pursuit of the development of tailored INH derivatives. The N'-acylated INH derivative with a long alkyl chain (INH-C) has been shown to be more effective than INH against the S315T variant of Mycobacterium tuberculosis, but the molecular details of this activity enhancement are still unknown.

Molecular details of INH-C10 binding to wt KatG and Its S315T mutant.

Isoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C10, a new acylated INH derivative.

Modeling preferential solvation in ternary solvent systems.

The theoretical solvent exchange model of Bosch and Rosés for binary solvents was extended to ternary solvent mixtures. The model was applied to ENT values for the mixture methanol/1-propanol/acetonitrile, in terms of 48 new values in a total of 79, measured at 25 degrees C over the whole range of solvent compositions. It was also applied to the mixture methanollethanol/acetone at the same temperature using 93 E(N)T values obtained from literature.