A Rational Approach To Antitubercular Drug Design: Molecular Docking, Prediction of ADME Properties and Evaluation of Antitubercular Activity of Novel Isonicotinamide Scaffold.

Introduction: One of the most devastating and leading diseases is Tuberculosis (TB), caused by Mycobacterium tuberculosis. Even though many synthetic drugs are available in the market, to increase the therapeutic efficacy and reduce toxicity. Isoniazid is the primary drug used in the treatment of tuberculosis.

Methods: The main objective of the study is to perform molecular docking studies and synthesize the derivatives of isonicotinamide along with the anti-tubercular activity. The isonicotinamide derivatives (a-j) are prepared using isoniazid, carbon disulphate, methyl cyanide, and benzaldehyde derivatives and characterized by TLC, IR, ¹HNMR, and Mass spectroscopy. The enzyme decaprenylphosphoryl-D-ribose oxidase (DprE1) of M. tuberculosis had good binding capacity with all the ligands revealed in molecular docking studies. In-vitro studies indicated that all the ligands showed anti-tuberculosis with strain M. tuberculosis.

Results: The analysis was based on the binding energy and minimum inhibitory concentration (MIC). The highest and lowest binding energy is -4.22 Kcal/mol (f) and -8.45 Kcal/mol (d), and the MIC for compound d was found to be 644.22 nM. Among all the ligands, compound 5d has the most cytotoxic effect and lower IC₅₀ values and better bioavailability.

Conclusion: This investigation helps in the development of better anti-tubercular therapy.