Design & Synthesis of Pyrazinamide Hybrid Conjugates as Potential Anti-tubercular Agents

Abstract

Tuberculosis (TB) is a bacterial pathogen caused by Mycobacterium tuberculosis, which generally causes pulmonary infection and is extremely pervasive within the lungs and between subjects. Pyrazinamide (PZA) is a first-line prodrug used synergistically with two or more chemotherapies to eradicate TB. PZA is hydrolyzed to its active constituent, pyrazinoic acid, intracellularly in M. tuberculosis via pyrazinamidase. With prolonged administration of the recommended dose, harmful side effects have been reported: hepatitis, acute hypertension, thrombocytopenia, and gastrointestinal discomfort Drug-amino acid conjugates are used because of increased tissue delivery, in which the amino acids act as effective carriers of these agents while maintaining, and even amplifying, their bioactive integrity. Amino acid conjugates can increase bioavailability and quantitatively decrease the required amount of active drug thus preventing toxic side effects. We have synthesized several pyrazinamide conjugates with secondary amines via amino acid linkers with retention of chiral integrity of the desired products. Secondary amines are known for enhancing biological properties of various potential molecules. All the synthesized compounds were characterized by NMR and X-ray studies. The synthesized conjugates are expected to have better anti-tubercular properties with less side effects.