PROCESS DEVELOPMENT FOR SYNTHESIS OF HETEROCYCLIC HYDRAZIDE COMPOUND USING AMIDASE

Abstract

Biocatalysis and biotransformation continue to attract considerable attention due to their competitive ‘natural’ advantages. Still, despite their high promise, however, industrialization of bio-catalytic processes so far has only been realized for a few large-scale operations. Therefore, in this thesis, the synthesis of a heterocyclic hydrazide compound in a solvent-free reaction condition was developed using the acyltransferase activity of amidase of Bacillus smithii strain IITR6b2. Tuberculosis is an infectious disease. The challenges in tuberculosis have become even more complicated with drug-resistant bacteria. The production of pyrazine-2-carboxylic acid hydrazide can be considered an invaluable heterocyclic hydrazide compound for developing drugs against multi-drug resistant tubercular bacteria. The thesis focuses on developing pyrazine- 2-carboxylic acid hydrazide employing pyrazinamide and hydrazine dihydrochloride as substrate and co-substrate in an aqueous medium. The pyrazine-2-carboxylic acid hydrazide or pyrazinamide derivative’s synthesis has been going on for more than 20 years to study the anti-tuberculosis activity against Mycobacterium tuberculosis, where the synthesis method involves a chemical transformation in the presence of solvents starting with esterification of pyrazine-2-carboxylic acid or reacting the methyl/ethyl pyrazine carboxylate with hydrazine hydrate. However, there has been no report of enzymatic production of the acid hydrazide that involves biotransformation in an aqueous environment. This is the first study on the bioprocess development for pyrazine-2-carboxylic acid hydrazide synthesis, an intermediate compound, while producing several pharmaceutical and heterocyclic compounds, polymers, and many more. This acid hydrazide compound contains hydrazine moiety as a backbone, an established antimicrobial agent. The whole-cell amidase of Bacillus smithii IITR 6b2 can transfer the acyl group of the amide to hydrazine in an aqueous system. This study involves a greener approach with no hazardous chemicals and one-step biotransformation to produce the pyrazine-2-carboxylic acid hydrazide (through hydrazinolysis).