Molecular Modelling Studies Synthesis and Biological Evaluation of some Novel Pyrazole Derivatives as Anti tubercular Agents

Abstract

Tuberculosis (TB) is an infectious airborne disease caused by different species of newlineMycobacterium tuberculosis (Mtb) and it is one of the greatest world s health hitches with gradually increase in the mortality and morbidity. Though effective chemotherapy has been place over 50 years, World Health Organisation has declared tuberculosis a global health emergency which is the leading cause of death. Worldwide, TB is one of the top 10 causes of death from a single infectious agent. Each year millions of people continue to fall sick with TB. In 2017, TB caused an estimated 1.3 million deaths among HIV-negative people and there were an additional 300 000 deaths from TB among HIV-positive people. Currently, resistance of Mycobacterium tuberculosis strains towards the main drugs isoniazide (INH) and rifampicin is of significant concern. Development of drug resistance has narrowed down the conventional anti-tuberculosis therapeutic regimen. There is an urgent need of new therapeutic agents which acting through different mechanism of action. Mycolic acids, with 60-90 carbons long chain and#945;-alkyl and#946;-hydroxyl fatty acids is the key constituents for the Mtb cell wall biosynthesis. Pathogenicity of Mtb is linked to its peculiar nature of cell envelope that possesses two fatty acid synthase (FAS) pathways, FAS-I and FAS-II involved in the synthesis of mycolic acid. newlineEnoyl-ACP reductase (InhA) participates in blocking the fatty acid biosynthesis pathway newlineFAS II. It utilises the NADH cofactor as a hydrogen bond donor to reduce the trans double bond conjugated to the carbonyl group of long chain fatty acid substrates for the purpose of synthesising mycolic acid and is an important factor for mycobacterium virulence. As there are limited numbers of inhibitors available for treating tuberculosis, there is a crucial requirement to develop medicinally useful enoyl acyl carrier protein reductase (InhA) inhibitors. So, it is a target of choice for the discovery of newer anti-tubercular agents. newline