Unlocking the Potential of Pyrazines: Structure–Activity Relationship Driven Studies against Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is one of the diseases that has affected a wide population in the world, and due to the constant
development of resistance, it has necessitated the development of potent drugs that can show anti-tubercular
activity on the resistant strains as well. Among nitrogen-containing heterocycles, pyrazine has attracted significant
attention in medicinal chemistry due to its chemical simplicity and adaptability in drug design. The current review
provides the summary of pharmacological aspects of pyrazine derivatives as an anti-tubercular agent, focusing
on examining the structure–activity relationship (SAR) trends, minimum inhibitory concentration (MIC) values
as well as the key modifications, such as integrating the electron-withdrawing groups, heterocyclic linkers, and
lipophilic side chains, that have led to the discovery of potent anti-tubercular drugs. The SAR studies suggest that
the addition of electron-withdrawing groups and heterocyclic linkers has resulted in compounds with improved
efficacy compared to the pyrazinamide. The evidence also provides significant insights into the therapeutic
potential of pyrazine derivatives as scaffolds for next-generation anti-TB drugs.