Recent Cutting-Edge Designing Strategies for Mtb-DHFR Inhibitors as Antitubercular Agents

Tuberculosis (TB) is an obstinate and infectious disease requiring a relatively longer treatment duration than other bacterial infections. The current treatment regime is prolonged and cumbersome, with adverse effects, often leading to nonadherence. The upsurge in TB's multidrug-resistant and extensively drug-resistant strains with evolved resistance to existing drugs has compounded the problems. The last two decades witnessed unprecedented progress in developing TB drugs with better efficacy and reduced toxicity. Of late, inhibitors targeting the dihydrofolate reductase (DHFR) enzyme were being explored and developed as antitubercular drugs. A plethora of diverse molecular cores, such as pteridines, diamino heterocycles, diamino triazoles, and nontraditional cores, were developed recently as Mtb-DHFR targets. Besides the characteristic binding pockets of Mtb-DHFR, an extended hydrophilic binding pocket was also studied for intermolecular interactions with the designed compounds to assess the enzyme specificity. In this study, prominent DHFR inhibitors developed in the last two decades were reported. Key features of the designed compounds, such as the structural similarities with existing pharmacophores, interactions with binding pockets, enzyme selectivity and specificity, and percentage of inhibition, were evaluated. The authors hope the study will help streamline the pharmacological pipeline of Mtb-DHFR inhibitors and bring the investigators one step closer to success.