Synthesis and Biological Investigation of Novel Heterocyclic Acetamide Derivatives as Potential Antitubercular agents Targeting Dpre1

Abstract

Tuberculosis (TB) remains a major global health concern due to the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. The urgent need for new therapeutic agents with novel mechanisms of action has directed attention toward validated molecular targets involved in mycobacterial cell wall biosynthesis. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1) is an essential enzyme in the synthesis of arabinogalactan, a critical component of the mycobacterial cell wall, and has emerged as a promising target for antitubercular drug development.

In the present study, a series of novel heterocyclic acetamide derivatives were rationally designed, synthesized, and evaluated for their in-vitro antitubercular activity targeting the DprE1 enzyme. Structure-based drug design and molecular docking studies were performed to predict binding interactions and affinity within the active site of DprE1. The designed compounds were synthesized through a multi-step synthetic approach involving heterocyclic amine formation followed by acetamide coupling. Structural confirmation was achieved using physicochemical and spectroscopic techniques including melting point determination, FTIR, ¹H-NMR, ¹³C-NMR, and mass spectrometry. 

The synthesized derivatives were screened against M. tuberculosis H37Rv strain using the Microplate Alamar Blue Assay (MABA). Several compounds exhibited significant inhibitory activity with minimum inhibitory concentration (MIC) values ranging from 0.78 to 6.25 µg/mL. Among them, compound 5d demonstrated the most potent activity and favorable selectivity index, correlating well with its superior docking score and predicted ADMET properties.

The findings suggest that heterocyclic acetamide scaffolds represent promising lead candidates for further optimization and development as novel antitubercular agents targeting DprE1.