Discovery of potent DprE1-targeted antitubercular agents: synthesis and evaluation of PBTZ169/TBA7371-based derivatives.

Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) has emerged as one of the most promising and validated drug targets for tuberculosis (TB), owing to its essential role in the biosynthesis of arabinogalactan, a crucial component of the Mycobacterium tuberculosis (Mtb) cell wall. In the present study, a series of sixteen novel derivatives (9a-9p) were synthesized based on the structural scaffolds of the clinical trial drugs PBTZ169 and TBA7371. The synthesized compounds were characterized by NMR and LC-MS techniques. All compounds were evaluated for their antitubercular activity against the Mtb HRv strain. Among them, five compounds exhibited minimum inhibitory concentrations (MICs) below 25 µg/mL, with compound 9m showing the most potent activity (MIC = 3.125 µg/mL). Molecular docking studies revealed that compound 9m  interacts with key catalytic residues His132 and Asn385 within the DprE1 binding site, and similar conformation was found upon superimposition with the standard ligand (36C). ADMET analysis demonstrated favorable pharmacokinetic and safety profiles for all synthesized derivatives. Furthermore, molecular dynamics (MD) simulations confirmed the high stability of the 9m -DprE1 complex compared to the standard reference compound. These findings suggest that compound 9m  could lead to the development of novel antitubercular agents.