Exploring the Antimycobacterial Potential of Purine‐Piperazine Hybrids via in Vitro and in Silico Approaches

ABSTRACT Novel purine‐based piperazine analogs were rationally designed and synthesized using fluoro‐substituted benzoyl chloride as a key intermediate. The synthesized compounds were characterized and evaluated for their potential anti‐tubercular activity. In vitro biological screening revealed that compounds S1C , S1D , and S1F exhibited significant antimycobacterial activity, with MIC values ranging from 8.5 to 18.8 µg/mL. To gain molecular insights into their mechanism of action, molecular docking studies were performed against UDP‐N‐acetylenolpyruvoylglucosamine reductase (MurB) from Mycobacterium tuberculosis. The docking results demonstrated favorable binding affinities, characterised by key hydrogen bonding and hydrophobic interactions at the active site. Additionally, 100 ns molecular dynamics simulations were conducted to assess the stability of the protein–ligand complexes. ADME profiles were predicted using the PreADME server, suggesting acceptable pharmacokinetic and pharmacodynamic properties. Overall, the biological evaluation, computational modeling, and favorable ADME profiles indicate that compounds S1C , S1D , and S1F are potential candidates for anti‐tubercular drug development.