Design, synthesis, molecular docking, and biological evaluation of coumarin‐thymidine analogs as potent anti‐TB agents

Abstract With the intent to discover new antituberculosis (TB) compounds, coumarin‐thymidine analogs were synthesized using second‐order nucleophilic substitution reactions of bromomethyl coumarin with thymidine. The newly synthesized coumarin‐thymidine conjugates ( 1a–l ) were characterized using IR, NMR, GC‐MS, and CHN elemental analysis. The novel conjugates were found to exhibit potent anti‐TB activity against the Mycobacterium tuberculosis H 37 Rv strain, with minimum inhibitory concentrations (MIC) of the active compounds ranging between 0.012 and 0.482 µM. Compound 1k was established as the most active candidate with a MIC of 0.012 µM. The toxicity study on HEK cells confirmed the nontoxic nature of compounds 1e , 1h , 1i , 1j , and 1k . Also, the most active compounds ( 1k , 1j , and 1e ) were stable in the pH range from 2.5 to 10, indicating compatibility with the biophysical environment. Based on the p K a studies, compounds 1k , 1j , and 1e are capable of crossing lipid‐membrane barriers and acting on target cells. Molecular docking studies on the M. tuberculosis β‐oxidation trifunctional enzyme (PDB ID: 7O4V) were conducted to investigate the mechanisms of anti‐TB activity. All compounds showed excellent hydrogen binding interactions and exceptional docking scores against M. tuberculosis , which was in accordance with the results. Compounds 1a–l possessed excellent affinity to proteins, with binding energies ranging from −7.4 to −8.7 kcal/mol.