In Silico Design, Synthesis, and Biological Evaluation of Molecular Hybrid of 3,4-Dihydropyrimidin-2(1h)-Ones With Oxadiazole and Pyrrole as Anti-Tubercular Agent

Objectives: The objectives of the study are to address this; molecular hybrids merging 3,4-dihydropyrimidin-2(1H)-ones with oxadiazole and pyrrole cores were designed through structure-activity relationship strategies to target acid-fast bacteria and exploit their bactericidal potential through the inhibition of cell wall synthesis. Methods: Following in silico validation using molecular docking, ADMET, and drug-likeness profiles, a series of 16 new hybrids (OPM1-OPM16) were synthesized with four step of synthesis such as chlorination of pyrrole-5 carboxaldehyde, synthesis of 2-substitited 1,3,4 oxadiazole from acids, hydrazine and sodium pyruvate, molecular hybrid through Claisen–Schmidt condensation, and finally, 3,4-dihydropyrimidin-2(1H)-ones with pyrrole and oxadiazole through urea condensation steps. In Vitro Antimycobacterial activity of All NCE’s were been performed through Microplate Alamar Blue Assay(MABA) against the mycobacterial strain Mtb H37Rv. Results: The derivatives OPM2 and OPM9 emerged as the most potent leads, both displaying a minimum inhibitory concentration of 0.8 μg/mL. This efficacy matches the first-line reference drug isoniazid and significantly outperforms pyrazinamide. In safety profiles evaluated on mouse fibroblast cell lines, the potent OPM2 molecule demonstrated no toxic effects, exhibiting an outstanding selectivity index of 212.5. Computational molecular docking with the active site of the methoxy mycolic acid synthase 4 (Protein Data Bank: 3HA7) receptor revealed that the exceptional docking score of OPM2 −10.9kcal/mol is anchored by key hydrogen-bonding interactions with GLN 36 and GLN 108 residues. Furthermore, in vivo pharmacokinetic evaluations confirmed that OPM2 possesses highly favorable drug-like absorption, distribution, and metabolic stability. Conclusion: OPM2 molecules have excellent intestinal absorption and more than 60% bioavailability. The OP2 is showing longer half-life that reduces dosage frequency and ignorance of drug administration.