In‐Silico Studies, Synthesis and Biological Assessment of Pyrrole Substituted Triazolo—Quinazoline Carbothioamide Derivatives as p38 MAP Kinase Inhibitors

ABSTRACT The p38 MAP kinase pathway is crucial for the control of cell proliferation, apoptosis, differentiation, and stress response; its dysregulation is closely associated with tumor growth and resistance to treatment. Consequently, inhibiting this kinase constitutes a possible therapeutic approach in cancer treatment. A series of 11 trisubstituted 5‐oxo‐4‐(3H‐pyrrole‐3‐carbonyl)‐N‐phenyl‐4,5‐dihydro[1,2,3]triazolo[1,5‐a]quinazoline‐3‐carbothioamides (8a–k) was synthesized and assessed for potential p38 MAP kinase inhibition and anticancer efficacy. Various spectroscopic techniques, particularly 1 H NMR, 1 3 C NMR, and mass spectrometry, were employed to establish and confirm their structures. Molecular docking analyses were conducted on the p38 MAP kinase (PDB ID: 1W7H). Compound 8 h exhibited the highest docking score of −7.9 kcal/mol. The synthesized compounds were evaluated for cytotoxicity against MCF‐7 breast cancer cell lines, with compound 8 h demonstrating the highest potency, with the IC 50 value of 29.52 ± 0.19 µM. Biochemical evaluation revealed that compound 8 h demonstrated significant inhibitory activity against p38 MAP kinase (IC 50 = 392.83 ± 0.19 nM). The findings indicate that compound 8 h may serve as the primary contender for the development of selective p38 MAP kinase inhibitors.