The current work focuses on the creation of novel derivatives of the quinazolinone ring system, with various substituted thiophene, thienopyrimidine, and thienopyridine scaffolds 3a,b-11. Employing the standard MTT assay, every target compound's in vitro antiproliferative efficacy was evaluated in comparison with doxorubicin against both normal WI-38 cells and various cancer cell lines. Derivatives 6, 8a, and 8b demonstrated the most potent activity, alongside their safety profiles against WI-38. The in vitro enzyme assay showed that the new analogues had a better ability to inhibit p38α MAPK kinase than SB 202190 (IC50s = 0.18 ± 0.02, 0.23 ± 0.05, 0.31 ± 0.04, and 0.27 ± 0.06 μM, respectively). Additionally, apoptosis tests conducted on MCF-7 cells revealed that 6, 8a, and 8b significantly increased the levels of Bax (by approximately 7.31, 13.8, and 8.86 fold) and caspase 3 (by approximately 3.55, 4.22, and 3.87 fold), respectively, in comparison to the untreated cells. They decreased the amount of Bcl-2 by ∼1.99, 3.69, and 2.66 fold, respectively. The most powerful counterpart, 8a, underwent additional investigation of the cell cycle and apoptosis. It caused necrotic and apoptotic effects in the late stages and stopped the MCF-7 cell cycle at the G2/M phase. Based on the molecular docking study, candidates 6, 8a, and 8b all fit well within p38α MAPK kinase, with energy scores of -10.88, -11.28, and -10.96 kcal mol-1, respectively. Based on the in silico computer examination of physico-chemical and ADMET properties, the latter analogues seem to be promising candidates for further development and optimization in research.
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