Development of Potent Type V MAPK Inhibitors: Design, Synthesis, and Biological Evaluation of Benzothiazole Derivatives Targeting p38α MAPK in Breast Cancer Cells.

Type V MAPK inhibitors are distinguished by their capacity to target both the ATP binding site and a specific allosteric site on the enzyme. The present work utilized in silico analysis with Maestro 13.8.135 (Schrodinger) software in conjunction with experimental investigations to enhance the antiproliferative efficacy and forecast the likely mechanism of action of benzothiazole derivatives. Approximately 28 compounds were developed, produced, and assessed for their antiproliferative properties against two breast cancer cell lines: ER+ (MCF7) and ER- (MDA-MB-231), in addition to one normal mouse fibroblast cell line (L929). Their antiproliferative activities were evaluated via the MTT test, with doxorubicin and cisplatin serving as reference drugs for comparison. Consequently, the compounds with the greatest activity against the MCF7 cell line were chosen, and their inhibitory effects on the p38α MAPK enzyme were examined. The molecular docking studies of compounds 15 and 19 demonstrated significant binding affinities for p38α MAPK. Molecular dynamics simulations conducted over 100 ns revealed that compounds 15 and 19 exhibit stability inside both the ATP-binding domain and the lipid domain of p38α MAPK. The research focused on creating effective Type V MAPK inhibitors demonstrate that compounds 15 and 19 possess considerable ability to inhibit p38α MAPK, hence establishing them as promising anticancer agents.