New Tetrazole-1,3,4-Oxadiazole and 1,2,4-Triazole-based Benzothiazole Hybrids: Synthesis, Anticancer Activity, and Computational Investigations

Abstract

Abstract Cancer is the most complex disease and safety of current drugs represents serious challenge to develop safer medications. Novel hybrids of sugar–benzothiazole–tetrazole–hydrazones, their derived 1,3,4-oxadiazoles and the 1,2,4-triazole glycoside were synthesized to study their anticancer potential with mechanistic investigations. The new hybrids were synthesized via a multistep strategy and glycosylation. Their potential on human pancreatic cancer (paca 2), human melanoma (Mel501), prostate cancer (PC3), melanoma (A-375), and colon carcinoma (caco2) cells was investigated. The safety and specificity of the compounds on normal cells were examined. The possible mechanism on different apoptotic proteins, molecular docking and MD simulations were studied. Compound 15 possessed promising anticancer impact on melanoma and paca2 cells (IC50:15 ± 1.7 and 45 ± 3.1 uM, respectively). The results demonstrated the safe mode of compounds on normal cell. The effect on P53 level in Mel501 cell, caspase-3 and caspase–7 levels, DNA fragmentation, cell cycle analysis, and apoptosis was studied. Compound 15 induced such targets thus increasing the DNA fragmentation%, which signals apoptosis of melanoma cells by causing cell cycle arrest. Molecular docking revealed favorable interactions and fitting into epidermal growth factor (EGFR) and caspase-3 targets. MD simulation indicated the binding stability of compound 15 within EGFR and caspase-3 structures. Promising anticancer impact on the Mel501 cell line. Cell cycle arrest and induced apoptosis in melanoma cells, Mel501. Increase the level of P53 in Mel501 cell and induce the production of caspase-7. Molecular Docking simulation study in caspase-3. Graphical AbstractComplex chemical structure labeled 15 with multiple rings and functional groups interconnected.The image illustrates a intricate chemical structure labeled 15. It features a blue hexagonal ring containing H3CO and sulfur, connecting to a carbonyl group (C=O). Adjacent is a red tetrazole ring encircled by a blue dashed line, linked to a magenta N-ring with SH, outlined in orange. Below, a brown cyclic structure resembling glucopyranose with hydroxyl groups (–OH) is shown in a dashed blue rectangle. The arrangement emphasizes the connectivity and relationships among the molecular components.