New 1,2,3-Triazole and Dipyridothiazine Hybrids-Synthesis, Analysis, Cytotoxicity and Molecular Docking.

Epigenetic and stress-response pathways play central roles in cancer progression and represent attractive therapeutic targets. In this study, a series of dipyridothiazine-1,2,3-triazole hybrids bearing -fluorophenyl and -trifluoromethylphenyl substituents was synthesized via efficient dipolar cycloaddition reactions. Structural characterization was performed using H, C, and F NMR spectroscopy and high-resolution mass spectrometry. Anticancer activity was evaluated using WST-1 and MTT assays against human cancer cell lines SNB-19 (glioblastoma), C32 (amelanotic melanoma), A549 (lung carcinoma), and MDA-MB-231 and MCF-7 (breast cancer), as well as normal HFF-1 fibroblasts and HaCaT keratinocytes, with doxorubicin and cisplatin as reference drugs. The hybrids and containing a -trifluoromethylphenyl moiety showed the highest cytotoxicity and cancer cell selectivity. RT-qPCR analysis of , , , , and expression for the lead compound revealed modulation of chromatin organization, p53-dependent stress responses, apoptosis, and cell cycle regulation. Molecular docking studies with human histone deacetylase 6 (HDAC6) demonstrated favorable binding of and , supporting their role as potential epigenetic anticancer agents.