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

Abstract

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 <i>p</i>-fluorophenyl and <i>p</i>-trifluoromethylphenyl substituents was synthesized via efficient dipolar cycloaddition reactions. Structural characterization was performed using ¹H, ¹³C, and ¹⁹F 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 <b>TDT2b</b> and <b>TDT3b</b> containing a <i>p</i>-trifluoromethylphenyl moiety showed the highest cytotoxicity and cancer cell selectivity. RT-qPCR analysis of <i>H3</i>, <i>TP53</i>, <i>CDKN1A</i>, <i>BCL-2</i>, and <i>BAX</i> expression for the lead compound <b>TDT2b</b> 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 <b>TDT2b</b> and <b>TDT3b</b>, supporting their role as potential epigenetic anticancer agents.