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

## TL;DR

Researchers synthesized new hybrid compounds that show strong anticancer activity and may act as epigenetic drugs by targeting histone deacetylase.

## Contribution

A novel series of dipyridothiazine–1,2,3-triazole hybrids with potent cytotoxicity and cancer cell selectivity was developed and evaluated.

## Key findings

- TDT2b and TDT3b showed highest cytotoxicity and selectivity against cancer cells.
- TDT2b modulated key genes related to apoptosis and cell cycle regulation.
- Molecular docking suggested favorable binding to HDAC6, supporting its epigenetic role.

## 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 p-fluorophenyl and p-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 TDT2b and TDT3b containing a p-trifluoromethylphenyl moiety showed the highest cytotoxicity and cancer cell selectivity. RT-qPCR analysis of H3, TP53, CDKN1A, BCL-2, and BAX expression for the lead compound TDT2b 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 TDT2b and TDT3b, supporting their role as potential epigenetic anticancer agents.