Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel Benzothiazole-Based 1,3,4-Thiadiazole Derivatives as Potential Anticancer Agents

Beyza Ecem Öz Bedir; Emine Terzi; Tuba Ozdemir Sanci; Francesco Melfi; Ecem Kaya-Sezginer; Betül Kaya; Ulviye Acar Çevik

doi:10.2174/0118715206353584241018051852

Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel Benzothiazole-Based 1,3,4-Thiadiazole Derivatives as Potential Anticancer Agents

Anticancer Agents Med Chem. 2025 Apr 15. doi: 10.2174/0118715206353584241018051852. Online ahead of print.

Authors

Beyza Ecem Öz Bedir^{1

2}, Emine Terzi^{1

2}, Tuba Ozdemir Sanci^{2

3}, Francesco Melfi⁴, Ecem Kaya-Sezginer⁵, Betül Kaya⁶, Ulviye Acar Çevik⁷

Affiliations

¹ Department of Medical Biology, Faculty of Medicine, Ankara Yildirim Beyazit University, 06800, Ankara, Türkiye.
² Ankara Yildirim Beyazit University Yenimahalle Training and Research Hospital, 06370, Ankara, Türkiye.
³ Department of Histology and Embryology, Faculty of Medicine, Ankara Yildirim Beyazit University, 06800, Ankara, Türkiye.
⁴ Department of Pharmacy, University "G. d'Annunzio" Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy.
⁵ Ankara University, Faculty of Pharmacy, Department of Biochemistry, 06560, Ankara, Türkiye.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Zonguldak Bulent Ecevit University, 67600, Zonguldak, Türkiye.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Türkiye.

PMID: 40237048
DOI: 10.2174/0118715206353584241018051852

Abstract

Objective: The present study aimed to design and synthesize a new series of benzothiazole analogues containing 1,3,4-thiadiazole, and assess their biological activities as potential anticancer agents.

Methods: N-(5,6-dimethylbenzo[d]thiazol-2-yl)-2-((5-(substituted amino)-1,3,4-thiadiazol-2-yl)thio)acetamide derivatives (4a-4h) were synthesized via the reaction of thiadiazole derivatives (3a-3h) with 2-chloro-N-(5,6- dimethylbenzo[d]thiazol-2-yl)acetamide (1) in the presence of potassium carbonate. All the target compounds have been characterized by spectral analysis. The anticancer activities of compounds 4a-4h were tested against two human HT-1376 bladder and HT-29 colorectal carcinoma cells using the WST-1 assay. Flow cytometry was used for the determination of apoptosis, cell cycle, and caspase 3/7 activity. Moreover, wound-healing assay was utilized to evaluate cell migration. In silico physicochemical, pharmacokinetics, and toxicological properties of compound 4g were determined by pkCSM, SwissADME, and SwissTargetPrediction online web tools.

Results: Among all synthesized derivatives, compound 4g (N-(5,6-dimethylbenzo[d]thiazol-2-yl)-2-((5-((3- methoxyphenyl)amino)-1,3,4-thiadiazol-2-yl)thio)acetamide) recorded the highest antiproliferative activity against HT-1376 cells with an IC50 as 26.51 μM at 24 h, which was less cytotoxic than cisplatin (IC50=14.85 μM). The combined treatment with compound 4g and cisplatin increased the cellular apoptosis with a higher impact compared with the cisplatin group. The higher accumulation of cells in the G2 phase, a significant increase of caspase 3/7 activity, and the inhibition of migration rate were also observed in HT-1376 following a combination of compound 4g and cisplatin treatment versus cisplatin alone, which might be involved in the apoptotic effects of compound 4g.

Conclusion: The in vitro anticancer potential of compound 4g lays the foundation for future research to focus on its value as a novel and advanced cancer therapy.

Keywords: 1; 3; 4-thiadiazole; Benzothiazole; apoptosis; caspase 3/7; cell cycle arrest; cell migration..