Title:Design, Synthesis, Molecular Modeling and Biological Evaluation of Novel Benzothiazole-Based 1,3,4-Thiadiazole Derivatives as Potential Anticancer Agents
Volume: 25
Issue: 20
Author(s): Beyza Ecem Oz Bedir, Emine Terzi, Tuba Ozdemir Sanci, Francesco Melfi*, Ecem Kaya Sezginer, Betul Kaya and Ulviye Acar Cevik
Affiliation:
- Department of Pharmacy, University “G.
d’Annunzio” Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy
Keywords:
Benzothiazole, apoptosis, 1, 3, 4-thiadiazole, caspase 3/7, cell cycle arrest, cell migration.
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.
