Thiazole-Based Thiosemicarbazones: Synthesis, Cytotoxicity Evaluation and Molecular Docking Study

Abstract

Introduction

Hybrid drug design has developed as a prime method for the development of novel anticancer therapies that can theoretically solve much of the pharmacokinetic disadvantages of traditional anticancer drugs. Thus a number of studies have indicated that thiazole-thiophene hybrids and their bis derivatives have important anticancer activity. Mammalian Rab7b protein is a member of the Rab GTPase protein family that controls the trafficking from endosomes to the TGN. Alteration in the Rab7b expression is implicated in differentiation of malignant cells, causing cancer.

Methods

1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethylidene) hydrazinyl) thiazol-5-yl) ethanone was used as building block for synthesis of novel series of 5-(1-(2-(thiazol-2-yl) hydrazono) ethyl) thiazole derivatives. The bioactivities of the synthesized compounds were evaluated with respect to their antitumor activities against MCF-7 tumor cells using MTT assay. Computer-aided docking protocol was performed to study the possible molecular interactions between the newly synthetic thiazole compounds and the active binding site of the target protein Rab7b. Moreover, the in silico prediction of adsorption, distribution, metabolism, excretion (ADME) and toxicity (T) properties of synthesized compounds were carried out using admetSAR tool.

Results

The results obtained showed that derivatives 9 and 11b have promising activity (IC₅₀ = 14.6 ± 0.8 and 28.3 ± 1.5 µM, respectively) compared to Cisplatin (IC₅₀ = 13.6 ± 0.9 µM). The molecular docking analysis reveals that the synthesized compounds are predicted to be fit into the binding site of the target Rab7b. In summary, the synthetic thiazole compounds 1–17 could be used as potent inhibitors as anticancer drugs.

Conclusion

Promising anticancer activity of compounds 9 and 11 compared with cisplatin reference drug suggests that these ligands may contribute as lead compounds in search of new anticancer agents to combat chemo-resistance.

Keywords:

• thiazoles
• hydrazones
• hydrazonoyl halides
• docking
• Rab7b
• MCF-7

Acknowledgments

The financial support by the Deanship of Scientific Research (Project Number 86), Islamic University, Saudi Arabia is gratefully acknowledged.

Author Contributions

All the authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or all in these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest for this work and declare that there is no conflict of interests regarding the publication of this paper.