Synthesis, Molecular Docking Screening and Anti-Proliferative Potency Evaluation of Some New Imidazo[2,1-b]Thiazole Linked Thiadiazole Conjugates.

Huda R M Rashdan,Abdel Mohsen M Soliman,Ihsan A Shehadi,Aboubakr H Abdelmonsef,Huda K Mahmoud,Sobhi M Gomha

doi:10.3390/molecules25214997

Abstract

Background: Imidazo[2,1-b]thiazole scaffolds were reported to possess various pharmaceutical activities. Results: The novel compound named methyl-2-(1-(3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethylidene)hydrazine-1-carbodithioate 3 acted as a predecessor molecule for the synthesis of new thiadiazole derivatives incorporating imidazo[2,1-b]thiazole moiety. The reaction of 3 with the appropriate hydrazonoyl halide derivatives 4a–j and 7–9 had produced the respective 1,3,4-thiadiazole derivatives 6a–j and 10–12. The chemical composition of all the newly synthesized derivatives were confirmed by their microanalytical and spectral data (FT-IR, mass spectrometry, 1H-NMR and 13C-NMR). All the produced novel compounds were screened for their anti-proliferative efficacy on hepatic cancer cell lines (HepG2). In addition, a computational molecular docking study was carried out to determine the ability of the synthesized thiadiazole molecules to interact with active site of the target Glypican-3 protein (GPC-3). Moreover, the physiochemical properties of the synthesized compounds were derived to determine the viability of the compounds as drug candidates for hepatic cancer. Conclusion: All the tested compounds had exhibited good anti-proliferative efficacy against hepatic cancer cell lines. In addition, the molecular docking results showed strong binding interactions of the synthesized compounds with the target GPC-3 protein with lower energy scores. Thus, such novel compounds may act as promising candidates as drugs against hepatocellular carcinoma.

Highlights

Exploring new leads for the identification of novel structures might be useful in designing less toxic selective and potent new anticancer agents and remains a major challenge for medicinal chemists.Imidazo[2,1-b]thiazole scaffolds have drawn a significant interest recently due to their wide spectrum of pharmaceutical activities, especially antitumor activities [1,2]
Compound 3 was used as a key precursor for the synthesis of new thiadiazole derivatives incorporating imidazo[2,1-b]thiazole in good yields
The synthetic thiadiazole compounds had shown good binding affinities compared to the standard drug and interacted significantly with the binding site region of the target Glypican-3 protein (GPC-3), through non-covalent interactions

Summary

Introduction

Exploring new leads for the identification of novel structures might be useful in designing less toxic selective and potent new anticancer agents and remains a major challenge for medicinal chemists.Imidazo[2,1-b]thiazole scaffolds have drawn a significant interest recently due to their wide spectrum of pharmaceutical activities, especially antitumor activities [1,2]. Imidazo[2,1-b]thiazole-guanylhydrazone derivative revealed potent anti-proliferative activities against a number of cancer cell lines and is considered as a promising lead for such therapeutic applications [3]. These fused heterocyclic compounds had shown anticancer activities via different molecular mechanisms as bytubulin polymerization and inhibiting p90 ribosomal S6 kinase 2 (RSK2) [4,5,6,7,8]. A computational molecular docking study was carried out to determine the ability of the synthesized thiadiazole molecules to interact with active site of the target Glypican-3 protein (GPC-3). The molecular docking results showed strong binding interactions of the synthesized compounds with the target

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Results

Conclusion