Molecular hybrids based on 1,2,3-triazole and 1,3,4-thiadiazole cores: Synthesis, characterization, anticancer activity and in silico study
•A novel series of 1,2,3-triazole based 1,3,4-thiadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activity.•Anti-proliferative activity was assessed against HT-1080, A-549, MCF-7 and MDA-MB-231 cells lines.•Hybrid compound 14a showed important inhibitory activity aga...
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Veröffentlicht in: | Journal of molecular structure 2024-09, Vol.1311, p.138339, Article 138339 |
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Sprache: | eng |
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Zusammenfassung: | •A novel series of 1,2,3-triazole based 1,3,4-thiadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activity.•Anti-proliferative activity was assessed against HT-1080, A-549, MCF-7 and MDA-MB-231 cells lines.•Hybrid compound 14a showed important inhibitory activity against MCF-7 and MDA-MB-231 cells lines.•Binding modes of all compounds were identified via molecular docking.•Compounds had higher affinity for Bcl-XL as compared to other compounds.
One sets of 1,3,4-thiadiazole analogs 14a-c and 15a-c were synthesized by the incorporation of two heterocyclic nuclei (1,2,3-triazole & 1,3,4-thiadiazoles) in objective of developing multifunctional molecules for anticancer disease. (R)-Carvone was used as precursors for the synthesis of new heterocycles. The 1,2,3-triazole-1,3,4-thiadiazoles 14a-c and 15a-c were synthesized in good yields from the precursors using simple procedures. The chemical structures of all the newly synthesized hybrids were established using (1H and 13C) NMR and HRMS analysis. The in vitro assessment of the activity of the resultant 1,2,3-triazole-1,3,4-thiadiazoles against human cancer cells, namely fibrosarcoma (HT-1080), lung carcinoma (A-549) and breast carcinoma (MCF-7 and MDA-MB-231) was performed using viability testing (MTT). Compound 14a was the most active heterocycle, and its cytotoxic activity was three times less actives comparable to that obtained for Doxorubicin (6 µM) as a reference. The 1,3,4-thiadiazoles 15a-c showed moderate cytotoxic activities with IC50 values ranging from 25.56 ± 1.13 to 61.81 ± 2.21 μM. Molecular docking studies were conducted against two antiapoptotic proteins namely Bcl-2, and Bcl-XL to elucidate the potential mechanisms of action. The results indicate that compounds interact favorably (binding energy = −7.6 to −9.8 kcal/mol) with the target proteins through hydrophobic, electrostatic interactions, and hydrogen bonding. The negative binding energy indicate the spontaneous nature of the interaction. Further, molecular dynamics simulation parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, and solvent accessible surface area provided insights into the stability and dynamics of the protein-ligand complexes.
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ISSN: | 0022-2860 1872-8014 |
DOI: | 10.1016/j.molstruc.2024.138339 |