Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors

• Published in: European journal of medicinal chemistry Vol. 156; pp. 774 - 789
• Main Authors: El-Sherief, Hany A.M., Youssif, Bahaa G.M., Abbas Bukhari, Syed Nasir, Abdelazeem, Ahmed H., Abdel-Aziz, Mohamed, Abdel-Rahman, Hamdy M.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-08-2018
• Subjects: 1,2,4-Triazoles; Antiproliferative; Apoptosis and EGFR inhibitors; Cell cycle; Thiazolo[3,2-b][1,2,4]-triazoles; Antiproliferative; Apoptosis and EGFR inhibitors; Thiazolo[3,2-b][1,2,4]-triazoles; 1,2,4-Triazoles; Cell cycle
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.07.024

A series of novel compounds carrying 1,2,4-triazole scaffold were prepared and evaluated for their antiproliferative activities against NCI 60 cell line. Compounds 10 (a, c), 11 (a-d), and 14 (a-e) were selected for evaluation at single concentration of 10 μM towards panel of sixty cancer cell lines. Some of nitric oxide (NO) donating triazole/oxime hybrids 11a-d showed antiproliferative activity better than their corresponding ketones. On the other hand, the thiazolo [3,2-b][1,2,4]-triazoles 14a-e showed remarkable antiproliferative activities against the same cell lines. Compound 14d was selected for five dose testing against the full panel of 60 human tumor cell lines. Compound 14d showed high selectivity against renal subpanel with selectivity ratio of 6.99 at GI50 level. Compounds 11a-d, 10a-d and 14a-e were tested against four cell lines using MTT assay then compounds of the least IC50 were evaluated against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compound 14d showed promising EGFR inhibitory activity of cancer cell proliferation and were also observed to be moderate BRAF and tubulin inhibitors. Moreover, cell cycle analysis and apoptosis assay were finished for compounds 14d and 14f. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes.
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•A series of novel compounds 10a-d, 11a-d and thiazolo[3,2-b][1,2,4]-triazoles 14a-f was designed and synthesized.•Compounds 10a, c, 11a-d, and 14a-e were selected by NCI for anticancer evaluation with 14d for in vitro five dose assay.•Compounds 10a, 11a, 14d and 14f showed potential activities in MTT assay.•Compounds 14d and 14f were selected for cell cycle analysis, apoptosis assay, EGFR, BRAF and tubulin inhibition activity.•Molecular modeling for compounds 14d and 14f were performed in the 3D crystal structures of EGFR (PDB ID:1M17).