New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFRWT and EGFRT790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study

Heba E Hashem; Abd El-Galil E Amr; Eman S Nossier; Manal M Anwar; Eman M Azmy

doi:10.1021/acsomega.1c06836

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFR^WT and EGFR^T790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study

ACS Omega. 2022 Feb 18;7(8):7155-7171. doi: 10.1021/acsomega.1c06836. eCollection 2022 Mar 1.

Authors

Heba E Hashem¹, Abd El-Galil E Amr^{2

3}, Eman S Nossier⁴, Manal M Anwar⁵, Eman M Azmy¹

Affiliations

¹ Department of Chemistry, Faculty of Women, Ain Shams University, Heliopolis, Cairo 11757, Egypt.
² Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
³ Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt.
⁴ Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
⁵ Department of Therapeutic Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt.

Abstract

A new series of benzimidazole, 1,2,4-triazole, and 1,3,5-triazine derivatives were designed and synthesized using a microwave irradiation synthetic approach utilizing 2-phenylacetyl isothiocyanate (1) as a key starting material. All the new analogues were evaluated as anticancer agents against a panel of cancer cell lines utilizing doxorubicin as a standard drug. Most of the tested derivatives exhibited selective cytotoxic activity against MCF-7 and A-549 cancer cell lines. Furthermore, the new target compounds 5, 6, and 7 as the most potent antiproliferative agents have been assessed as in vitro EGFR^WT and EGFR^T790M inhibitors compared to the reference drugs erlotinib and AZD9291. They represented more potent suppression activity against the mutated EGFR^T790M than the wild-type EGFR^WT. Moreover, the compounds 5, 6, and 7 down-regulated the oncogenic parameter p53 ubiquitination. A docking simulation of compound 6b was carried out to correlate its molecular structure with its significant EGFR inhibition potency and its possible binding interactions within the active site of EGFR^WT and the mutant EGFR^T790M.