New 1,3-Diphenylquinoxaline-6-Carboxamide Derivatives As Promising Anticancer Agents: Design, Synthesis, Cytotoxic Assays, Molecular Modeling, and Binding Studies With Hsa/Dna Publisher



Dastyafteh N ; Sayahi MH ; Kermaninia S ; Khouzani MA ; Sepehri N ; Biglar M ; Emadi M ; Larijani B ; Mohammadikhanaposhti M ; Ghofrani S ; Mahdavic M
Source: Journal of Molecular Structure Published:2026

Abstract

The present study reports the design and synthesis of new 1,3-diphenylquinoxaline-6-carboxamide derivatives 5a-l as promising anticancer agents. Cytotoxicity of these compounds was evaluated against cancer cell lines MDA-MB-231, MCF-7, and HeLa and the obtained data were compared to Etoposid that is a known anti-cancer drug. The best compound against the latter cell lines was compound 5c. This compound acted better than Etoposide against all three cell lines MDA-MB-231, MCF-7, and HeLa. Therefore, additional in vitro and in silico studies were performed on compound 5c. Flow cytometry studies on compound 5c showed that this compound clearly induces apoptosis. In silico study in the binding site of Etoposide in DNA topoisomerase IIα showed that compound 5c interacts with this enzyme with a binding energy comparable to Etoposide. In vitro and in silico human serum albumin (HSA) and DNA binding profiles of compound 5c were explored by employing spectrofluorimetry and molecular docking studies. Obtained data demonstrated that compound 5c had acceptable profiles in terms of binding to HSA and DNA. Compound 5c was docked into the active pockets of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2), and the results showed that it interacts more strongly and favorably with EGFR. Based on predicted pharmacokinetic properties (ADME), compound 5c demonstrates acceptable characteristics and could be considered a potential drug candidate. © 2025 Elsevier B.V., All rights reserved.