Design, Synthesis, ADME/Tox, and Molecular Modeling of Novel <i>Bis</i> ‐1,2,3‐triazoles‐Linked Quinoxalines as Significant Anticancer Agents

Abstract In order to target lung and breast cancer therapy, a novel series of quinoxaline‐substituted‐ bis ‐1,2,3‐triazoles 6a–6l was devised and synthesized by click reaction. All of the synthesized compounds' structures were thoroughly determined using IR, HRMS, and NMR ( 1 H/ 13 C) investigations. With IC 50 values of 11.20 ± 2.60, 3.12 ± 2.80, 10.37 ± 1.26, 4.10 ± 0.90, and 3.04 ± 3.13 µM, respectively, five compounds— 6b , 6e , 6f , 6j , and 6l —showed encouraging anticancer activity on the A549 cell line. These compounds were all more effective than doxorubicin (DXN), which had an IC 50 of 3.26 ± 0.87 µM. The representative compounds in this series, 6j and 6l , exhibited higher anticancer activity than other compounds and DXN control against the lung (H358) cell line with IC 50 of 5.71 ± 3.20 and 6.29 ± 0.80 µM. Studies into the physicochemical characteristics of novel compounds, such as 6e and 6j , found problems with Lipinski violations and bound GI absorption, despite their superior ADME/Tox characteristics, which can be used to design new anticancer medicines. In order to better understand the mechanism and binding modalities of these ligands 6c , 6e , and 6j in the EGFR‐binding pocket of lung cancer as an alternative target (PDB codes: 2ITO, 1X2R), molecular docking studies were additionally carried out. Through their distinct chemical characteristics, the expertise provided may eventually result in the creation of new, useful anticancer drugs to combat the increasing issue of drug resistance.