New Benzimidazole-Triazole Derivatives as Topoisomerase I Inhibitors: Design, Synthesis, Anticancer Screening, and Molecular Modeling Studies.

In this study, we designed, synthesized, and evaluated a series of 1,2,4-triazole benzimidazoles for their cytotoxic effects against the A549, C6, and NIH3T3 cell lines. Additionally, these compounds were assessed for their inhibitory activity against DNA topoisomerase I, aiming to develop novel anticancer agents. The synthesized final compounds - were characterized using H NMR, C NMR, and HRMS. Among them, compounds and emerged as the most potent agents against the A549 cell line, exhibiting an IC value of 7.34 ± 0.21 μM and 4.56 ± 0.18 μM, respectively. These results were compared to standard drugs, doxorubicin (IC = 12.420 ± 0.5 μM) and Hoechst 33342 (IC = 0.422 ± 0.02 μM). Notably, all tested compounds displayed higher cytotoxicity toward A549 cells than C6 cells. Compounds and demonstrated significant inhibitory activity against topoisomerase I, highlighting their potential as lead compounds in anticancer therapy. Subsequent in silico molecular docking studies were conducted to elucidate the potential binding interactions of compounds and with the target enzyme topoisomerase I. Molecular dynamics studies also assessed and validated the binding affinity and stability. These studies confirmed the promising binding affinity of these compounds, reinforcing their status as lead candidates. According to DFT, compound having the lower energy gap value (Δ = 3.598 eV) is more chemically reactive than the others, which is consistent with significant inhibitory activity against topoisomerase I. Furthermore, in silico ADME profiles for compounds and were evaluated using SwissADME, providing insights into their pharmacokinetic properties.