Synthesis, molecular docking, and <i>In-vitro</i> cytotoxic evaluation of Thiadiazolo-acridines analogues as anti-cancer agents

Recent studies on thiadiazolo-acridine derivatives have demonstrated their notable biological activity, particularly in the field of cancer drug discovery. This study investigates the development of N-(5-((acridin-9-yl amino)methyl)-1,3,4-thiadiazol-2-yl)-substituted benzamide derivatives as potential anticancer agents targeting topoisomerase I. Molecular docking studies revealed moderate to significant interactions, with compound 27 achieving a docking score of -8.6 kcal/mol, outperforming the standard drug doxorubicin. <i>In vitro</i> cytotoxicity assays showed that most derivatives were relatively non-toxic at 100 µg/mL, with compound 26 demonstrating notable inhibition (IC50: 39.42 and 42.31 μg/mL) and compound 27 displaying the strongest activity (IC50: 29.72 and 31.31μg/mL). A 100 ns Molecular dynamics simulation further confirmed the stability and efficacy of compound 26 as an inhibitor. These findings highlight compounds 26 and 27 as promising candidates for further <i>in vivo</i> studies and structure-activity relationship (SAR) analysis to enhance anticancer potential.