Synthesis and Anticancer Evaluation of Novel Sulfonamide–Imidazole Hybrid Piperazines: In Vitro and In Silico Studies

Abstract A series of novel sulfonamide‐attached 1‐(4‐((1‐(2,4‐dichlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethoxy)methyl)phenyl)piperazines (12a–l) were designed, synthesized, and evaluated for their anticancer potential against three human cancer cell lines: MCF‐7 (breast), A549 (lung), and A2780 (ovarian). The rationale behind the synthesis of these compounds was to integrate the pharmacologically significant imidazole and sulfonamide scaffolds, known for their anticancer activities, into a single molecular framework. The key intermediate (10), was synthesized via a Pd‐catalyzed coupling reaction followed by deacetylation. Subsequent sulfonylation of 10 with various sulfonyl chlorides afforded the target compounds 12a–l. In vitro cytotoxicity assays demonstrated that compounds 12a, 12b, and 12c exhibited significant anticancer activity against MCF‐7 cells, with IC50 values comparable to the standard drug, Etoposide. Moreover, 12a and 12b exhibited considerable activity against A549 and A2780 cell lines, suggesting broad‐spectrum efficacy. Molecular docking with human topoisomerase IIβ (PDB ID: 3QX3) revealed significant hydrogen bonding and hydrophobic interactions, indicating a plausible mode of action. ADME and toxicity profiling suggested favorable drug‐like characteristics for most derivatives, though 12l emerged as a potential reproductive toxicant. Structure–activity relationship analysis highlighted the impact of specific sulfonyl substitutions on cytotoxic potency. These results support further exploration and optimization of sulfonamide–imidazole hybrids for anticancer therapy.