Dependence on linkers' flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents.

Herein we reported the design and synthesis of two series comprising twenty-two benzenesulfonamides that integrate the -triazine moiety. Target compounds successfully suppressed the hCA IX, with IC ranging from 28.6 to 871 nM. Compounds , , , and were the most active analogues, which inhibited hCA IX isoform in the low nanomolar range ( = 28.6, 31.9, 33.4, and 36.6 nM, respectively). Furthermore, they were assessed for their cytotoxic activity against a panel of 60 cancer cell lines following US-NCI protocol. According to five-dose assay, showed significant anticancer activity than with GI-MID values of 25.08 and 189.01 µM, respectively. Additionally, 's effects on wound healing, cell cycle disruption, and apoptosis induction in NCI-H460 cancer cells were examined. Further, docking studies combined with molecular dynamic simulation showed a stable complex with high binding affinity of to hCA IX, exploiting a favourable H-bond and lipophilic interactions.HIGHLIGHTSCarbonic anhydrase (CA) inhibitors comprising rigid and flexible linkers were developed.Compound is the most potent CA IX inhibitor in the study (IC50: 28.6 nM).Compounds and displayed the greatest antiproliferative activity towards 60 cell lines.Compound exposed constructive outcomes on normal cell lines, metastasis, and wound healing.Molecular docking and molecular dynamics (MDs) simulation was utilised to study binding mode.