Novel 3‑Sulfonamide Dual-Tail Pyrrol-2-one Bridged Molecules as Potent Human Carbonic Anhydrase Isoform Inhibitors: Design, Synthesis, Molecular Modeling Investigation, and Anticancer Activity in MeWo, SK-BR-3, and MG-63 Cell Lines

Novel 3-sulfonamide pyrrol-2-one derivatives containing
two sulfonamide groups were synthesized via a one-pot, three-component
method using trifluoroacetic acid as a catalyst. Structural confirmation
was achieved using spectroscopic techniques. The compounds were tested
against four selected human carbonic anhydrase isoforms (hCA I, hCA
II, hCA IX, and hCA XII). Most derivatives showed significant selectivity
for hCA II, with 4h, 4i, 4n, 4k, and 4j demonstrating enhanced activity
due to methoxy and hydroxy group patterns. Compound 4o exhibited strong
dual selectivity for hCA II and hCA IX, while 4l was the most effective
inhibitor of hCA XII. Additionally, 4e showed a preference for hCA
XII inhibition. Biological evaluation on MeWo, SK-BR-3, and MG-63
cancer cells showed that compound 4l was cytotoxic for
MeWo cells without significantly affecting normal fibroblasts’
viability. Compounds 4e, 4l, and 4o were shown to affect tumor cell viability in combination with doxorubicin
in additional testing on MeWo cancer cells.