Synthetic Approaches to Novel Human Carbonic Anhydrase Isoform Inhibitors Based on Pyrrol-2-one Moiety

New dihydro-pyrrol-2-one
compounds, featuring dual sulfonamide
groups, were synthesized through a one-pot, three-component approach
utilizing trifluoroacetic acid as a catalyst. Computational analysis
using density functional theory (DFT) and condensed Fukui function
explored the structure–reactivity relationship. Evaluation
against human carbonic anhydrase isoforms (hCA I, II, IX, XII) revealed
potent inhibition. The widely expressed cytosolic hCA I was inhibited
across a range of concentrations (KI 3.9–870.9 nM). hCA II, also cytosolic, exhibited good
inhibition as well. Notably, all compounds effectively inhibited tumor-associated
hCA IX (KI 1.9–211.2
nM) and hCA XII (low nanomolar). Biological assessments on MCF7 cancer
cells highlighted the compounds’ ability, in conjunction with
doxorubicin, to significantly impact tumor cell viability. These findings
underscore the potential therapeutic relevance of the synthesized
compounds in cancer treatment.