New anthranilic acid-incorporating N-benzenesulfonamidophthalimides as potent inhibitors of carbonic anhydrases I, II, IX, and XII: Synthesis, in vitro testing, and in silico assessment

The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4–21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6–11 gave the best potent hCA inhibitors with inhibition constants (KIs) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: KIs, 250.0 and 5080 nM, respectively). Compounds 6–11 proved to be effective hCA II inhibitors (KIs, 8.9–51.5 nM); they were almost equally potent to AAZ (KI, 12.0 nM) and had superior potency to SLC-0111 (KI, 960.0 nM). For hCA IX inhibition, compounds 6–11 proved to be potent inhibitors, with KI values of 3.9–36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (KIs, 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6–11 displayed effective inhibition with KI values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (KIs, 5.7 and 4.5 nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization. Compounds 6–11 exhibited potent inhibitory activity against human isoforms CA I, II, IX, and XII (KIs: 81.9–456.6, 8.9–51.5, 3.9–36.0, and 4.6–86.3 nM respectively), with values comparable to that of the standard inhibitor, acetazolamide (AAZ; KI: 250.0, 12.0, 25.0, and 5.7 nM, respectively). [Display omitted] •A novel phthalimide with sulfonamide and carboxylate tails was synthesized.•CA I, II, IX, and XII inhibition profiles were evaluated.•New compounds were compared to standard sulfonamide inhibitors, (AAZ) and SLC-0111.•Among this series; benzensulfonamides 6–11 gave the best potent hCA inhibitors.•The molecular modeling was used to study the binding mode of compounds 6,7,10 &11.