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 (K Is) ranging from 81.9 to 456.6 nM (AAZ and SLC-0111: K Is , 250.0 and 5080 nM, respectively). Compounds 6 – 11 proved to be effective hCA II inhibitors (K Is , 8.9–51.5 nM); they were almost equally potent to AAZ (K I , 12.0 nM) and had superior potency to SLC-0111 (K I , 960.0 nM). For hCA IX inhibition, compounds 6 – 11 proved to be potent inhibitors, with K I values of 3.9–36.0 nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (K Is , 25.0 and 45.0 nM, respectively). For hCA XII inhibitory activity, compounds 6 – 11 displayed effective inhibition with K I values ranging from 4.6 to 86.3 nM and were therefore comparable to AAZ and SLC-0111 (K Is , 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 (K I s: 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; K I : 250.0, 12.0, 25.0, and 5.7 nM, respectively). Image 1 • 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. [ABSTRACT FROM AUTHOR]