New 1H‐indole‐2,3‐dione 3‐thiosemicarbazones with 3‐sulfamoylphenyl moiety as selective carbonic anhydrase inhibitors

Abstract

1-Methyl/ethyl/benzyl-5-(un)substituted 1H-indole-2,3-diones (2, 3, and 4) were synthesized by reaction of 5-(un)substituted 1H-indole-2,3-diones (1) with methyl iodide, ethyl chloride, and benzyl bromide. (3-Sulfamoylphenyl)isothiocyanate (6) was obtained by the treatment of 3-aminobenzenesulfonamide (5) with thiophosgene. Compound 6 was reacted with hydrazine to yield 4-(3-sulfamoylphenyl) thiosemicarbazide (7). Novel 1-(un)substituted/methyl/ethyl/benzyl-5-(un) substituted 1H-indole-2,3-dione 3-[4-(3-sulfamoylphenyl)thiosemicarbazone] derivatives (8−11) were prepared by condensation of 7 and 1−4. The structures of the synthesized compounds were confirmed by elemental analysis and spectral data. Inhibition of the widely distributed cytosolic off-targets human carbonic anhydrases (hCAs) I and II, and two tumor-associated membrane-bound isoforms (hCAs IX and XII), by 8−11 was investigated. The hCA II inhibitory effects of all tested compoundswere in the subnanomolar to low nanomolar levels (K i = 0.32−83.3 nM), and generally high selectivity for hCA II isoenzyme over hCA I, IX, and XII isoenzymes was observed. The strongest inhibitors of hCA II, 1-benzyl-5-(trifluoromethoxy)substituted 11c (K i = 0.32 nM) and 1-ethyl-5-chloro-substituted 10e (K i = 0.35 nM), were docked within the enzyme active site. Molecular modeling studies with the most effective hCA IX and XII inhibitors were also carried out.

Synthesis, Theoretical, in Silico and in Vitro Biological Evaluation Studies of New Thiosemicarbazones as Enzyme Inhibitors

“…For h CA II, K I s range from 323.04‐991.62 nM. Eraslan‐Elma and colleagues [39] created 1 H ‐indole‐2,3‐dione 3‐thiosemicarbazones and investigated how to block h CA I, II, IX, and XII enzymes. They demonstrated that compared to other isoenzymes, hCA II isoenzyme was more inhibited by produced drugs with nanomolar values ( K I ranged between 0.32 and 83.3 nM).…”