Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII

Abstract

Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a pair of identical amino acids, possessing a polar (Ser, Thr, Asn, Gln) and non-polar (Ala, Tyr, Trp) side chain, have been synthesized. The optimized synthetic, purification, and isolation procedures provided several pronounced benefits such as a short reaction time (in sodium bicarbonate aqueous medium), satisfactory yields for the majority of new products (20.6–91.8%, average 60.4%), an effective, well defined semi-preparative RP-C18 liquid chromatography (LC) isolation of desired products with a high purity (>97%), as well as preservation of green chemistry principles. These newly synthesized conjugates, plus their 4-aminobenzenesulfonamide analogues prepared previously, have been investigated in in vitro inhibition studies towards hCA I, II, IV and tumor-associated isozymes IX and XII. The experimental results revealed the strongest inhibition of hCA XII with low nanomolar inhibitory constants (Kis) for the derivatives with amino acids possessing non-polar side chains (7.5–9.6 nM). Various derivatives were also promising for some other isozymes.

Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review

“…Synthesized compounds were also subjected to molecular docking studies and it was observed that compound 184 (R 1 = Trp) showed binding energy −219.74, −156.70, and −225.14 kJ/mol for hCA II, hCA IX, and hCA XII, respectively, and proved to be a good inhibitor [39] (Scheme 20). | 13 of 208 Newly synthesized compounds were tested for their inhibitory activity against hCA I, II, IX, XII by taking AAZ as standard drug by using stopped flow CO 2 hydration assay and it was observed that compound 204a (sulfonamide moiety) showed potent inhibitory activity against hCA IX and XII with K i values of 11.7 and 9.8 nM, respectively, and compound 205a (sulfonamide moiety) showed activity against hCA IX and XII with K i values of 29.7 and 45.5 nM, respectively.…”

“…Synthesized compounds were also subjected to molecular docking studies and it was observed that compound 184 (R 1 = Trp) showed binding energy −219.74, −156.70, and −225.14 kJ/mol for hCA II, hCA IX, and hCA XII, respectively, and proved to be a good inhibitor [ 39 ] (Scheme 20).…”