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Abstract #106279 Published in IGR 23-3
Tail approach synthesis of triazolylthiazolotriazole bearing benzenesulfonamides as carbonic anhydrase inhibitors capable of inducing apoptosis
Vats L; Siwach K; Angeli A; Bikal P; Bhardwaj JK; Supuran CT; Sharma PKArchiv der Pharmazie 2023; 356: e2200439
Inhibition of human carbonic anhydrase (hCA) isoform IX with concurrent induction of apoptosis is a promising approach for targeting cancer in humans. Prompted by the scope, novel benzenesulfonamides containing the 1,2,3-triazolylthiazolotriazole tail were synthesized and screened as inhibitors of hCA isoforms I, II, IV, and IX. The tumor-associated isoform hCA IX was strongly inhibited by the sulfonamides reported here with K values ranging from 45 nM to 1.882 μM. Overall, nine compounds showed hCA IX inhibition with K < 250 nM. The glaucoma-associated isoform hCA II was moderately inhibited while the cytosolic isoform hCA I and membrane-bound isoform hCA IV were weakly inhibited by the synthesized sulfonamides. Compound 6Ac (K = 3.6 nM) was found to be an almost three times more potent inhibitor of hCA II as compared to the standard drug acetazolamide (K = 12.1 nM). The selective hCA IX inhibitors were further studied for their apoptotic efficacy in goat ovarian cells and showed better results as compared to the control. A comparative study of previously synthesized compounds and molecular docking study of representative compounds revealed some important generalizations that could prove beneficial in further investigations of isoform-selective hCA inhibitors.
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