Tail approach synthesis of triazolylthiazolotriazole bearing benzenesulfonamides as carbonic anhydrase inhibitors capable of inducing apoptosis
Lalit Vats, Kiran Siwach, Andrea Angeli, Prerna Bikal, Jitender Kumar Bhardwaj, Claudiu T. Supuran, Pawan K. Sharma
Abstract
Abstract 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 I values ranging from 45 nM to 1.882 μM. Overall, nine compounds showed hCA IX inhibition with K I < 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 I = 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 I = 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.