Design and synthesis of chromene-1,2,3-triazole benzene sulfonamide hybrids as potent carbonic anhydrase-IX inhibitors against prostate cancer

Considering the promising effects of molecular hybridization on drug discovery in recent years and the ongoing endeavors to develop bioactive scaffolds tethering the 1,2,3-triazole core, the present study sought to investigate whether the 1,2,3-triazole-linked chromene and benzene sulfonamide nucleus could exhibit activity against the human breast Cancer cell line MCF-7 and prostate Cancer cell line PC-3. To this end, three focused bioactive series of mono- and -bis-1,2,3-triazoles were effectively synthesized via copper-assisted cycloaddition of mono- and/or di-alkyne chromenone derivatives 2a and b and 9 with several sulfa drug azides 4a-d and 6. The resulting molecular derivatives were tested for cytotoxicity against prostate and breast Cancer cells. Among the derivatives, 10a, 10c, and 10e exhibited potent cytotoxicity against PC-3 cells with IC₅₀ values of 2.08, 7.57, and 5.52 μM compared to doxorubicin (IC₅₀ = 2.31 μM) with potent inhibition of CA IX with IC₅₀ values of 0.113, 0.134, and 0.214 μM. The most active compound, 10a, was tested for apoptosis-induction; it induced Apoptosis by 31.9-fold cell cycle arrest at the G1-phase. Further, the molecular modeling approach highlighted the relevant binding affinity for the top-active compound 10a against CA IX as one of the most prominent PC-3 prostate cancer-associated biotargets.