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

Abstract

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.