Diversity-oriented synthesis of Para-aryl Sulfonamides as potent human carbonic anhydrase inhibitors via modular click chemistry

Carbonic Anhydrase represents a highly promising target in drug discovery, as the dysregulation or overexpression of its various isoforms in humans is closely associated with a range of diseases. Carbonic Anhydrase inhibitors can modulate the activity of human carbonic anhydrases, thereby exerting diuretic, anti-glaucoma, antiepileptic, analgesic, antitumor, and anti-obesity effects. In this study, to obtain structurally diverse human Carbonic Anhydrase inhibitors, we employed a modular click chemistry library strategy to construct 401 para-aryl sulfonamide-triazoles in 96-well plates. Through this diversity-oriented clicking approach followed by enzymatic activity screening, we identified 16 hit compounds that exhibit potent inhibitory activity against hCA II with considerable structural diversity. Among them, compounds 3o and 3h showed excellent inhibitory activity against hCA II, with K_i values of 1.65 nM and 2.26 nM, respectively, while compounds such as 3e also demonstrated certain selectivity among different hCA isoforms. Furthermore, these compounds displayed favorable predicted drug-like properties.

Aryl sulfonamide; Carbonic anhydrase; Diversity-oriented clicking; Inhibitor; Modular click chemistry.