Synthesis and biological evaluation of novel pyrazoline-based aromatic sulfamates with potent carbonic anhydrase isoforms II, IV and IX inhibitory efficacy

Abstract

Herein we report the synthesis of a new series of aromatic sulfamates designed considering the sulfonamide COX-2 selective inhibitors celecoxib and valdecoxib as lead compounds. These latter were shown to possess important human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties, with the inhibition of the tumor-associated isoform hCA IX likely being co-responsible of the celecoxib anti-tumor effects. Bioisosteric substitution of the pyrazole or isoxazole rings from these drugs with the pyrazoline one was considered owing to the multiple biological activities ascribed to this latter heterocycle and paired with the replacement of the sulfonamide of celecoxib and valdecoxib with its equally potent bioisoster sulfamate. The synthesized derivatives were screened for the inhibition of four human carbonic anhydrase isoforms, namely hCA I, II, IV, and IX. All screened sulfamates exhibited great potency enhancement in inhibiting isoform II and IV, widely involved in glaucoma (K_Is in the range of 0.4-12.4 nM and 17.7 and 43.3 nM, respectively), compared to the lead compounds, whereas they affected the tumor-associated hCA IX as potently as celecoxib.

Keywords: Aromatic sulfamates; Carbonic anhydrase; Celecoxib; Sub-nanomolar inhibition; Sulfamoylation; ZInc-binding group.