Synthesis, human carbonic anhydrase I and II inhibition, and in silico studies of 2-ethoxy-6-formylphenyl [1,1'-biphenyl]-4-sulfonate derived thiosemicarbazones.

This study describes the synthesis and biological evaluation of 2-ethoxy-6-formylphenyl [1,1'-biphenyl]-4-sulfonate-based thiosemicarbazones 5(a-s) as potential inhibitors of human carbonic anhydrase isoforms hCA I and hCA II. Among the synthesized compounds, 5 k exhibited potent inhibition, with IC50 values of 89.25 nM and 54.50 nM for hCA I and hCA II, respectively, surpassing that of acetazolamide as the standard inhibitor. Structure-activity relationship (SAR) analysis indicates that the presence of electron withdrawing groups, especially the fluoro substituent, contributed to the enhanced inhibitory activity. Molecular docking and dynamics simulations demonstrated the strong binding capability of compound 5 k and showed its stability throughout the simulation period. Overall, these findings highlight 2-ethoxy-6-formylphenyl [1,1'-biphenyl]-4-sulfonate-based thiosemicarbazones, with 5 k notably, as promising candidates for the development of therapeutic agents targeting hCA I and hCA II.