Synthesis, biological evaluation, and in silico studies of phenyl naphthalene-2-sulfonate derived thiosemicarbazones as potential carbonic anhydrase inhibitors

Abstract

A series of novel phenyl naphthalene-2-sulfonate-based thiosemicarbazones (5a-v) were synthesized and evaluated for their inhibitory activity against human carbonic anhydrases I and II (hCA I and hCA II). Compounds 5d and 5p demonstrated the highest inhibitory potency, with IC50 values of 4.32 f 0.02 nM and 5.24 f 0.03 nM for hCA I, and 3.89 f 0.01 nM and 4.72 f 0.01 nM for hCA II, respectively. Notably, compound 5d exhibited superior potency compared to the reference drug acetazolamide. The structure-activity relationship (SAR) analysis revealed that electron-withdrawing groups, particularly the dichlorophenyl group in 5d and 5p , enhanced inhibitory activity. Molecular docking and molecular dynamics simulations confirmed the high binding affinity of compound 5d , with docking scores of-9.7 kcal/mol for hCA I and-9.5 kcal/mol for hCA II. Stability in MD simulations further supported its potent inhibitory action. ADMET predictions suggested that compounds 5d and 5p have favorable pharmacokinetic profiles. In conclusion, phenyl naphthalene-2-sulfonate-based thiosemicarbazones, especially compound 5d , show strong potential as therapeutic agents targeting hCA I and hCA II.