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

[Display omitted] •A series of 2-formylphenyl naphthalene-2-sulfonate-based thiosemicarbazones 5(a-v) was synthesized and characterized.•Explored as Carbonic anhydrase (hCA I, hCA II) Inhibitors.•In silico, molecular docking was carried out to study binding of active compounds with enzymes.•Molecular dynamics (MD) simulations were conducted for the most active compounds to assess ligand-protein stability. 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 ± 0.02 nM and 5.24 ± 0.03 nM for hCA I, and 3.89 ± 0.01 nM and 4.72 ± 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.