Synthesis, carbonic anhydrase inhibition and in silico insights of 4-formyl-2-nitrophenyl naphthalene-2-sulfonate hybrid thiosemicarbazones.

A novel series of thiosemicarbazones derived from 4-formyl-2-nitrophenyl naphthalene-2-sulfonate is synthesized and assessed for inhibitory potential against human carbonic anhydrase isoforms hCA I and hCA II and metal chelating properties. Among the tested compounds, 6 l exhibited the most potent inhibition with (IC50 = 88.43 ± 3.25 nM) (Ki = 73.70 ± 3.47 nM) for hCA I and (IC50 = 61.82 ± 0.60 nM) (Ki = 55.22 ± 5.32 nM) for hCA II. Remarkably, compound 6 l exhibited greater potency than the reference drug acetazolamide (IC50 = 290.50 ± 9.12 nM for hCA I) and (IC50 = 177.03 ± 6.08 nM for hCA II). Additionally, the IC50 values of metal chelation for novel compounds ranged from (9.43 ± 0.80 to 75.24 ± 8.35 nM). SAR analysis indicated that dichlorophenyl substituent having electron withdrawing effect played a key role in enhancing inhibitory activity. To support these findings, molecular docking and dynamics simulations were performed to investigate the binding interactions and potential inhibitory mechanisms. The results highlight the significant inhibitory potential of the synthesized thiosemicarbazones as carbonic anhydrase inhibitors, suggesting their suitability for future development in treating conditions related to carbonic anhydrase disorders.