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

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

  • Bioorg Chem. 2025 Feb:155:108118. doi: 10.1016/j.bioorg.2024.108118.
Javeria Eshal 1,  Hafiza Zara Tariq 2,  Jing Li 2,  Hina Aftab 1,  Halil Şenol 3,  Parham Taslimi 4,  Nastaran Sadeghian 5,  Rima D Alharthy 6,  Muhammad Safwan Akram 7,  Rimsha Talib 1,  Zahid Shafiq 8
Affiliations

Affiliations

  • 1 Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan.
  • 2 School of Chemistry, Xi'an Jiaotong University, Xianning West Road, Xi'an 710049, China.
  • 3 Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093 Fatih, İstanbul, Turkey.
  • 4 Department of Biotechnology, Faculty of Science, Bartin University, 74110 Bartin, Turkey. Electronic address: parham_taslimi_un@yahoo.com.
  • 5 Department of Biotechnology, Faculty of Science, Bartin University, 74110 Bartin, Turkey.
  • 6 Department of Chemistry, Science & Arts College, Rabigh Branch, King Abdulaziz University, Rabigh 21911, Saudi Arabia.
  • 7 School of Science & Health, Teesside University, Middlesbrough TS1 3BA, UK; National Horizons Centre, Teesside University, 38 John Dixon Ln, Darlington DL1 1HG, UK.
  • 8 Institute of Chemical Sciences, Bahauddin Zakariya University, 60800 Multan, Pakistan. Electronic address: zahidshafiq@bzu.edu.pk.
PMID: 39793219 DOI: 10.1016/j.bioorg.2024.108118
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 ± 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.

Keywords

Carbonic anhydrase inhibitors; In silico studies; Molecular docking; Napthalene-2-sulfonate; Thiosemicarbazones.

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