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Published January 1, 2021 | Version v1
Journal article Open

Comprehensive study on potent and selective carbonic anhydrase inhibitors: Synthesis, bioactivities and molecular modelling studies of 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl) benzenesulfonamides

Creators

  • 1. Meikai Univ, Res Inst Odontol M RIO, Saitama, Japan
  • 2. Meiji Pharmaceut Univ, Dept Med Mol Informat, Tokyo, Japan
  • 3. Meikai Univ, Div Pharmacol, Sch Dent, Saitama, Japan
  • 4. Matsumoto Dent Univ, Dept Operat Dent, Nagano, Japan
  • 5. Meikai Univ, Div Endodont & Operat Dent, Sch Dent, Sakado, Saitama, Japan
  • 6. Biruni Univ, Fac Pharm, Dept Pharmaceut Chem, Istanbul, Turkey
  • 7. Univ Firenze, Neurofarba Dept, Sez Sci Farmaceut & Nutraceut, Via U Schiff 6, I-50019 Florence, Italy
  • 8. Ataturk Univ, Fac Pharm, Dept Pharmaceut Chem, Erzurum, Turkey

Description

In this research, rational design, synthesis, carbonic anhydrases (CAs) inhibitory effects, and cytotoxicities of the 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl)benzenesulfonamides 1-20 were reported. Compound 18 (Ki = 7.0 nM) was approximately 127 times more selective cancer-associated hCA IX inhibitor over hCA I, while compound 17 (Ki = 10.6 nM) was 47 times more selective inhibitor of hCA XI over hCA II compared to the acetazolamide. Compounds 11 (CC50 = 5.2 mM) and 20 (CC50 = 1.6 mM) showed comparative tumor-specificity (TS= > 38.5; >128.2) with doxorubicin (TS > 43.0) towards HSC-2 cancer cell line. Western blot analysis demonstrated that 11 induced slightly apoptosis whereas 20 did not induce detectable apoptosis. A preliminary analysis showed that some correlation of tumor-specificity of 1-20 with the chemical descriptors that reflect hydrophobic volume, dipole moment, lowest hydrophilic energy, and topological structure. Molecular docking simulations were applied to the synthesized ligands to elucidate the predicted binding mode and selectivity profiles towards hCA I, hCA II, and hCA IX. (C) 2021 Elsevier Masson SAS. All rights reserved.

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