2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2021 May 5:217:113351. doi: 10.1016/j.ejmech.2021.113351.
Cem Yamali 1,  Hiroshi Sakagami 2,  Yoshihiro Uesawa 3,  Kota Kurosaki 3,  Keitaro Satoh 4,  Yoshiko Masuda 5,  Satoshi Yokose 6,  Abdulilah Ece 7,  Silvia Bua 8,  Andrea Angeli 8,  Claudiu T Supuran 8,  Halise Inci Gul 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey; Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Cukurova University, Adana, Turkey.
  • 2 Research Institute of Odontology (M-RIO), Meikai University, Saitama, Japan.
  • 3 Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo, Japan.
  • 4 Division of Pharmacology, Meikai University School of Dentistry, Saitama, Japan.
  • 5 Department of Operative Dentistry, Matsumoto Dental University, Nagano, Japan.
  • 6 Division of Endodontics and Operative Dentistry, Meikai University School of Dentistry, Sakado, Saitama, Japan.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul, Turkey.
  • 8 Neurofarba Department, Sezione di Scienza Farmaceutiche e Nutraceutiche, Universita Degli Studi di Firenze, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.
  • 9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey. Electronic address: incigul1967@yahoo.com.
PMID: 33744685 DOI: 10.1016/j.ejmech.2021.113351
Abstract

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 μM) and 20 (CC50 = 1.6 μM) 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.

Keywords

Anticancer; Apoptosis; Benzenesulfonamide; Carbonic anhydrase; Docking; Hydrazone; OSCC; Pyrazole; hCA IX.

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