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.

Yamali C., Sakagami H., Uesawa Y., Kurosaki K., Satoh K., Masuda Y., ...More

European journal of medicinal chemistry, vol.217, pp.113351, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 217
  • Publication Date: 2021
  • Doi Number: 10.1016/j.ejmech.2021.113351
  • Journal Name: European journal of medicinal chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.113351
  • Keywords: Carbonic anhydrase, hCA IX, Anticancer, OSCC, Apoptosis, Pyrazole, Benzenesulfonamide, Hydrazone, Docking, MANNICH-BASES, DRUG DESIGN, HCA II, IX, XII, SULFONAMIDES, CYTOTOXICITY, METASTASIS, EXPRESSION, HYDRAZONES
  • Çukurova University Affiliated: Yes

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 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.