2. Academic Validation
  3. Novel rhodanine based inhibitors of aldose reductase of non-acidic nature with p-hydroxybenzylidene functional group

Novel rhodanine based inhibitors of aldose reductase of non-acidic nature with p-hydroxybenzylidene functional group

  • Eur J Med Chem. 2022 Nov 12;246:114922. doi: 10.1016/j.ejmech.2022.114922.
Martin Kratky 1,  Peter Sramel 2,  Pavol Bodo 3,  Marta Soltesova Prnova 2,  Lucia Kovacikova 2,  Magdalena Majekova 2,  Jarmila Vinsova 4,  Milan Stefek 5
Affiliations

Affiliations

  • 1 Department of Organic and Bioorganic Chemistry, Charles University, Faculty of Pharmacy in Hradec Kralove, Heyrovskeho, 1203, Hradec Kralove, Czech Republic.
  • 2 Institute of Experimental Pharmacology and Toxicology, CEM, SAS, Dubravska Cesta 9, 841 04, Bratislava, Slovakia.
  • 3 Institute of Experimental Pharmacology and Toxicology, CEM, SAS, Dubravska Cesta 9, 841 04, Bratislava, Slovakia; Department of Biochemistry, Comenius University, Faculty of Natural Sciences, Ilkovicova 6, 841 04, Bratislava, Slovakia.
  • 4 Department of Organic and Bioorganic Chemistry, Charles University, Faculty of Pharmacy in Hradec Kralove, Heyrovskeho, 1203, Hradec Kralove, Czech Republic. Electronic address: vinsova@faf.cuni.cz.
  • 5 Institute of Experimental Pharmacology and Toxicology, CEM, SAS, Dubravska Cesta 9, 841 04, Bratislava, Slovakia. Electronic address: Milan.Stefek@savba.sk.
PMID: 36455357 DOI: 10.1016/j.ejmech.2022.114922
Abstract

Aldose Reductase, the first Enzyme of the polyol pathway represents a key drug target in therapy of diabetic complications. In this study a series of six novel rhodanine based inhibitors of Aldose Reductase was designed, synthesized, and tested for their ability to inhibit Aldose Reductase and for selectivity relative to structurally related aldehyde reductase. Aldose Reductase inhibitory activities of the compounds were characterized by the IC50 values ranging from 2000 nM to 20 nM. The values of selectivity factors relative to aldehyde reductase were decreasing in the same array from 24 to 5. In silico docking into the inhibitor binding site of Aldose Reductase revealed a specific binding pattern of the compounds comprising interaction of the deprotonated 4-hydroxybenzylidene group with the anion-binding sub-pocket of Aldose Reductase, creating a strong H-bond and charge interactions. Predicted pH-distribution profiles of the novel compounds into octanol, supported by experimentally determined distribution ratios, favour drug uptake at the physiological pH, as a result of the presence of the low-acidic phenolic group, instead of the more acidic carboxymethyl functional group.

Keywords

Non-carboxylate aldose reductase inhibitors; Rhodanine; p-Hydroxybenzylidene; pH-distribution profile.

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