1. Synthesis and molecular modeling of novel non-sulfonylureas as hypoglycemic agents and selective ALR2 inhibitors.
- Author
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Salem MG, Aziz YMA, Elewa M, Elshihawy HA, and Said MM
- Subjects
- Aldehyde Reductase metabolism, Animals, Diabetes Complications metabolism, Diabetes Mellitus, Experimental metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents chemistry, Mice, Mice, Inbred BALB C, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Sulfonylurea Compounds chemical synthesis, Sulfonylurea Compounds chemistry, Aldehyde Reductase antagonists & inhibitors, Diabetes Complications drug therapy, Diabetes Mellitus, Experimental drug therapy, Enzyme Inhibitors pharmacology, Hypoglycemic Agents pharmacology, Sulfonylurea Compounds pharmacology
- Abstract
Novel non-sulfonylureas derivatives bearing an acetamide linker between a spirohydantoin scaffold and a phenyl ring were prepared and their hypoglycemic activity was estimated in vivo. Their abilities to discriminate in vitro between aldehyde reductase (ALR1) and aldose reductase (ALR2) were determined. The molecular docking and the in silico prediction studies were performed to rationalize the obtained biological results and to predict the physicochemical properties and drug-likeness scores of the new compounds. N-(2,4-Dichlorophenyl)-2-(2',4'-dioxospiro[fluorene-9,5'-imidazolidine]-3'-yl)acetamide (3e) displayed an 84% reduction in blood glucose level superior to that of repaglinide 66% and showed an IC
50 value of 0.37 μM against ALR2 that is superior to that of sorbinil 3.14 µM. Compound (3e) was selective 96 fold towards ALR2 which is closely related to serious diabetic complications. Based on the identification of this hit candidate, a new generation of safe and effective antidiabetic agents could be designed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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