Design, synthesis and biological evaluation of selective hybrid coumarin-thiazolidinedione aldose reductase-II inhibitors as potential antidiabetics

• Published in: Bioorganic chemistry Vol. 114; pp. 104970 - 104984
• Main Authors: Kumar Pasala, Vijay, Gudipudi, Gopinath, Sankeshi, Venu, Basude, Manohar, Gundla, Rambabu, singh Jadav, Surendar, Srinivas, Burra, Yadaiah Goud, E., Nareshkumar, Devasani
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.09.2021; Elsevier
• Subjects: 1,3-Thiazolidine-2,4-diones; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldose reductase inhibitors; Animals; Benzopyrans; Biochemistry & Molecular Biology; Cataract - prevention & control; Chemistry; Chemistry, Organic; Coumarins - chemical synthesis; Coumarins - metabolism; Coumarins - pharmacokinetics; Coumarins - therapeutic use; Diabetes Mellitus, Experimental - drug therapy; Diabetic complications; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Life Sciences & Biomedicine; Male; Molecular Docking Simulation; Molecular modeling; Molecular Structure; Physical Sciences; Protein Binding; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Thiazolidinediones - chemical synthesis; Thiazolidinediones - metabolism; Thiazolidinediones - pharmacokinetics; Thiazolidinediones - therapeutic use; 1,3-Thiazolidine-2,4-diones; Diabetic complications; Benzopyrans; Aldose reductase inhibitors; Molecular modeling; MULTICENTER; DOCKING; PREVENTION; EPALRESTAT; ALDEHYDE REDUCTASE; 1; reductase inhibitors; Aldose  3 Thiazolidine-2; CARBOCYCLIC NUCLEOSIDES; PHARMACOLOGY; DIABETIC PERIPHERAL NEUROPATHY; COMPLICATIONS; DERIVATIVES; 4-diones
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104970

Confluence of two promising skeletons helped in planning the design of the test compounds 10a-n as selective aldose reductase II inhibitors, in which 10c emerged as the potent inhibitor in arresting the progression of cataract, creating interest further in the treatment in a chemically more advanced manner. This revelation was further verified with invivo and insilico studies. [Display omitted] •Synthesis of coumarin-TZD inhibitors of aldose reductase II based on benzopyran and 1,3-thiazolidine-2,4-dione fragments.•Design embellished with strategies- simplification of the structure, change of position and grafting TZD moiety.•Inhibition potencies of compounds 10a-n obtained invitro were verified with invivo studies.•Compound 10c emerged as the potent candidate in arresting the cataract progression in diabetes-induced STZ rats.•Further binding interactions of 10a-n were studied using docking studies. Thiazolidinediones (TZD), benzopyrans are the proven scaffolds for inhibiting Aldose reductase (ALR2) activity and their structural confluence with the retention of necessary fragments helped in designing a series of hybrid compounds 2-(5-cycloalkylidene-2,4-dioxothiazolidin-3-yl)-N-(2-oxo-2H-chromen-3-yl)acetamide (10a-n) for better ALR2 inhibition. The compounds were synthesized by treating substituted 3-(N-bromoacetyl amino)coumarins (9a-d) with potassium salt of 5-cyclo alkylidene-1,3-thiazolidine-2,4-diones (4a-d). The inhibition activity against ALR2 with IC50 values range from 0.012 ± 0.001 to 0.056 ± 0.007 μM. N-[(6-Bromo-3-coumarinyl)-2-(5-cyclopentylidene-2,4-dioxothiazolidin-3-yl)] acetamide (10c) with cyclopentylidene group on one end and the 6-bromo group on the other end showed better inhibitory property (IC50 = 0.012 μM) and selectivity index (324.166) against the ALR2, a forty fold superiority over sorbinil, a better molecule over epalrestat and rest of the analogues exhibited a far superior response over sorbinil and slightly better as compared with epalrestat. It was further confirmed by the insilico studies that compound 10c showed best inhibition activity among the synthesized compounds with a high selectivity index against the ALR2. In invivo experiments, supplementation of compound 10c to STZ induced rats delayed the progression of cataract in a dose-dependent manner warranting its further development as a potential agent to treat thediabetic secondary complications especially cataract.