Design and synthesis of chiral 2 H -chromene- N -imidazolo-amino acid conjugates as aldose reductase inhibitors

• DOI: 10.1016/j.ejmech.2016.08.070
• Publication Date: 2016-09-08T22:21:40Z
• Authors: Gudipudi Gopinath; Venu Sankeshi; Shaym perugu; Malini D. Alaparthi; Srinivas Bandaru; Vijay K. Pasala; Prasad Rao Chitti...; G.L.David Krupadanam; Someswar R. Sagurthi
• Keywords: Blood Glucose; 0301 basic medicine; Imidazoles; Stereoisomerism; Cataract; Rats; 3. Good health; Diabetes Complications; Enzyme Activation; Molecular Docking Simulation; Disease Models, Animal; Inhibitory Concentration 50; Structure-Activity Relationship; 03 medical and health sciences; Aldehyde Reductase; Catalytic Domain; Drug Design; Animals; Benzopyrans; Amino Acids; Enzyme Inhibitors

Aldose reductase (ALR2) inhibitors provide a viable mode to fight against diabetic complications. ALR2 exhibit plasticity in the active site vicinities and possible shifts in the nearby two supporting alpha helices. Therefore, a novel series of amino acid conjugates of chromene-3-imidazoles (13-15) were designed and synthesized based on natural isoflavonoids. The compounds were identified on the basis of spectral (1H NMR, 13C NMR and MS) data and tested in vitro for ALR2 inhibitory activity with an IC50 value ranges from 0.031 ± 0.082 μM to 4.29 ± 0.55 μM. Our in silico and biochemical studies confirmed that 15e has the best inhibition activity among the synthesized compounds with a high selective index against the Aldehyde reductase (ALR1). Supplementation of 15e to STZ induced rats decreased the blood glucose levels and delayed the progression of cataract in a dose-dependent manner. The present study thus provides novel series of compounds with a promising inhibitor to prevent or delay the cataract progression.