RESUMO
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.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Aminoácidos/síntese química , Aminoácidos/farmacologia , Desenho de Fármacos , Imidazóis/química , Aminoácidos/química , Animais , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Glicemia/efeitos dos fármacos , Domínio Catalítico , Catarata/tratamento farmacológico , Catarata/etiologia , Complicações do Diabetes/tratamento farmacológico , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Advanced Glycation End products (AGEs) interaction with Receptor for AGEs (RAGE) activates downstream signaling and evokes inflammatory responses in vascular cells. Therefore, it is of interest to design a novel series of molecules with a library of 352 compounds based on natural Isoflavone and Argpyrimidine moities. The compounds screened against the optimized structure of RAGE (PDB code: 3CJJ) using MolDock aided with molecular docking algorithm. This exercise identified compound number 62 with appreciable ADME properties having no toxicity and pharmacophore features. Therefore, compound 62 identified as a RAGE inhibitor is proposed for further validation in the context of Diabetic Retinopathy (DR) and vascular complications.
