Design and Synthesis of Potent and Multifunctional Aldose Reductase Inhibitors Based on Quinoxalinones

Abstract

Quinoxalin-2(1H)-one based design and synthesis produced several series of aldose reductase (ALR2) inhibitor candidates. In particular, phenolic structure was installed in the compounds for the combination of antioxidant activity and strengthening the ability to fight against diabetic complications. Most of the series 6 showed potent and selective effects on ALR2 inhibition with IC50 values in the range of 0.032-0.468 μM, and 2-(3-(2,4-dihydroxyphenyl)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid (6e) was the most active. More significantly, most of the series 8 revealed not only good activity in the ALR2 inhibition but also potent antioxidant activity, and 2-(3-(3-methoxy-4-hydroxystyryl)-2-oxoquinoxalin-1(2H)-yl)acetic acid (8d) was even as strong as the well-known antioxidant Trolox at a concentration of 100 μM, verifying the C3 p-hydroxystyryl side chain as the key structure for alleviating oxidative stress. These results therefore suggest an achievement of multifunctional ALR2 inhibitors having both potency for ALR2 inhibition and as antioxidants.

Quinoxalinones Based Aldose Reductase Inhibitors: 2D and 3D‐QSAR Analysis

“…Data set : The dataset selected for the present work comprises eighty‐nine structurally diverse quinoxalinones with different type of substituents like −F, −Cl, −OH, etc. at various positions . The compounds were assayed against ALR2 and the reported IC 50 varies from few micro‐molar (μM) to single digit nano‐molar (nM).…”

“…At present only one drug ‘epalrestat’ is marketed for the treatment of neuropathy in Japan, India and China. In past few decades, structurally diverse Aldose reductase inhibitors (ARIs) have been reported (Figure ) . Unfortunately, many of the clinically tested ARIs have been found to be inappropriate as drug candidates because of adverse pharmacokinetics, toxic effects or low efficacy, only few of them have reached advanced clinical stages .…”

“…Recently, research group of Wang etal reported the synthesis and aldose reductase inhibitory activity of diverse quinoxalinones. The quinoxalinones were found to be efficient inhibitors of aldose reductase with activity ranging from μM to nM.…”

Synthesis and biological evaluation of novel neoflavonoid derivatives as potential antidiabetic agents

“…31 The enzyme aldose reductase (ALR2) is a member of the aldo-keto reductase superfamily. Diabetic complications including cataracts, retinopathy, accelerated atherosclerosis, and increased 33 Kunming mice were used as targets to estimate oral toxicity of each compound to mice.…”

Electrosynthesis of C3 Alkoxylated Quinoxalin‐2(1H)‐ones through Dehydrogenative C–H/O–H Cross‐Coupling

“…Meanwhile, quinoxalin‐2(1 H )‐ones have attracted much attention due to their abundant existence in anti‐inflammatory, antineoplastic, antithrombotic agents and aldose reductase inhibitors Conventional installation of C–O bond at C3 of quinoxalin‐2(1 H )‐ones largely rely on the nucleophilic substitution between 3‐chloroquinoxalin‐2(1 H )‐ones and phenols (see Scheme a) . Tremendous efforts have been made to develop C–H/O–H direct coupling to avoid the use of pre‐functionalized substrates and strong basic conditions during the synthesis of 3‐alkoxylated quinoxalin‐2(1 H )‐ones.…”