Abstract
To develop multifunctional aldose reductase (AKR1B1) inhibitors for anti-diabetic complications, a novel series of 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives were designed and synthesised. Most of the derivatives were found to be potent and selective against AKR1B1, and 2-(7-chloro-2-(3,5-dihydroxyphenoxy)-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl) acetic acid (4k) was the most active with an IC50 value of 0.023 µM. Moreover, it was encouraging to find that some derivatives showed strong antioxidant activity, and among them, the phenolic 3,5-dihydroxyl compound 4l with 7-bromo in the core structure was proved to be the most potent, even comparable to that of the well-known antioxidant Trolox. Thus the results suggested success in the construction of potent and selective AKR1B1 inhibitors with antioxidant activity.
Highlights
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion, insulin action, or both[1]
Increasing clinical research indicated that the abnormal polyol pathway flux of blood glucose is obviously related to pathogenesis of diabetes complications[4]
In the tissues implicated in these pathologies, the increased polyol pathway flux would directly cause the accumulation of sorbitol, which is hard to penetrate through cellular membranes, resulting in osmotic imbalance, cell swelling, and membrane permeability changes
Summary
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion, insulin action, or both[1]. In the tissues implicated in these pathologies, the increased polyol pathway flux would directly cause the accumulation of sorbitol, which is hard to penetrate through cellular membranes, resulting in osmotic imbalance, cell swelling, and membrane permeability changes. All these AKR1B1-mediated biochemical alterations contribute to the pathogenesis of diabetic complications[8–10]. Design and synthesis aldose reductase inhibitors (ARIs) to inhibit the activity of AKR1B1 and further regulate the polyol pathway of glucose are likely to be a promising therapy to prevent the development of diabetic complications.
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