An Efficient Synthesis of Quinoxalinone Derivatives as Potent Inhibitors of Aldose Reductase

Abstract

A novel and facile synthesis of quinoxalinone derivatives was developed in which a wide range of 3-chloroquinoxalin-2(1H)-ones as key intermediates can be generated chemo- and regioselectively in good yields from corresponding quinoxaline-2,3(1H,4H)-diones. This new protocol is arguably superior, as it allows the design and preparation of a variety of bioactive quinoxaline-based compounds, which are particularly effective in the treatment of diabetes and its complications. Through this procedure, a new class of quinoxalinone-based aldose reductase inhibitors were synthesized successfully. Most of the inhibitors, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC(50) values ranged from 11.4 to 74.8 nM. Among them, 2-(3-(4-bromophenoxy)-7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetic acid and 2-(6-bromo-3-(4-bromophenoxy)-2-oxoquinoxalin-1(2H)-yl)acetic acid were the most active. Structure-activity relationship and molecular docking studies highlighted the importance of the ether spacer in the C3-phenoxy side chains, and provided clear guidance on the contribution of substitutions both at the core structure and the side chain to activity.

Phenolic compounds inhibit the aldose reductase enzyme from the sheep kidney

“…They examined its inhibitory effects on AR and determined that 3,6,7,4’,5’‐pentamethoxy‐5,3’‐dihydroxyflavone has significant inhibition on AR of rat's retina. Recently, researchers found various classes of ARIs, in which quinoxaline derivatives having a substituted phenoxyl or benzyl group as C3 side chain showed distinguished activity . Hussain et al .…”

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…Ponalrestat was withdrawn from clinical trials due to lack of efficacy. Besides, a number of potent ARIs were recently designed and synthesized based on various chemical core structures including (benzothiazol-2-yl)methylindole (lidorestat) [36], naphtho [1,2-d]isothiazole [55], oxadiazole [56], aromatic thiadiazine-1,1-dioxide [57,58], and quinoxalinone [59]. All of them bear a chemical group of acetic acid on the core.…”

Biological evaluation of selected 3,4‐dihydro‐2(1H)‐quinoxalinones and 3,4‐dihydro‐1,4‐benzoxazin‐2‐ones: Molecular docking study

“…Heterocycles such as quinoxalines and benzoxazines are structural motifs of wide spectrum of biologically active compounds. Quinoxalines display a broad spectrum of pharmacological activity such as antimicrobial, anti‐inflammatory, antidiabetic, antiviral, anticancer, and antituberculosis . In fact, one of the primary targets in medicinal chemistry and one of the biggest health problem in society nowdays is cancer.…”