New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase

Abstract

Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N′-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a–f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a–f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b–d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC50 = 9.99 ± 0.18 µM); which is comparable to quercetin (IC50 = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC50 > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.

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

“…IC 50 values for compounds 9 – 11 were less than IC 50 values of standard antidiabetic drug (acarbose). These results are in concordance with some previous studies with quinoxalinones, that indicated that this type of scaffolds can inhibit α‐glucosidase and have antidiabetic properties . The results suggest that compounds 10 and 11 could be further analyzed as new potential control postprandial hyperglycemia compounds.…”

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…Quinoxalinone derivatives with dual activities on biochemically unrelated enzymes, but mutually involved in diabetes and its complications, were presented [96]. All of the studied compounds showed low micromolar IC 50 values against the different sPLA 2 isozymes (IC 50 s < 20 μM) and satisfactory IC 50 values (IC 50 s < 50 μM) against pancreatic α-glucosidase.…”

Design, Synthesis, and Biological Activity of Conformationally Restricted Analogues of Silibinin

“…Alasmary et al reported details of the interaction between the flavonoid quercetin and an active site of α-glucosidase, including a stacking interaction in the aromatic rings (A and B rings) of quercetin and the amino acid residue Trp432 in α-glucosidase, hydrogen bonds between the hydroxyl group in quercetin and residues Asp568, His626, and Asp357 in α-glucosidase, and hydrophobic interactions between the hydroxyl group in quercetin and residues Phe601 and Trp329 in α-glucosidase. 27 As quercetin exhibits a planar structure resulting from the conjugated system with an α,β-unsaturated ketone, it can bind to the active site of α-glucosidase. As SibC exhibits a highly planar structure and a molecular size similar to that of quercetin, we predicted that SibC could fit easily into the active site of α-glucosidase.…”