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New quinoxalinone inhibitors targeting secreted phospholipase A2 and alpha-glucosidase

Alasmary, Fatmah A.S. and Alnahdi, Fatima S. and Ben Bacha, Abir G. and El-Araby, Amr M. and Moubayed, Nadine Ms and Alafeefy, Ahmed Mahmoud and El-Araby, Moustafa E. (2017) New quinoxalinone inhibitors targeting secreted phospholipase A2 and alpha-glucosidase. Journal of Enzyme Inhibition and Medicinal Chemistry, 32 (1). pp. 1143-1151. ISSN 1475-6366 E-ISSN 1475-6374

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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.

Item Type: Article (Journal)
Additional Information: 7668/62986
Uncontrolled Keywords: coronary heart disease; diabetic complications; phospholipase A2; Quinoxalinone; α-amylase α-glucosidase
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button): Kulliyyah of Science
Kulliyyah of Science > Department of Chemistry
Depositing User: Engku Norulizati Engku Aziz
Date Deposited: 02 Nov 2018 12:34
Last Modified: 02 Nov 2018 12:36
URI: http://irep.iium.edu.my/id/eprint/62986

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