Molecular modelling insights into a physiologically favourable approach to eicosanoid biosynthesis inhibition through novel thieno[2,3-b]pyridine derivatives

In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2018-01, Vol.33 (1), p.755-767
Main Authors: Mohamed, Mosaad S., Mansour, Yara E., Amin, Hatem K., El-Araby, Moustafa E.
Format: Article
Language:English
Subjects:
5-LOX
Anti-inflammatory
COX-1
COX-2
Research Paper
thieno[2,3-b]pyridine
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Summary:In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most active compounds 7a, 7b, 8b, and 8c were screened against COX-1/2 and 5-LOX enzymes. Compound 7a was the most powerful inhibitor of 5-LOX with IC 50  = 0.15 µM, while its p-chloro analogue 7b was more active against COX-2 (IC 50  = 7.5 µM). The less desirable target COX-1 was inhibited more potently by 8c with IC 50  = 7.7 µM. Surflex docking programme predicted that the more stable anti- conformer of compound (7a) formed a favourable complex with the active site of 5-LOX but not COX-1. This is in contrast to the binding mode of 8c, which resembles the syn-conformer of series 7 and binds favourably to COX-1.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2018.1457657