Molecular modelling insights into a physiologically favourable approach to eicosanoid biosynthesis inhibition through novel thieno[2,3-b]pyridine derivatives |
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Authors: | Mosaad S Mohamed Yara E Mansour Hatem K Amin |
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Institution: | 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt;2. Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt |
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Abstract: | In this research, we exploited derivatives of thieno2,3-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 IC50?=?0.15?µM, while its p-chloro analogue 7b was more active against COX-2 (IC50?=?7.5?µM). The less desirable target COX-1 was inhibited more potently by 8c with IC50?=?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. |
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Keywords: | Anti-inflammatory COX-2 5-LOX COX-1 thieno[2 3-b]pyridine |
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