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

Journal of Enzyme Inhibition and Medicinal Chemistry

Hatem K. Amin¹  Moustafa E. El-Araby²  Yara E. Mansour²  Mosaad S. Mohamed² 

[1] Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egyp;Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt;

关键词: Anti-inflammatory;    COX-2;    5-LOX;    COX-1;    thieno[2,3-b]pyridine;   

DOI  :  10.1080/14756366.2018.1457657

来源: publisher

【 摘 要 】

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 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.

【 授权许可】

CC BY