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

ABSTRACT: 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.

SUBMITTER: Mohamed MS 

PROVIDER: S-EPMC6009894 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature