Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases.

Shady Burayk,Mahmoud Kandeel,Kentaro Oh-Hashi

doi:10.3390/ph15030282

Abstract

The goal of achieving anti-inflammatory efficacy with the fewest possible adverse effects through selective COX-2 inhibition is still being investigated in order to develop drugs with safe profiles. This work shows the efficacy and safety profile of two novel benzimidazole piperidine and phenoxy pyridine derivatives in reaching this goal, which would be considered a major achievement in inflammatory therapy. The compounds were evaluated by virtual screening campaign, in vitro cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition, in vivo carrageenan-induced rat paw edema assay, cytotoxicity against Raw264.7 cells, and histopathological examination of rat paw and stomach. Two new compounds, compound 1 ([(2-{[3-(4-methyl-1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)amino]acetic acid) and compound 2 (ethyl 1-(5-cyano-2-hydroxyphenyl)-4-oxo-5-phenoxy-1,4-dihydropyridine-3-carboxylate) showed high selectivity against COX-2, favourable drug-likeness and ADME descriptors, a lack of cytotoxicity, relived paw edema, and inflammation without noticeable side effects on the stomach. These two compounds are promising new NSAIDs.

Highlights

Inflammation is a chain of physiological responses involving a wide range of different molecules and cellular responses [1]
The rationale behind this study was to discover new selective COX-2 inhibitors utilizing virtual screening of a library of chemical compounds that consisted of 1.2 million compounds from the Chembridge Inc core library
Following a two-step, virtual screening procedure that included standard precision docking (SP) followed by extreme precision docking (XP), the compounds with the highest docking scores were obtained from the database (Figure 1)

Summary

Introduction

Inflammation is a chain of physiological responses involving a wide range of different molecules and cellular responses [1]. Leukotrienes (LTs) are the first class of mediators that contribute to the inflammatory process, and they play a significant part in the inflammatory process overall. Arachidonate 5-lipoxygenase (5-LOX) [2,3]. The second set is more diverse and comes in effect after the activity of COXs that convert arachidonic acid to prostaglandin. PGE2 and PGI2 increase blood flow in inflamed areas by their potent vasodilator action. The vasodilation effect of Prostacyclin E2 and Prostacyclin I2 contributes to the protection of the gastric mucosa by boosting mucus secretion and preventing an increase in acidity and pepsin content in the stomach. PGE and PGI play roles in increasing the flow of the blood and regulation of the glomerular filtration rate [4,5]

Methods

Results

Discussion

Conclusion