Design, synthesis and biological evaluation of new pyridine/bipyridine carbonitriles and some related compounds Interfering with arachidonic acid pathway as potential anti-inflammatory agents

Management of inflammation constitutes an unmet medical need because more people are afflicted with these conditions than any other disease state. Thus, there is a rising demand for safer and efficacious anti-inflammatories. Two pathways correlated to the arachidonic acid (ARA) cascade have been recognized, namely cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Emerging approaches for the treatment of inflammation have shifted towards simultaneously targeting multiple enzymes in the ARA cascade through combination therapy and multi-target inhibitors, to circumvent the risks associated with single enzyme or pathway inhibition. Pyridine nucleus represents an important scaffold in drug discovery due to its diversified biological activities. Based on these premises, it was rationalized to synthesize some pyridine/bipyridine carbonitrile derivatives and some related compounds, substituted or fused to other heterocyclic/aromatic rings, to be explored for their anti-inflammatory activity.

In vitro assay results revealed that 5 compounds showed significant COX-2 inhibitory potential with IC₅₀ values of 0.1 µM, compared to 0.049 µM for the reference celecoxib. 15-LOX inhibitory activities of the test compounds were also assessed (IC₅₀ values 2.09-7.21 µM, compared to 3.34 µM for the reference quercetin). Three compounds showed significant in vivo anti-inflammatory activity (higher % inhibition of edema than celecoxib). Moreover, histopathological examination revealed that they showed superior gastrointestinal safety profile (normal gastric mucosa with no ulceration). Some compounds reduced the expression levels of pro-inflammatory enzymes (COX-2 and iNOS) while increased that of anti-inflammatory cytokine (IL-10) in LPS-stimulated monocytes. They also restored TNF-α titer to the normal level of the control untreated cells. Docking of the most active compounds into COX-2 and 15-LOX active sites showed similar binding pattern to those of the cocrystallized ligands.