Synthetically-tailored and nature-derived dual COX-2/5-LOX inhibitors: Structural aspects and SAR

Abstract

Inflammation is a most complex pathological process that gives birth to different diseases. Different inflammatory mediators are released during an inflammation responsible for acute pain and chronic inflammatory diseases like cancer, asthma, rheumatoid arthritis, osteoarthritis, neurodegenerative diseases, metabolic and cardiovascular disorders. The arachidonic acid pathway, which results in the production of inflammatory mediators, provides several targets for anti-inflammatory intervention. The most popularly used medications for inflammation are non-steroidal anti-inflammatory agents (NSAIDs) but it has some limitations, in particular traditional NSAIDs which inhibit the COX pathway non-selectively, producing gastrointestinal side effects, and other adverse effects like stroke and renal failure. On the other hand, selective COX-2 inhibitors commonly known as 'coxibs' produce cardiovascular side effects. Frequent inhibition of either cyclooxygenase or lipoxygenase enzyme switches the metabolism of arachidonic acid from one to another which could lead to serious consequences. Therefore, a need to develop novel, effective and safe anti-inflammatory agents which can inhibit the release of both prostaglandins and leukotrienes from the respective cyclooxygenase and lipoxygenase pathways has emerged. This resulted in the discovery of new anti-inflammatory agents derived from natural and synthetic sources as dual COX-2/5-LOX inhibitors. To further contribute towards the discovery in this field, we have attempted to summarize structural features and pharmacological activities of heterocyclic scaffolds and natural products explored as dual COX-2/5-LOX inhibitors. We have emphasized the designing of the dual inhibitors inspired by the previously reported COX-2 and 5-LOX inhibitors. This outline could render us to identify the best pharmacophores catering to dual COX-2/5-LOX inhibitory activity while improving their efficiency as anti-inflammatory agents.

Keywords: 5-Lipoxygenase; Arachidonic acid pathway; Cyclooxygenase-2; Dual COX-2/5-LOX inhibitors; Inflammation.