Biomaterial Database

Synthesis and biological evaluation of new nicotinate derivatives as potential anti-inflammatory agents targeting COX-2 enzyme. 2021

Yara El-Dash, and Nadia A Khalil, and Eman M Ahmed, and Marwa S A Hassan

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: yara.el-dash@pharma.cu.edu.eg.

Two novel series derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against cyclooxygenases COX-1 and COX-2, and their selectivity indices were determined. Celecoxib, diclofenac and indomethacin were used as reference drugs. All compounds showed highly potent COX-2 inhibitory activity and higher selectivity towards COX-2 inhibition compared to indomethacin. In addition, these compounds except 3a showed clear preferential COX-2 over COX-1 inhibition compared to diclofenac. Compounds 3b, 3e, 4c and 4f showed COX-2 inhibitory activity equipotent to celecoxib. Compounds 4c and 4f demonstrated selectivity indices 1.8-1.9 fold higher than celecoxib. These two most potent and COX-2 selective compounds were further tested in vivo for anti-inflammatory activity by means of carrageenan induced rat paw edema method. Ulcerogenic activity with histopathological studies were performed. The results showed no ulceration, which implies their safe gastric profile. Compound 4f exhibited the most potent in vivo anti-inflammatory activity comparable to all reference drugs. Further, compounds 4c and 4f were investigated for their influence on certain inflammatory cytokines TNF-α and IL-1β in addition to PEG2. The findings revealed that these candidates could be identified as promising potent anti-inflammatory agents. Molecular docking of 4c and 4f in the COX-2 active site was performed to rationalize their COX-2 inhibitory potency. The results were found to be in line with the biological findings as they exerted more favorable interactions compared to that of celecoxib, explaining their remarkable COX-2 inhibitory activity.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D009525	Niacin	A water-soluble vitamin of the B complex occurring in various animal and plant tissues. It is required by the body for the formation of coenzymes NAD and NADP. It has PELLAGRA-curative, vasodilating, and antilipemic properties.	Nicotinic Acid,3-Pyridinecarboxylic Acid,Enduracin,Induracin,Lithium Nicotinate,Niacin Aluminum Salt,Niacin Ammonium Salt,Niacin Calcium Salt,Niacin Cobalt (2+) Salt,Niacin Copper (2+) Salt,Niacin Hydrochloride,Niacin Iron (2+) Salt,Niacin Lithium Salt,Niacin Lithium Salt, Hemihydrate,Niacin Magnesium Salt,Niacin Manganese (2+) Salt,Niacin Potassium Salt,Niacin Sodium Salt,Niacin Tartrate,Niacin Tosylate,Niacin Zinc Salt,Nicamin,Nico-400,Nicobid,Nicocap,Nicolar,Nicotinate,Wampocap,3 Pyridinecarboxylic Acid,Aluminum Salt, Niacin,Hydrochloride, Niacin,Nico 400,Nico400,Nicotinate, Lithium,Potassium Salt, Niacin,Sodium Salt, Niacin,Tartrate, Niacin,Tosylate, Niacin
D004008	Diclofenac	A non-steroidal anti-inflammatory agent (NSAID) with antipyretic and analgesic actions. It is primarily available as the sodium salt.	Diclophenac,Dichlofenal,Diclofenac Potassium,Diclofenac Sodium,Diclonate P,Dicrofenac,Feloran,GP-45,840,Novapirina,Orthofen,Orthophen,Ortofen,SR-38,Sodium Diclofenac,Voltaren,Voltarol,Diclofenac, Sodium,GP 45,840,GP45,840,SR 38,SR38
D004487	Edema	Abnormal fluid accumulation in TISSUES or body cavities. Most cases of edema are present under the SKIN in SUBCUTANEOUS TISSUE.	Dropsy,Hydrops,Anasarca
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000893	Anti-Inflammatory Agents	Substances that reduce or suppress INFLAMMATION.	Anti-Inflammatory Agent,Antiinflammatory Agent,Agents, Anti-Inflammatory,Agents, Antiinflammatory,Anti-Inflammatories,Antiinflammatories,Antiinflammatory Agents,Agent, Anti-Inflammatory,Agent, Antiinflammatory,Agents, Anti Inflammatory,Anti Inflammatories,Anti Inflammatory Agent,Anti Inflammatory Agents
D000897	Anti-Ulcer Agents	Various agents with different action mechanisms used to treat or ameliorate PEPTIC ULCER or irritation of the gastrointestinal tract. This has included ANTIBIOTICS to treat HELICOBACTER INFECTIONS; HISTAMINE H2 ANTAGONISTS to reduce GASTRIC ACID secretion; and ANTACIDS for symptomatic relief.	Anti-Ulcer Drugs,Agents, Anti-Ulcer,Anti Ulcer Agents,Anti Ulcer Drugs,Drugs, Anti-Ulcer
D001665	Binding Sites	The parts of a macromolecule that directly participate in its specific combination with another molecule.	Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013276	Stomach Ulcer	Ulceration of the GASTRIC MUCOSA due to contact with GASTRIC JUICE. It is often associated with HELICOBACTER PYLORI infection or consumption of nonsteroidal anti-inflammatory drugs (NSAIDS).	Gastric Ulcer,Gastric Ulcers,Stomach Ulcers,Ulcer, Gastric,Ulcer, Stomach,Ulcers, Gastric,Ulcers, Stomach
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships