Design, Synthesis and Pharmacological Evaluation of Gastro- Protective Anti-inflammatory Analgesic Agents based on Dual Oxidative Stress / Cyclooxygenase Inhibition.
Anti-Inflammatory Agents, Non-Steroidal
/ pharmacology
Antioxidants
/ pharmacology
Cyclooxygenase Inhibitors
/ pharmacology
Drug Design
In Vitro Techniques
Inflammation
/ drug therapy
Molecular Docking Simulation
Organs at Risk
Oxidative Stress
/ drug effects
Pain
/ drug therapy
Stomach
/ drug effects
Stomach Ulcer
/ chemically induced
Benzimidazole
analgesics.
cyclooxygenase
gastro protective
inflammation
oxidative stress
Journal
Anti-inflammatory & anti-allergy agents in medicinal chemistry
ISSN: 1875-614X
Titre abrégé: Antiinflamm Antiallergy Agents Med Chem
Pays: United Arab Emirates
ID NLM: 101462262
Informations de publication
Date de publication:
2020
2020
Historique:
received:
04
02
2019
revised:
12
03
2019
accepted:
20
03
2019
pubmed:
28
3
2019
medline:
3
8
2021
entrez:
28
3
2019
Statut:
ppublish
Résumé
Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration. Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects. In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed. Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research. From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.
Sections du résumé
BACKGROUND
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) derived local generation of reactive oxygen species (ROS) plays a crucial role in the formation of gastric ulceration.
OBJECTIVE
OBJECTIVE
Therefore, anti-inflammatory analgesics with potent antioxidant activity could be a potential therapeutic strategy for the treatment of pain and inflammatory disorders without gastrointestinal (GI) side effects.
METHODS
METHODS
In an effort to develop gastroprotective analgesic and anti-inflammatory agents, a series of 2-methylamino-substituted-1H-benzo[d] imidazol-1-yl) (phenyl) methanone derivatives were synthesized and evaluated in vitro for cyclooxygenase (COX) inhibition as well as anti-oxidant potential by the FRAP assay. The compounds with significant in vitro COX-1/COX-2 inhibitory activity and antioxidant activity were further screened in vivo for their anti-inflammatory and analgesic activities. Moreover, the ulcerogenic potential of test compounds was also studied. To gain insight into the plausible mode of interaction of compounds within the active sites of COX-1 and COX-2, molecular docking simulations were performed.
RESULTS
RESULTS
Among the various synthesized molecules, most of the compounds showed good cyclooxygenase inhibitory activity and efficient antioxidant activity in FRAP assay. After preliminary and indicative in vitro assays, three compounds exhibited most significant antiinflammatory and analgesic activity with better gastric tolerability during their in vivo evaluation. Ligand interaction studies indicated highest dock score -43.05 of 1,2- disubstituted benzimidazole derivatives in comparison to the reference ligand -30.70. Overall studies provided us (2-((4-methoxyphenylamino) methyl) -1h-benzo [d] imidazol- 1-yl) (phenyl) methanone as a lead with potent gastro-protective anti-inflammatory and analgesic activities that can be used for future research.
CONCLUSION
CONCLUSIONS
From the above results, it can be concluded that designing of multifunctional molecules with COX-1/COX-2 inhibitory and anti-oxidant activities could hold a great promise for further development of GI-safer NSAIDs.
Identifiants
pubmed: 30914035
pii: AIAAMC-EPUB-97529
doi: 10.2174/1871523018666190325155244
doi:
Substances chimiques
Anti-Inflammatory Agents, Non-Steroidal
0
Antioxidants
0
Cyclooxygenase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
268-290Informations de copyright
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