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Open AccessArticle

Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

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Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
3
Rangel College of Pharmacy, Health Science Center, Texas A & M University, Kingsville, TX 78363, USA
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Department of Pharmacology, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
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Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
6
Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
*
Author to whom correspondence should be addressed.
Molecules 2016, 21(2), 201; https://doi.org/10.3390/molecules21020201
Received: 18 December 2015 / Revised: 29 January 2016 / Accepted: 1 February 2016 / Published: 8 February 2016
(This article belongs to the Special Issue Drug Design and Discovery: Principles and Applications)
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed anti-inflammatory and pain relief medications. However, their use is associated with many drawbacks, including mainly serious gastric and renal complications. In an attempt to circumvent these risks, a set of N-(4-bromophenyl)-7-cyano-6-substituted-H-pyrrolizine-5-carboxamide derivatives were designed, synthesized and evaluated as dual COX/5-LOX inhibitors. The structural elucidation, in vivo anti-inflammatory and analgesic activities using a carrageenan-induced rat paw edema model and hot plate assay, were performed, respectively. From the results obtained, it was found that the newly synthesized pyrrolizines exhibited IC50 values in the range of 2.45–5.69 µM and 0.85–3.44 µM for COX-1 and COX-2, respectively. Interestingly, compounds 12, 13, 16 and 17 showed higher anti-inflammatory and analgesic activities compared to ibuprofen. Among these derivatives, compounds 16 and 19 displayed better safety profile than ibuprofen in acute ulcerogenicity and histopathological studies. Furthermore, the docking studies revealed that compound 17 fits nicely into COX-1 and COX-2 binding sites with the highest binding affinity, while compound 16 exerted the highest binding affinity for 5-LOX. In light of these findings, these novel pyrrolizine-5-carboxamide derivatives represent a promising scaffold for further development into potential dual COX/5-LOX inhibitors with safer gastric profile. View Full-Text
Keywords: pyrrolizine; anti-inflammatory; analgesic; COX; 5-LOX; ulcerogenicity pyrrolizine; anti-inflammatory; analgesic; COX; 5-LOX; ulcerogenicity
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MDPI and ACS Style

Gouda, A.M.; Ali, H.I.; Almalki, W.H.; Azim, M.A.; Abourehab, M.A.S.; Abdelazeem, A.H. Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability. Molecules 2016, 21, 201.

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