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Non-selective inhibition of cyclooxygenase enzymes by aminoacetylenic isoindoline 1,3-diones.
MedLine Citation:
PMID:  22583483     Owner:  NLM     Status:  Publisher    
The reported pharmacological activities of acetylenic and phthalimide groups promoted our interest to synthesize a novel series of N-[4-(t-amino-yl)-but-2-yn-1-yl] isoindoline-1,3-diones as an anti-inflammatory compounds. The aim of this research is to investigate the selectivity of two compounds designed, called ZM4 and ZM5, on inhibiting cyclooxygenase (COX) in vitro and in silico as well as reducing carrageenan-induced edema in rats. Oral administration of 5-20 mg/kg ZM4 and ZM5 reduced significantly carrageenan-induced edema in dose-and time dependent manner. Furthermore, the IC50 induced by ZM4 and ZM5 were in the range of 3.0-3.6 µM for COX1 and COX 2 but were higher than those induced by Diclofenac and Celecoxib, respectively. Docking of ZM4 and ZM5 in both COX enzymes, on the other hand, exhibited the conventional binding modes that usually adopted by different non-steroidal anti-inflammatory drugs (NSAIDs). Furthermore, they were able to bind to COX enzymes as strongly as Flurbiprofen and Celecoxib. In conclusion, aminoacetylenic isoindoline 1, 3-dione compounds have shown anti-inflammatory activity by inhibiting COX-1 and COX-2 enzymes. Interestingly, the best hits showed inhibition at low micromolar levels although they are not selective at this stage. Further research will be conducted to improve both selectivity and potency of our best hits.
Nidal A Qinna; Zuhair A Muhi-Eldeen; Mohammad Ghattas; Tawfiq M Alhussainy; Jenan Al-Qaisi; Khalid Z Matalka
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-11
Journal Detail:
Title:  Inflammation & allergy drug targets     Volume:  -     ISSN:  2212-4055     ISO Abbreviation:  Inflamm Allergy Drug Targets     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101266886     Medline TA:  Inflamm Allergy Drug Targets     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, Petra University, Amman, Jordan.
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