Design, synthesis and analgesic/anti-inflammatory evaluation of novel diarylthiazole and diarylimidazole derivatives towards selective COX-1 inhibitors with better gastric profile
| Autor: | Hany A. Omar, Asmaa G. Safi El-Din, Ahmed H. Abdelazeem, Samir M. El-Moghazy, Mohammed T. El-Saadi |
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| Rok vydání: | 2017 |
| Předmět: |
Male
medicine.drug_class Clinical Biochemistry Analgesic Pain Pharmaceutical Science Pharmacology Carrageenan 010402 general chemistry 01 natural sciences Biochemistry Anti-inflammatory Structure-Activity Relationship Mofezolac In vivo Drug Discovery medicine Animals Edema Humans Cyclooxygenase Inhibitors Molecular Biology IC50 Acetic Acid Analgesics Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Anti-Inflammatory Agents Non-Steroidal Organic Chemistry Imidazoles In vitro Rats 0104 chemical sciences Molecular Docking Simulation Thiazoles Gastric Mucosa Drug Design Glycine Cyclooxygenase 1 biology.protein Molecular Medicine Cattle Female Cyclooxygenase medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 25:665-676 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2016.11.037 |
| Popis: | The inhibition of gastric cyclooxygenase 1 (COX-1) enzyme was believed to be the major cause of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcer. Recent studies disproved this belief and showed that the gastric tissues vulnerability is not solely connected to COX-1 inhibition. This work aimed at exploring and rationalizing the differential analgesic and anti-inflammatory activities of novel selective COX-1 inhibitors with improved gastric profile. Two novel series of 4,5-diarylthiazole and diarylimidazole were designed, synthesized in analogy to selective COX-1 inhibitors (mofezolac and FR122047) which lack gastric damaging effects. The new compounds were evaluated in vitro for their COXs inhibitory activity and in vivo for their anti-inflammatory and analgesic potentials. Four compounds; diphenylthiazole glycine derivatives (15a, 15b) and diphenylimidazolo acetic acid derivatives (19a, 19b), which possess carboxylic acid group exhibited significant activity and selectivity against COX-1 over COX-2. Of these compounds, (4,5-bis(4-methoxyphenyl)thiazol-2-yl)glycine 15b was the most potent compound against COX-1 with an inhibitory half maximal concentration (IC50) of 0.32μM and a selectivity index (COX-2 IC50/COX-1 IC50) of 28.84. Furthermore, an ulcerogenicity study was performed where the tested compounds demonstrated a significant gastric tolerance. Interestingly, the most selective COX-1 inhibitor showed higher analgesic activity in vivo as expected compared to their moderate anti-inflammatory activity. This study underscores the need for further design and development of novel analgesic agents with low tendency to cause gastric damage based on improving their COX-1 affinity and selectivity profile. |
| Databáze: | OpenAIRE |
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