Design, synthesis and biological evaluation of benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivatives as potential dual cyclooxygenase-2/5-lipoxygenase inhibitors
| Autor: | Chen-Ming Tan, Grace Shiahuy Chen, Chien Shu Chen, Ji-Wang Chern, Pei-Teh Chang |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry Clinical Biochemistry Anti-Inflammatory Agents Pharmaceutical Science Biochemistry Mass Spectrometry Inhibitory Concentration 50 Structure-Activity Relationship Drug Discovery Ic50 values Animals Edema Humans Moiety Structure–activity relationship Lipoxygenase Inhibitors Rats Wistar Molecular Biology Biological evaluation chemistry.chemical_classification Arachidonate 5-Lipoxygenase Cyclooxygenase 2 Inhibitors Molecular Structure biology Chemistry Organic Chemistry Rats Thiazoles Design synthesis Cyclooxygenase 2 Ylide Arachidonate 5-lipoxygenase biology.protein Molecular Medicine Cyclooxygenase |
| Zdroj: | Bioorganic & Medicinal Chemistry. 19:6316-6328 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2011.09.003 |
| Popis: | 3-(4-Bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide (5) was discovered as a new prototype for dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Thus, the structure–activity relationships of benzo[1.3.2]dithiazolium ylide 1,1-dioxide skeleton were carried out. The 6-NO2 group played an essential role in the inhibitory activity. In addition, moderate-sized lipophilic substituents at the para-position of the 3-aryl moiety were required for dual COX-2/5-LOX inhibitory activity. Among the identified potent dual inhibitors, 3-(4-tbutylphenyl) derivative 30c (IC50 values of 0.27 μM and 0.30 μM against COX-2 and 5-LOX, respectively) and 3-(4-biphenyl) derivative 30f (IC50 values of 0.50 μM and 0.15 μM against COX-2 and 5-LOX, respectively) were the most potent dual COX-2/5-LOX inhibitors. Intraperitoneal administration of 30c at 100 mg/kg demonstrated potent acute anti-inflammatory activity. As a result, benzo[1.3.2]dithiazolium ylide 1,1-dioxide represented a novel scaffold for the exploitation in developing dual COX-2/5-LOX inhibitors. |
| Databáze: | OpenAIRE |
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