A substituted 3,4-dihydropyrimidinone derivative (compound D22) prevents inflammation mediated neurotoxicity; role in microglial activation in BV-2 cells

• Published in: Bioorganic & medicinal chemistry letters 2012-08, Vol.22 (16), p.5199-5203
• Main Authors: Kwon, Oh Wook, Moon, Eunjung, Chari, Murugulla A., Kim, Tae Woo, Kim, Ae-jung, Lee, Pyeongjae, Ahn, Kwang-Hyun, Kim, Sun Yeou
• Format: Article
• Language: English
• Subjects: Animals; anti-inflammatory activity; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Apoptosis - drug effects; bcl-2-Associated X Protein - metabolism; Biological and medical sciences; Caspase 3 - chemistry; Caspase 3 - metabolism; caspase-3; cell death; Cell Line; chemistry; Cyclooxygenase 2 - metabolism; DHPM; Dinoprostone - metabolism; Ethyl 6-methyl-4-(3-phenoxyphenyl)-2-thioxo-3,4-dihydropyrimidine-5-carboxylate; inflammation; Inflammation - metabolism; Inflammation - prevention & control; interleukin-1beta; Interleukin-1beta - metabolism; Lipopolysaccharides - toxicity; Medical sciences; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; neurodegenerative diseases; Neuroinflammation; neurons; Neuroprotection; neurotoxicity; nitric oxide; Nitric Oxide - metabolism; nitric oxide synthase; Nitric Oxide Synthase Type II - metabolism; Pharmacology. Drug treatments; prostaglandin synthase; prostaglandins; proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Thiones - chemical synthesis; Thiones - chemistry; Thiones - pharmacology; Toxicity Tests; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.06.082

A novel synthetic 3,4-dihydropyrimidinone derivative, compound D22 (ethyl 6-methyl-4-(3-phenoxyphenyl)-2-thioxo-3,4-dihydropyrimidine-5-carboxylate), was found to exert anti-inflammatory properties in lipopolysaccharide-stimulated microglial BV-2 cells. Compound D22 reduced the pro-inflammatory factors such as nitric oxide, prostaglandin E2, tumor necrosis factor-α and interleukin-1β. Moreover, it suppressed the expressions of inducible NO synthase and cyclooxygenase-2. Compound D22 inhibited the activation of mitogen-activated protein kinases. When compound D22-conditioned media from BV-2 cells were applied to N2a cells, neuronal cell death was inhibited via suppression of caspase-3 activation and regulation of Bcl-2 and Bax proteins expression. These results suggest that compound D22 may be useful for treating neurodegenerative diseases related with neuroinflammation.