Synthesis and biological evaluation of 5-nitropyrimidine-2,4-dione analogues as inhibitors of nitric oxide and iNOS activity.

Abstract

Fifty two compounds based on 5-nitropyrimidine-2,4-dione moiety have been synthesized and evaluated for their inhibitory potency on the production of nitric oxide. Among them, compound 36 inhibited the production of nitric oxide (IC50 : 8.6 μm) on lipopolysaccharide-induced RAW 264.7 cells and inducible nitric oxide synthase activity (IC50 : 6.2 μm), as well as exerted no potential cytotoxicity (IC50 > 80.0 μm). Docking study confirmed that compound 36 was an inducible nitric oxide synthase inhibitor with perfect binding to the active site of inducible nitric oxide synthase. At a dose of 10 mg/kg, oral administration of 36 possessed protective properties in carrageenan-induced paw edema of male ICR mice.

• Authors: Liang Ma, Linhong He, Lei Lei, Xiaolin Liang, Kai Lei, Ronghong Zhang, Zhuang Yang, Lijuan Chen
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 85 Issue 3 Pg. 296-9 (Mar 2015) ISSN: 1747-0285 [Electronic] England
• PMID: 24985766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons A/S.

Chemical References

• 5-nitro-6-(3-nitrostyryl)pyrimidine-2,4(1H,3H)-dione
• Enzyme Inhibitors
• Lipopolysaccharides
• Pyrimidinones
• Styrenes
• Nitric Oxide
• Uracil
• Carrageenan
• Nitric Oxide Synthase Type II

Topics

• Administration, Oral
• Animals
• Binding Sites
• Carrageenan (toxicity)
• Catalytic Domain
• Cell Line
• Drug Evaluation, Preclinical
• Edema (chemically induced, drug therapy)
• Enzyme Inhibitors (chemical synthesis, pharmacology, therapeutic use)
• Hydrogen Bonding
• Lipopolysaccharides (toxicity)
• Macrophages (cytology, drug effects, metabolism)
• Male
• Mice
• Mice, Inbred ICR
• Molecular Docking Simulation
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Pyrimidinones (chemistry, pharmacology, therapeutic use)
• Styrenes (chemical synthesis, therapeutic use, toxicity)
• Uracil (analogs & derivatives, chemical synthesis, therapeutic use, toxicity)