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

Liang Ma; Linhong He; Lei Lei; Xiaolin Liang; Kai Lei; Ronghong Zhang; Zhuang Yang; Lijuan Chen

doi:10.1111/cbdd.12386

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

Chem Biol Drug Des. 2015 Mar;85(3):296-9. doi: 10.1111/cbdd.12386. Epub 2014 Sep 5.

Authors

Liang Ma¹, Linhong He, Lei Lei, Xiaolin Liang, Kai Lei, Ronghong Zhang, Zhuang Yang, Lijuan Chen

Affiliation

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.

PMID: 24985766
DOI: 10.1111/cbdd.12386

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.

Keywords: 5-nitropyrimidine-2,4-dione; docking study; inducible NOS; nitric oxide production; paw edema.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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