5-Substituted 2-amino-4,6-dihydroxypyrimidines and 2-amino-4,6-dichloropyrimidines: synthesis and inhibitory effects on immune-activated nitric oxide production

Abstract

A series of 5-substituted 2-amino-4,6-dihydroxypyrimidines were prepared by a modified condensation of the corresponding monosubstituted malonic acid diesters with guanidine in an excess of sodium ethoxide. The optimized procedure using Vilsmeier-Haack-Arnold reagent, followed by immediate deprotection of the (dimethylamino)methylene protecting groups, has been developed to convert the 2-amino-4,6-dihydroxypyrimidine analogs to novel 5-substituted 2-amino-4,6-dichloropyrimidines in high yields. Pilot screening for biological properties of the prepared compounds was done in mouse peritoneal cells using the in vitro nitric oxide (NO) assay. Irrespective of the substituent at the 5 position, 2-amino-4,6-dichloropyrimidines inhibited immune-activated NO production. The most effective was 5-fluoro-2-amino-4,6dichloropyrimidine with an IC 50 of 2 lM (higher activity than the most potent reference compound) while the IC 50 s of other derivatives were within the range of 9-36 lM. The 2-amino-4,6-dihydroxypyrimidine counterparts were devoid of any NO-inhibitory activity. The compounds had no suppressive effects on the viability of cells. The Mechanism of action remains to be elucidated.

Research developments in the syntheses, anti-inflammatory activities and structure–activity relationships of pyrimidines

“…Compounds (112 and 114) were noticed to be more potent inhibitors than 7-nitro-1H-indazole (7-NI) versus nNOS and eNOS, respectively. Similarly, all the six pyrido[1,2-a] pyrimidines (112)(113)(114)(115)(116)(117) potently suppressed the iNOS, with derivatives (114 and 115) being noticed to be stronger inhibitors than L-NNA under the same experimental conditions. The IC 50 values of the tested derivatives were calculated to be 10-100 mM with reference to L-NNA, and 7-NI.…”

“…Moreover, nNOS was partially suppressed by 100 mM of four derivatives (111)(112)(113)(114). The eNOS was most potently inhibited by three derivatives (113)(114)(115)) (all at 100 mM). Compounds (112 and 114) were noticed to be more potent inhibitors than 7-nitro-1H-indazole (7-NI) versus nNOS and eNOS, respectively.…”

“…Additionally, they had no suppressive effects on the survival of the cells. 113 Numerous polysubstituted pyrimidines carrying several substituents (-H, -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH(CH 3 ) 2 , -CH 2 -C^CH, -CH 2 -HC]CH 2 , -C 4 H 9 , -CH(CH 3 )-CH 2 -CH 3 , -C 6 H 5 , -CH 2 -C 6 H 5 , and -F) at position-5 of the ring were studied for their potential to suppress the immune-induced NO production. The inhibitory effects of such pyrimidines were evaluated against the in vitro generation of immune-stimulated NO in mouse peritoneal cells.…”

Investigation of Novel Pesticides with Insecticidal and Antifungal Activities: Design, Synthesis and SAR Studies of Benzoylpyrimidinylurea Derivatives

“…Intermediate In was prepared according to [ 19 ]. Elemental sodium (0.30 g, 13.0 mmol) was added into absolute ethanol (7 mL) under N 2 while being intensively stirred with a magnetic stirrer.…”

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

“…Bayramoğlu et al accomplished the synthesis of 2-aminopyrimidines 3a–f ( Scheme 1 ) by performing the corresponding reactions under both conventional and ultrasonic irradiation conditions. Conventional methods of pyrimidine synthesis have long reaction times and the crude product yields vary from 54–78% [ 34 , 35 , 36 , 37 ], while the ultrasound-assisted cyclization reactions facilitate the formation of target molecules in less than 1 h. Strong bases such as NaOC 2 H 5 were used in several experiments giving final yields close to those of the conventional method. Numerous experimental parameters were explored in an effort to optimize the synthetic procedures.…”