Synthesis and structure-activity relationship studies of polysubstituted pyrimidines as inhibitors of immune-activated nitric oxide production
Abstract
Based on the previous discovery of the inhibitory effect of the 5-substituted 2-amino-4,6-dichloropyrimidines on nitric oxide (NO) production in vitro, a series of novel pyrimidine derivatives, namely 4,6-dichloro-2-[(N,N-dimethylamino)methyleneamino]pyrimidines, 2,4-diamino-6-chloropyrimidines, and 2,4-diamino-6-(2-hydroxyethoxy)pyrimidines, were prepared bearing various substituents at the C-5 position on the pyrimidine, such as hydrogen, methyl, ethyl, propyl, isopropyl, propargyl, allyl, butyl, sec-butyl, phenyl, benzyl, and fluorine. The intrinsic biological potential of the prepared compounds was characterized by effects on the in vitro production of immune-activated NO in mouse peritoneal cells.
All 5-substituted 4,6-dichloro-2-[(N,N-dimethylamino)methyleneamino]pyrimidines strongly inhibited NO production. The IC(50)s were < 5 A mu M in most cases.
The highest inhibitory activity was observed for the 5-sec-butyl analog (IC50 = 2.57 A mu M), the lowest one for 5-unsubtituted compound (IC50 = 11.49 A mu M). With the exception of the 5-fluoro-4,6-dichloro-2-[(N,N-dimethylamino)methyleneamino] derivative, all other compounds were devoid of cytotoxic effects.
The hitherto obtained data suggest that the NO-inhibitory activity depends on the presence of the 2-amino-4,6-dichloropyrimidine scaffold.