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Synthesis and structure–activity relationship studies of polysubstituted pyrimidines as inhibitors of immune-activated nitric oxide production

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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 IC50s were <5 µM in most cases. The highest inhibitory activity was observed for the 5-sec-butyl analog (IC50 = 2.57 µM), the lowest one for 5-unsubtituted compound (IC50 = 11.49 µM). 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.

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Acknowledgments

The research was supported by Grant CZ: GA ČR: GA303/12/0172 from the Czech Science Foundation and by the Ministry of Interior of the Czech Republic (VG20102015046).

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Authors and Affiliations

  1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10, Prague 6, Czech Republic

    Petr Jansa, Antonín Holý, Martin Dračínský, Viktor Kolman & Zlatko Janeba

  2. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20, Prague 4, Czech Republic

    Eva Kmoníčková & Zdeněk Zídek

  3. Institute of Pharmacology and Toxicology, Faculty of Medicine in Pilsen, Charles University, Karlovarská 48, 30 166, Pilsen, Czech Republic

    Eva Kmoníčková

Authors
  1. Petr Jansa
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  2. Antonín Holý
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  3. Martin Dračínský
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  4. Viktor Kolman
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  5. Zlatko Janeba
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  6. Eva Kmoníčková
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  7. Zdeněk Zídek
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Correspondence to Petr Jansa or Zdeněk Zídek.

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Antonín Holý—deceased.

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Jansa, P., Holý, A., Dračínský, M. et al. Synthesis and structure–activity relationship studies of polysubstituted pyrimidines as inhibitors of immune-activated nitric oxide production. Med Chem Res 24, 2154–2166 (2015). https://doi.org/10.1007/s00044-014-1285-5

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  • DOI: https://doi.org/10.1007/s00044-014-1285-5

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