Polysubstituted 4,6-bis(hetero)arylpyrimidines as dual inhibitors of nitric oxide and prostaglandin E2 production

•Synthesis of novel polysubstituted 2-aminopyrimidine derivatives.•Significant inhibition of immune-activated production of nitric oxide.•Low micromolar dual inhibitors of nitric oxide and prostaglandin E2 production.•Potential anti-inflammatory properties.

As a part of our extensive structure-activity relationship study of anti-inflammatory heterocycles, a novel series of 67 polysubstituted 2-aminopyrimidines was prepared bearing one (at the C-4 position of the pyrimidine ring) or two (in the C-4 and C-6 positions) (hetero)aryl substituents attached directly through the C-C bond. The key synthetic steps involved either Suzuki-Miyaura or Stille cross-coupling reactions carried out on easily available 4,6-dichloropyrimidines. All prepared compounds, except one, were able to inhibit immune-activated production of nitric oxide (NO) significantly. Moreover, several compounds were found to be low micromolar dual inhibitors of NO and prostaglandin E2 (PGE2) production. Although the exact mode of action of the prepared compounds remains to be elucidated, non-toxic dual inhibitors of NO and PGE2 production may have great therapeutic benefit in treatment of various inflammation diseases and deserve further preclinical evaluation.

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