Synthesis of 2,6-dialkyl derivatives of pyrimidine-4 (1H)-one with an anti-inflammatory effect

Introduction. Pharmaceutical science requires that new highly effective nonsteroidal anti-inflammatory drugs (NSAIDs) should be sought because of different negative pharmacological properties of this group of drugs. Previous studies may suggest that further molecular design of novel anti-inflammatory structures should be carried out by varying with different alkyl substituents at 2 and 6 positions of the heterocyclic nucleus. Objective: to synthetize 2,6-dialkyl N-sulfonamide and N-diphenylsulfone derivatives of pyrimidine-4(1H)-one, which have a pronounced anti-inflammatory effect compared to that of the comparison drug. Material and methods. The targeted products were obtained by cyclocondensation of N-acyl-β-ketoamides with aromatic amines in acetic acid. The purity of the synthesized substances was determined by thin-layer chromatography (TLC); the structure of the synthesized compounds was confirmed by spectral studies. The synthesis of the predicted substances used 4-aminobenzenesulfonamide and 2-(4-aminobenzenesulfonamide)-thiazole and 4,4'-diaminodiphenylsulfone as primary aromatic amines. Their anti-inflammatory activity was investigated using a model of acute exudative inflammation according to the guidelines for the study of anti-inflammatory activity versus that of diclofenac, one of the most widely used NSAIDs. Results. The yield of 6-methyl-2-ethylpyrimidine-4(1H)-one derivatives was found to be higher than that of 2-methyl-6-ethylpyrimidine-4(1H)-one. The difference in the yields of the reaction products can be explained by the spatial structure of the starting carbonyl compound, which considerably affects its reactivity. The results of primary pharmacological screening for acute aseptic inflammation could reveal the leading compounds with anti-inflammatory activity at the level of the comparison drug diclofenac. Conclusion. Based on the spatial structure of N-acyl-β-ketoamides, the authors explained the yields of 2,6-dialkyl derivatives of pyrimidine-4 (1H)-one with fragments of 4-aminobenzenesulfonamide, 2-(4-aminobenzenesulfamide)-thiazole and 4,4'-diaminodiphenylsulfone. The investigation of the targeted compounds for anti-inflammatory activity could identify the most promising compounds among them, which had an effect commensurable with that of diclofenac.

2,6-dialkylpyrimidine-4(1H)-one derivatives, quantum chemical calculations, anti-inflammatory activity