Design, synthesis and SAR study of novel sulfonylurea derivatives containing arylpyrimidine moieties as potential anti-phytopathogenic fungal agents

Abstract

Acetohydroxyacid synthase (AHAS) was considered as a promising target for antifungal agents. Herein, three series of novel sulfonylureas (SUs) 9−11 containing aromatic-substituted pyrimidines were designed and synthesized according to pharmacophore-combination and bioisosterism strategy. The in vitro fungicidal activities against ten phytopathogenic fungi indicated that most of the title compounds exhibited broad-spectrum and excellent fungicidal activities. Based on the preliminary fungicidal activities, a CoMFA model was constructed and the 3D-QSAR analysis indicated that either a bulky group around the 5-position of the pyrimidine ring or electropositive group around the 2-position of the benzene ring would be favour to fungicidal activities. In order to study interaction mechanism, 10k was automatically docked into yeast AHAS and it further indicated that bearing bulky groups-aryl at the pyrimidine ring was critical to enhance antifungal activities. It revealed that the antifungal activity of derivatives 9−11 probably results from the inhibition of fungal AHAS. Thus, the present results strongly showed that SUs should be considered as lead compounds or model molecules to develop novel anti-phytopathogenic fungal agents.