Design, Synthesis, Antifungal Activity, Structure-Activity Relationship Of Novel Amide Fungicides

Amide fungicides, an old type of fungicide, it crossed the half-century of history and still play an important role in the agricultural chemistry field nowadays. Amide fungicides target the complex II (succinate dehydrogenase, SDH) in the mitochondrial respiratory chain. As SDH inhibitors (SDHIs), they can inhibit the growth and even cause the death of pathogens by disrupting the mitochondrial tricarboxylic acid cycle and then interfering with their respiration. With the invention of a number of new high activity and broad spectrum of SDHIs, Amide fungicides become one of the hot pot of new direction in development of pesticides again.Most of the heterocyclic compounds containing nitrogen atom have broad biological activities. After analyzing the structure of the known amides in most previous studies, based on bioisosterism and computational docking experiments, we introduced a N atom to replace the C atom and thus designed and synthesized the target compounds (a,b and c).159novel amide compounds were designed and synthesized. All the compounds were confirmed by1H NMR、13C NMR and HRMS.All the target compounds were tested for their activities against seven phytopathogenic fungi {Rhizoctonia solani, Colletotrichum orbiculare, Phytophthora infestans (Mont.) De Bary, Pythium aphanidermatum, Fusarium moniliforme Sheld, Botryosphaeria berengeriana, Botrytis cinerea) by an in vitro mycelia growth inhibitionassay. Most of them displayed moderate activity. The antifungal activity of N-acyl-2-(substituted amino) anilines are higher than N-acyl-2-substituted phenyl pyridine-3-anilines. The N-acyl-2-(benzothiazol-2-yl) anilines exhibit poor activity. The compounds ZNQ-15090,ZNQ-15092,ZNQ-15095>ZNQ-15105andZNQ-15115exhibit higher activity to the most fungi at their concentration of50μg/mL. Precision virulence test results showed that compound ZNQ-15092and ZNQ-15115exhibited the highest antifungal activity against seven kind of phyto-pathogenic fungi. Their antifungal activity and broad spectrum are slightly higher than boscalid. Bioassay in vivo results show that the compound ZNQ-15008cucumber anthracnose, ZNQ-15074rice blast a higher inhibition.QSAR Studies (CoMFA、CoMSIA�'�Topomer CoMFA) show that the stereoselectivity and positively charged on the benzene ring of Indazolyl given a higher activity to compounds with a indazolyl.The research results of docking show that the target compound and boscalid adopted similar conformations and locations in the active site. They were both well bound to the receptor protein with their carboxyl oxygen forming hydrogen bonds toward the hydroxyl hydrogen of TYR58and the amino hydrogen of TRP173. The Total_Score of target compounds are higher than boscalid. Explained the indazolyl aniline binding more tightly than biphenyl aniline receptor in the SDH ligand binding pocket, suggesting that the introduction of the groups in the binding to the receptor level is very favorable.