Design, Synthesis, and Bioevaluation of Novel Strobilurin Derivatives  

作　　者：朱晓磊 王福 李慧 杨文超 陈琼 杨光富 

机构地区：[1]Key Laboratory of Pesticide and Chemical Biology of Ministry of Education College of Chemistry,Central China Normal University,Wuhan,Hubei 430079,China

出　　处：《Chinese Journal of Chemistry》2012年第9期1999-2008,共10页中国化学（英文版）

摘　　要：Strobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally benign characteristics. Design and syntheses of strobilurin analogues therefore have attracted great attention in the field of agrochemistry. Previously, we successfully developed a new molecular design method of pharmacophore-linked fragment virtual screening （PFVS） and discovered a lead compound （E）-methyl-2-（2-（（（3-（imino-（phenyl）- methyl）phenyl）thio）methyl）phenyl）-3-methoxyacrylate （1）. To discover new strobilurin analogues with higher fun- gicidal activity, the structural modification of compound 1 was carried out guided by bioisosterism. A series of benzophenone derivatives 2a--2j were synthesized, among which compound 2j with a Ki value of 1.89 nmol/L was identified as the most promising inhibitor of porcine cytocbrome bcl complex, 157-fold improved binding affinity compared to the commercially available bCl inhibitor Azoxystrobin （AZ）. In addition, most of the new compounds displayed excellent fungicidal activity against Sphaerothecafuliginea at the concentration of 200μmol/L. The pre- sent work indicates that strobilurin analogues containing benzophenone side chains may be the ideal leads for future fungicide discovery.Strobilurins are one of the most important natural products with fungicidal activities and well known for their novel action mode, broad fungicidal spectrum, lower toxicity against mammalian cells, and environmentally benign characteristics. Design and syntheses of strobilurin analogues therefore have attracted great attention in the field of agrochemistry. Previously, we successfully developed a new molecular design method of pharmacophore-linked fragment virtual screening （PFVS） and discovered a lead compound （E）-methyl-2-（2-（（（3-（imino-（phenyl）- methyl）phenyl）thio）methyl）phenyl）-3-methoxyacrylate （1）. To discover new strobilurin analogues with higher fun- gicidal activity, the structural modification of compound 1 was carried out guided by bioisosterism. A series of benzophenone derivatives 2a--2j were synthesized, among which compound 2j with a Ki value of 1.89 nmol/L was identified as the most promising inhibitor of porcine cytocbrome bcl complex, 157-fold improved binding affinity compared to the commercially available bCl inhibitor Azoxystrobin （AZ）. In addition, most of the new compounds displayed excellent fungicidal activity against Sphaerothecafuliginea at the concentration of 200μmol/L. The pre- sent work indicates that strobilurin analogues containing benzophenone side chains may be the ideal leads for future fungicide discovery.

关 键 词：STROBILURIN cytochrome bcl complex BENZOPHENONE BIOISOSTERISM 

分 类 号：TQ455.49[化学工程—农药化工] S482.2[农业科学—农药学]