title: Discovery and quantitative structure-activity relationship study of lepidopteran HMG-CoA reductase inhibitors as selective insecticides.
abstract: BACKGROUND
  In a previous study we have demonstrated that insect 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) can be a potential selective insecticide target. Three series of inhibitors were designed on the basis of the difference in HMGR structures from Homo sapiens and Manduca sexta, with the aim of discovering potent selective insecticide candidates.
  
  
  RESULTS
  An in vitro bioassay showed that gem-difluoromethylenated statin analogues have potent effects on JH biosynthesis of M. sexta and high selectivity between H. sapiens and M. sexta. All series II compounds {1,3,5-trisubstituted [4-tert-butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-4-yl) acetate] pyrazoles} have some effect on JH biosynthesis, whereas most of them are inactive on human HMGR. In particular, the IC50value of compound II-12 (37.8 nm) is lower than that of lovastatin (99.5 nm) and similar to that of rosuvastatin (24.2 nm). An in vivo bioassay showed that I-1, I-2, I-3 and II-12 are potential selective insecticides, especially for lepidopteran pest control. A predictable and statistically meaningful CoMFA model of 23 inhibitors (20 as training sets and three as test sets) was obtained with a value of q2and r2of 0.66 and 0.996 respectively. The final model suggested that a potent insect HMGR inhibitor should contain suitable small and non-electronegative groups in the ring part, and electronegative groups in the side chain.
  
  
  CONCLUSIONS
  Four analogues were discovered as potent selective lepidopteran HMGR inhibitors, which can specifically be used for lepidopteran pest control. The CoMFA model will be useful for the design of new selective insect HMGR inhibitors that are structurally related to the training set compounds. © 2017 Society of Chemical Industry.
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Zang
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Yuan-Mei
authors.initials: YM
authors.lastname: Li
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Institute of Agro-food Standards and Testing Technologies, Shanghai Academy of Agricultural Science, Shanghai, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Chen
authors.affiliation: School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, China.
authors.forename: Zhen-Peng
authors.initials: ZP
authors.lastname: Kai
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007306:Insecticides / Q000737:chemistry* / Q000494:pharmacology*; D007915:Lepidoptera / Q000201:enzymology*; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007306:Insecticides; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: CoMFA; HMG-CoA reductase inhibitors; JH biosynthesis; gem-difluoromethylene substitution; selective insecticides; structural comparison