Synthesis And Bioactivity Evaluation Of Novel Cantharidin Derivatives Through The Active Ligand-based Design

Chemical pesticides have contributed a lot to solve the food problem in the world, which would also dominate the market of pesticide in the foreseeable future. However, the efficiency of many commercial pesticides has variably decreased due to the long and broad use of a single pesticide or several pesticides with the same mode of action, which has brought a great loss for agriculture. Thus, it becomes the focus about the development of new pesticide with new skeleton and new target enzyme.Recently, it becomes an important trend todevelop new pesticide with natural products as lead compound. For example, insecticides with diamides skeleton have unique mode of action, high bioactivity and no cross resistance with currently used insecticides, because of their new skeleton from natural product rotenone and new target ryanodine receptor. Considering the broad bioactivity of cantharidin derivatives and their potential as insecticides or fungicides. Herein, we would like to synthesize a series of Norcantharidin derivatives with highly insecticidal activity or fungicidal activity through structure modification.1. A series of△-5,6-norcantharimides weredesigned and synthesized based on the5,6-bridge modification. The insecticidal activityevaluation showed that among all the 37 compounds only compounds 3a~3p exhibited low insecticidal activity against Plutella xylostella, and the others didn’t show any activity. The structure-activity relationship revealed that the oxygen atom of ether bond coordinated to the metal ion in catalytic site, so the derivative lost bioactivity immediately when the oxygen was exchanged by other group. Moreover, the 5,6-bridge also played an important role in influencing the bioactivity.2. A series of 1,5-disubstituted norcantharidin derivatives weredesigned and synthesized based on the hexatomic ring modification. The insecticidal activityevaluation showed that these compounds didn’t exhibit significant insecticidal activity againstP. xylostella. Molecular docking results of the compound 8awith PP5 c implied that the synthesized compound couldn’t bind withPP5 c very well because of the steric configuration difference caused by the introduction of substituent on C5 site.3. Two series of norcantharidin derivatives containing alkyl and aryl groups weredesigned and synthesized based on the anhydride ring modification. The larvicidal activities of cantharidin and its derivatives against the pre-third-instarP. xylostella were evaluated. All the cyclic derivativesdid not exhibit any larvicidal activity. The ring-opened cantharidin derivatives demonstrated different activities, and compound11-f showed the highest larvicidal activity with LC50 value of 0.43 mM. Structure-activity relationship study indicated that the form of compound, cyclic or ring-opened, or their ability to hydrolyze facilely was the key to determine whether it exhibited larvicidal activity. Meanwhile, this revealed that the improvement of insecticidal activity required a reasonable combination of both aliphatic amide and aromatic amide moieties, and the type of substituent Y on the aniline ring was critical.4. A series of norcantharidin derivatives with aromatic amine moietyweredesigned and synthesized based on the aminolysis reaction. The fungicidal activity against eight fungal phytopathogens were evaluated. Seven of these synthetic compounds presented significant fungistatic activities against all of the eight fungi. Especially, compound 12-8 exhibited the most significant activity on all eight fungi, much better than thiabendazole(TBZ), norcantharidin and cantharidin. And compound 12-8 showed excellent antifungal properties against Sclerotinia fructigenaand S. sclerotiorum with IC50 values of 0.88 and 0.97 μg/mL, respectively. SAR data for these compounds are as follows:(1) the benzene ring is critical for the improvement of the spectrum of antifungal activity and the fungistatic activity;(2) among the three sites, including C-2’, C-3’ and C-4’ positions of the phenyl ring, the presence of the halogen atom at the C-3’position of the phenyl ring caused the most significant increase in antifungal activity;(3) compounds with substitutions of strongly electron-drawing or electron-donating groups were found to have a poor antifungal activity;(4) compared with fluorine, bromine and iodine, one chlorine atom substituted at C-3’ position of the benzene ring gave the highest fungistatic activity.