Studies On The Chemical Modification And Their Bioactivities Taking Validoxylamine A And Novel Pyridine Heterocycles As Lead Compounds

Natural bioactive compound validoxylamine A is one of highly effective inhibitor of trehalase. The chemical modification and their bioactivities were studied taking validoxylamine A as lead compound according to the related theory of molecular design in the creation of novel pesticides. A novel lead structure containing pyridine heterocycle and three high bioactive derivatives were discovered during the research. 4 new compound banks of validoxylamine A and 87 novel compounds containing pyridine heterocycle were totally synthesized in the thesis and the main research work were described as follows:1, One novel modified procedure for the synthesis of validoxylamine A was developed via hydrolysis of Validamycin A in Br(o|¨)nsted acidic ionic liquid BMImHS04 which avoided using strong acids in high temperature. The single crystal structure of validoxylamine A was illustrated which gave important information for the study of QSAR and pharmacophore.2, Four banks of validoxylamine A, namely sulfonate, ether, carboxylate and acylamide banks were synthesized by chemical modification of validoxylamine A. The biological tests showed that sulfonate bank exhibited certain bioactivity against Aphis meolicaginis koch, Leucania seoarata walker and Pelliculario sasakii (Shirai)Ito. This study expanded the bioactivity range of validoxylamine A. 3, A novel lead structure containing pyridine heterocycle was discovered in the process of chemical modification of validoxylamine A and a series of corresponding chrysanthemic esters derivates were synthesized. The biological tests showed that some compounds exhibited certain insecticidal and fungicidal activities.4, A series of fluorine-containing pyridine-heterocyclic carboxylate compounds were synthesized starting from the materials of methyl fluoroacetate, cyanacetamide, ethyl formic ester, alkanols and phenolic compounds via ring closure, chlorination, hydrolyzation, acylchloriration and esterification reaction. The bioassay results showed that some compounds exhibited certain fungicidal and insecticidal activities.5, A series of pyridine-heterocyclic thiophosphate compounds were synthesized and three high bioactive compounds were screened which exhibited high mortality against Aphis meolicaginis koch and Leucania seoarata walker at 10 mg/L. Among the three high bioactive compounds, the field trial effect tests and acute toxicity tests of 5-2a and 5-2b were investigated. The field test bioassay showed they exhibited good effect against Aphis meolicaginis koch and the acute toxicity test proved that they are middle-toxicity compounds without mutation.6, The pharmacophore model of trehalase inhibitors was studied showing that the main role played in the interaction between donors and acceptors was hydrogen bond recognition. The pharmacophore model of trehalase inhibitors was obtained for the first time which gave valuable information for other relative researches in the future. Three methods were adopted to study the QSAR of those novel biological compounds. The pharmacophore model results showed that the pharmacophore characters of above compounds lied in hydrophobic, hydrogen bond acceptor and ring aromatic group. The AM1 calculation revealed that the main factors affecting on bioactivity were net charge of hydrogen atom at pyridine cycle and LUMO energy of the molecule. The Cerius2 software calculation showed that the relative negative charges surface area (Jurs-RNCS) was the main effect factor for the bioactivity.