Chiral γ-aryl-1H-1, 2, 4-triazole Derivatives As Highly Potential Antifungal Agents: Synthesis, Structure And Fungicidal Activities

The development of the society and the enhancement of national awareness of environment protection have put forward higher and higher requirements to the research and development of pesticide,namely the novel agrochemicals must achieve the features of high activity,low toxicity,low residue,and better environment compatibility.During the course of the research on the modern pesticide,the studies and applications of chiral pesticides have drawn more and more attentions because the effect factors of high activity,low dose,low environmental impact,management, intellectual property,market and efficiency.Chiral azaheterocycle triazole derivatives have been paid close attention to by all the world in the research of chiral pesticides.Therefore,we report our efforts in designing and synthesis of novel chiralγ-aryl-1H-1,2,4-triazole derivatives by using chiral induction method,and we expect to find high-activity lead compound through the systematic research of rational design,synthesis and bioactivity of chiral triazoles derivatives.Sixty novel chiral triazole derivatives were designed and synthesized based on chiral induction asymmetric synthesis,which have not been reported in the literature.Their bioactivities,structure-activity relationships and spectral properties were evaluated and some of the compounds exhibited good biological properties,which might be developed as potential lead compounds for further optimization.The research contents are as follows:1.This text takes Oppolzer's sultam as chiral auxiliary,and realized the asymmetric conjugate addition of Grignard reagents to aryl substitutedα,β-unsaturated carbonyl compounds with great regioselectivities and excellent diastereoselectivities.Through systematic detailed studies and discussions about the reaction rules of this novel approach,whose application in asymmetric synthesis has been expanded.A series of important intermediates were synthesized with high diastereoselectivities(de up to 99%).All these compounds were well structurally characterized by spectral methods,and some representative compounds have been elucidated by X-ray diffraction analysis.Moreover,many important building blocks and medicinal intermediates such as chiral ketones,alcohols can be conveniently obtained with excellent enantioselectivies.2.Whereafter,we achieved a highly enantioselective approach towards the synthesis ofβ-substituted chiral ketones utilizing Oppolzer's sultam as chiral auxiliary.The(R)-and(S)-enantiomer of target chiral ketones were obtained with up to 99%ee.This could be a fascinating method for the practical syntheses of chiral synthons as valuable building blocks and important medicinal intermediates.3.Series of novel optical pureγ-aryl-1H-1,2,4-triazole derivatives were designed and synthesized by using the chiral auxiliary(Oppolzer's sultam),and all these target compounds were structurally characterized by ¹H NMR,¹³C NMR,MS and elemental analysis,at the same time,some representative compounds have been elucidated by X-ray diffraction analysis.On the other hand,the preliminary bioassay results indicated that some of chiralγ-aryl-1H-1,2,4-triazole derivatives exhibited superior fungicidal activity.4.In this study,we evaluate the inhibition activity of chiral triazole derivatives LSH1 and LSH2 targeting cytochrome P450(PdCYP51)using binding spectrum method,and a batch of novel antifungal compounds with high binding ability and excellent fungicidal activity were screened out. The preliminary test results indicate that twenty compounds exhibit better inhibition activity compared with the commercially avilable fungicides triadimefon(EC₅₀＜2.27 mg/L),and nineteen compounds have better activity than that of triadimenol(EC₅₀＜1.44 mg/L),as well as four compounds are better than tebuconazole(EC₅₀＜0.37 mg/L).Generally speaking,the activities of LSH2 are better than LSH1,and the compounds of LSH2 have the stronger binding ability with target enzyme PdCYP51 than other compounds,and the binding constants Kd are in the range of 0.003～0.446μM, which are worthy to be futher investigated.During the course of test for EC₅₀of P.digitatum,we find that there are nine pairs of target compounds,the enantiomers(R and S)of which embody significant activity differences.The most exiting outcome is the huge difference in biological activity between compounds LSH1019 and LSH1020,and the activity of LSH1019 is about 230-fold more than that of LSH 1020.Furthermore,the binding activity tests with Ustilago maydis CYP51 for compounds LSH1 are also determined,and the results indicate that all the tested compounds can bind with Ustilago maydis CYP51.