Synthesis And Biological Activities Of Piperine And Indole-based Thiazinanone Derivatives

The structure modification and biological activities of piperine and indole were studied in this dissertation,which is mainly composed of two parts as the follows:Part I:Piperine(1-1)is a class of alkaloids and isolated from the fruits of Black pepper(Piper nigrum L.,family Piperaceae).1-1 and its derivatives have been demonstrated to possess a wide range of biological properties,including antitumor,anti-oxidant,anti-inflammatory,anti-spasmodics,lipid-lowering and enhancing the bioavailability of some drugs as well as antibacterial and insecticidal activities.Although synthetic chemical insecticides have played a significant role in modern agricultural pest management,repeat application of those agrochemicals over the years has led to the development of resistance in insect pest populations and environmental problems.On the other hand,as plant secondary metabolites resulting from the interaction between plants and environment(life and non-life)during the long period of evolution,pesticides originated from plant secondary metabolites may lead to less or slower resistance development and lower pollution.It is one of the important ways of developing new and environmentally-friendly pesticides to directly utilize secondary metabolism of plants or use it as precursors for structure modifying.Based on these studies,the following research has been done in this paper:1.The eighty-eight piperine derivatives were prepared and all the compounds have not been reported.The structures were well determined by 1H NMR,13C NMR and HR-MS.The single-crystal structure of 6c,6q and 6w were confirmed by X-ray crystallography.2.The antifeedant(during 48 h)and insecticidal activities of these derivatives were evaluated against pre-third-instar larvae of M.separata by the leaf-dipping method at the concentration of 1 mg/mL.(a).The study found that the compounds 7b-e showed narcotic activity to the larvae of M.separata.(b).The results of insecticidal activity tests indicated that some of these compounds have shown remarkable activity and were greater than piperine,especially compounds 6b,6i,6r,9d,9g’,13e,14a and 13b have shown excellent insecticidal activity,the final mortality rate of which were 62.1%、65.5%、65.5%、64.3%、64.3%、60.7%、67.9%and 67.9%,respectively,much more potent than Toosendanin,a commercial botanical insecticide isolated from Melia azedarach.3.The results of the study of structure-activity relationships indicated that introduction of the substituents at the C-2 position on the phenyl ring of the piperine-based hydrazone derivatives was important for their insecticidal activity;to some extent,the introducing of chlorine atom for piperine-based esters 9a-z and 9a’-h’ could improve insecticidal activities compared to their precursor piperine;the piperine-based amides 13a-o,which showed relatively better insecticidal activities when aniline derivatives with electron-withdrawing substituents(containing chlorine atom or nitro on the phenyl ring)as its substrates than that with electron-donating substituents(containing methyl,methoxyl,ethyoxyl on the phenyl ring).4.Based on observation of symptom,the narcotic activity of compounds 7a-f against larvae of M.separate was studied.Among them,especially 7c exhibited the more pronounced narcotic activity,the NO50 of 7c against pre-third-instar,pre-fourth-instar and pre-fifth-instar larvae of M.separate were 2.84 μg/larva,5.77 μg/larva and 15.22 μg/larva,respectively.5.The ultrastructure of the ganglion and myocyte of the sixth-instar larvae of A.separata at deep paralysis stage treated by 7c were studied.The results showed that the mitochondria and neurofilament of nervous system as well as internal membrane system and myofibrils of myocyte were destroyed.All of these might bring bad effects on transport of neurotransmitters and metabolites,block the normal muscle contraction,and finally cause paralysis of M.separate.Part Ⅱ.Indole alkaloids existing in lots of plants(eg.robinia pseudacacia,jasmines and orange blossoms et al.),as important heterocyclic compound,display a wide range of biological activities.In recent years,thiazinanone derivatives have gained widespread attention due to their important role in biological activities,such as their potent cyclooxygenase(COX-2)inhibitory activity,antitumour activity,antimalarial activity and antifungal activity against human pathogenic fungi.Therefore,a series of 2-(N-arylsulfonylindol-3-yl)-3-aryl-l,3-thiazinan-4-one derivatives were synthesized and evaluated as HIV-1 inhibitors and against seven phytopathogenic fungi in vitro,taking advantage of the combination of active groups.The key results were found as follows:1.Ten novel 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-one derivatives(Ⅵ-1～Ⅵ-10)were prepared,all of which have not been reported.Their structures were well characterized by 1H NMR,13C NMR,and ESI-MS.2.The compounds Ⅵ-1～Ⅵ-10 were evaluated as HIV-1 inhibitors in vitro,all of which showed weak anti-HIV-1 activities.3.The antifungal activities of compounds Ⅵ-1～Ⅵ-10 against seven phytopathogenic in vitro were evaluated by mycelial growth rate assay at 50 μg/mL.Of all the derivatives,compound VI-10 showed a potent antifungal activity against four phytopathogenic fungi.The growth inhibition ratio by Ⅵ-10 of A.solani,A.brassicae,A.alternata,and P.oryzae was 39.7%,48.1%,57.3%,and 55.1%,respectively.The study of structure-activity relationships indicated that introduction of an electron-withdrawing group(cyano)on the indolyl ring of VI-1 could generally increased the antifungal activity.