Synthesis And Biological Activity Of Pyrroloindoles Analogues

Infestations of various pests and diseases cause annual crop losses roughly equivalent to one third of the world’s annual harvest.Traditional chemical control can be very effective,but also leads to serious ecological and environmental problems.Compounds of natural origin,such as pesticides of plant origin,with the advantages of low toxicity,easy degradation,less susceptible to resistance and easy availability have caused an increasing interest in the use of these plant-derived pesticides in agricultural production processes.The pyrroloindole ring key skeleton is a very important structure,which is contained in the structure of various alkaloids isolated from plants and fungi with a variety of medical and agrobiological activities,such as Calycanthaceous alkaloids and Physostigmine,etc.Therefore,it is important to use this structure as a precursor to develop a series of new botanical pesticides with antibacterial activity.In this thesis,a series of pyrroloindole analogues were synthesized from indole-3-acetonitrile and L-tryptophan,respectively,and their fungicidal activities against plant pathogenic fungi were determined.（1）Synthetic route:T₄ series was obtained by oxidation of indole-3-acetonitrile with DMSO under strong acidic conditions to obtain indol-3-acetonitrile T₁ in about 94%yield;4-bromobenzyl alkylation using anhydrous tetrahydrofuran as solvent and Na H extraction to obtain T₂ in 68%yield;anhydrous tetrahydrofuran as solvent and Li Al H₄ in anhydrous and oxygen-free conditions to obtain T₂ in 68%yield.Finally,20 acylation reactions of 20 different acyl chlorides with the 1-N positions of the indolizopyrrole ring compounds were carried out using anhydrous DCM as solvent to give 20 indolizopyrrole derivatives of the first series in moderate to high yields.The B₄ series was based on the esterification of carboxylic acids with L-tryptophan in the presence of methanol and sulfoxide chloride to give L-tryptophan methyl ester B₁ in about 94%yield;the substitution of amino groups with isopropyl chloroformate using pyridine as solvent and providing alkaline conditions to give compound B₂ in 75%yield;he ring closure reaction of compound B₂ with85%phosphoric acid gave the key backbone compound B₃ with an indole and pyrrole ring in about 85%yield;finally,19 first class pyrroloindole derivatives were synthesized by acylation of the 8-N position with 19 different acyl chlorides.The structures of these 39 novel compounds,which have not been reported before,were confirmed by synthetic resonance ¹H-NMR,¹³C-NMR and MS.（2）The biological activity tests of all compounds:The 96-well plate method was used to determine the minimum inhibitory concentrations of all compounds against against Sclerotinia sclerotiorum,Alternaria solani,Verticillium dahliae,Colletotrichum orbiculare,Cytospora juglandis and Curvularia lunata.T₄-2 and B₄-13 compounds were found to be significantly effective in the inhibition of Sclerotinia sclerotiorum with an MIC value of 1.95μg/m L.compounds T₄-2,B₄-7 and B₄-13 showed excellent inhibition against Alternaria solani with an MIC value of 3.9μg/m L;Compounds T₄-2,B₄-13 and B₄-17showed the same significant inhibitory activity against Verticillium dahliae with a minimum inhibitory concentration of 1.95μg/m L.Compounds T₄-15,B₄-13 and B₄-17 showed excellent inhibition of Colletotrichum orbiculare with an MIC value of 3.9μg/m L;compound B₄-17 also showed excellent inhibition of Cytospora juglandis with an MIC value of 3.9μg/m L;compound B₄-17 showed excellent inhibition of Curvularia lunata with an MIC value of 1.95μg/m L.Compound B₄-13,a2-chloro-3-pyridyl structured acylated 8-N compound,and compound T₄-2,a chlorinated pyrazinylated compound,as well as compound B₄-17.In the first series,the activity is outstanding when the substituent is in the meso position,when the opposite position of N in the meso position is N.However,the activity decreases when the N neighbour is replaced by an electron-rich amine group or a hydroxyl group.In the second series,the N atom in the substituent at the interposition,with Cl,F or OH groups at position 2,shows excellent antibacterial activity,again with reduced activity when the N neighbour is replaced by an electron-rich amine group.