Design,Synthesis,and Antifungal Activity Of Novel 3-Substituted Isoquinolines

The isoquinoline skeleton exists extensively in numerous drugs and natural products,such as Shuanghuanglian,Papaverine,Palmatine and Sanguinarine.Inspired by the previous work on the research of aryl oxazoline pharmacophore,novel isoquinoline-3-oxazoline and isoquinoline-3-amide compounds were designed and synthesized to explore their application as new antifungal leads and chiral ligands in asymmetric synthesis.The main results obtained are as follows:(1)18 isoquinoline-3-oxazoline were synthesized based on cheap natural phenylalanine through the pictet-spengler reaction,KMnO4 oxidation,Steglich esterification and other reaction.Then 39 isoquinoline-3-amide synthesized as simplified isosteres of 18 isoquinoline-3-oxazoline.A highly selectivity method of asymmetric Michael addition was established based on isoquinoline-3-oxazoline compounds.The structures were confirmed by nuclear magnetic resonance spectrum of hydrogen spectrum(1H-NMR),nuclear magnetic resonance spectrum of carbon(13C-NMR),Electrospray ionization high-resolution mass spectrometry(ESI-HRMS)and X-ray single crystal diffraction.(2)The target compounds were tested against Rhizoctonia solani,Sclerotinia sclerotiorum,Fusarium graminearum,Phytophthora capsici,Botrytis cinerea and Magnaporthe grisea at the concentration of 50 μg/mL.The antifungal activity assay showed that chiral isoquinoline-3-oxazoline molecules 1dg、1dh have a good inhibitory effect against Rhizoctonia solani which protruded as antifungal candidates against R.solani,with the EC50 value of 8.60 μg/mL and 8.10 μg/mL,respectively.The simplified structure isoquinoline-3-amides were further optimized in synthesis and antibacterial activity.Structure-antifungal activity showed that antibacterial activity of these compounds were higher than isoquinoline-3-oxazoline and isoquinoline-3-oxazoline amide.The EC50 of compounds 2ba,2bb,2bg,2bh,2bi,2bn,2bo and 2ca were all less than positive control Boscalid.When the amine fragment for benzyl amine(2ba),the activity is good;when the fluorine substitution for benzyl amine(2bi)the activity is further improved,At a concentration of 50 μg/mL,compound 2bi had an inhibition rate of 99.5%against R.solani,with the EC50 of 7.73 μg/mL,which could be used as antifungal lead compounds.The compounds 2bz was protruded as antifungal candidates against R.solani,B.cinerea,F.graminearum and M.grisea,with the EC50 value of 0.089 μg/mL,3.15 μg/mL,1.084 μg/mL,1.872 μg/mL,respectively,which demonstrating its potential as a fungicides lead.(3)Using the chiral isoquinoline-3-oxazoline compounds as ligands,aiming the asymmetric synthesis of β-arylamine in amides fungicides and related drugs,a highly selectivity method for asymmetric addition of nitrostyrene and phenylboric acid was established.When palladium trifluoroacetate used as mediated,methanol used as solvent,the target product could be obtained with 93%ee value,and the reaction system had good functional group tolerance and wider substrate applicability.The PKB inhibitor analogs were obtained by using the developed asymmetric addition method.Based on natural phenylalanine,2 types of 57 new 3-substituted isoquinoline compounds were designed and synthesized.The study on the structure-activity relationship protruded four antifungal candidates.A highly selectivity method of asymmetric addition of nitrostyrene and phenylboric acid was established,Which can be used in the preparation of PKB inhibitor analogs and provides technical support for the discovery and asymmetric synthesis of new amides agrochemical.