Design,Synthesis,Anti-Phytopathogenic Fungi Activity And Structure-Activity Relationship Of 2-Aryl-3,4-Dihydro-?-carboline Salts

Plant fungal pathogens have significant impacts on a wide range of crops,often resulting in severe yield losses and quality decrease of agricultural products.Furthermore,many of the fungi can produce mycotoxins harmful to animal and human health.Therefore,various fungicides have been extensively used to protect plant growth in current agriculture.However,prolonged use of antifungal agents can lead to the growing resistance of plant pathogens,environmental problems,and residue toxicity.Thus,it is necessary to develop new fungicides with novel molecular framework and action mechanisms.In recent decades,natural product-based or-derived plant protectants have attracted attention from researchers due to their lower environmental and mammalian toxicity.?-Carboline alkaloids are a large group of indole alkaloids with diverse structures and widely distribution in nature.?-Carboline alkaloids exhibited various kinds of bioactivity such as antitumor,antibacterial,antifungal,anti-HIV,anti-inflammatory,antimalarial and antileishmania,which makes this skeleton to be a hot spot for researchers.Besides,in recent years,lots of studies indicated that ?-carbolines participate in nerve growth and signal transduction processes in the human nerve system.However,the anti plant fungal pathogens activity of ?-carbolines is rarely reported.Based on our previous research,we combined 2-aryl-3,4-dihydroisoquinolin-2-ium salts(a successful antifungal skeleton analogue designed from natural produts sanguinarine and chelerythrine)and ?-carboline skeleton together in order to discover a promising lead compound for the development of new antifungal agents.The major results of this research are listed below:1.Designed a series of 2-aryl-3,4-dihydro-?-carboline salts with the strategy of structure bionic and active skeleton combination.2.The target compounds were prepared via Fischer indole synthesis reaction starting from phenylhydrazine-HCl and ?-ketoglutaric acid,reduction of ester groups,selective oxidation,bromination and condensation.A1 and B1 were dehydrogenated by Pd/C to provide A1 H and B1 H.The structures of all synthesized compounds including the intermediates were confirmed by 1H NMR,13 C NMR,and MS analyses.Due to the structural similarity,only some representative compounds were analyzed for their HRMS and X-ray diffraction.A literature survey showed that all compounds are new.3.According to the mycelium linear growth rate method,all compounds were screened for antifungal activity in vitro at 150 ?M(ca.50 ?g/mL)against 12 plant pathogenic fungi.The compounds with higher initial activities were further assayed for median effective concentrations(EC50).The structure-activity relationship(SAR)was discussed also.Almost all of the test compounds displayed some inhibition activity against each of the fungi at 150 ?M.Some compounds showed a wide antifungal spectrum like B2?B3?B4?B20?B21?B22.B4,B20,B22 were more active than thiabendazole against F.solani,with EC50 values of 2.18,2.35,2.47 against 12.53 ?M.B7 was far more active than thiabendazole against A.solani,with EC50 values of 3.95 against 391.60 ?M.SAR showed that N9-methylation improves the activity;aromatization of ring C decreases the activity;the substitution patterns and position of ring D significantly influence the activity.This study represented a simple synthetic route of 2-aryl-3,4-dihydro-?-carboline salts and found a series of lead compounds to develop new carboline-type antifungal agents.It also proves that combining two bioactive skeleton together is a workable solution for drug design.