Antifungal Exploration Of Newly Chemical Entities Of Quinoline Inspired By Natural Alkaloids Quinine-Ⅱ

Quinine is an alkaloid isolated from the traditional antimalarial plant cinchona.Its derivatives have antiproliferative activity,antiarrhythmic activity,antibacterial activity,and many other pharmacological properties.In our previous work,we obtained the active core 2,8-bis（trifluoromethyl）-4-quinolinol through activity screening of quinine and its simplified structure.In order to further explore antifungal potency,2,8-bis（trifluoromethyl）-4-quinolinol was selected to be a lead compound and its derivatives were successfully obatined.Morever,the research of their anti-phytopathogenic action and preliminary mechanism of action was conducted.1:Design,synthesis,and antifungal activity of quinine derivatives modified at 4-hydroxyl.Enlightened from our previous efforts,we selected 2,8-bis（trifluoromethyl）-4-quinolinol as active core,then phenylpiperazines,anilines,thiophenols,cinnamic acids,aliphatic amines,and other groups were intoduced to explore the antifungal effects against pathogenic fungi.Outcomes obtained from experiments illustrated that the inhibition of cinnamic acid derivative d10 against Sclerotinia sclerotiorum was 81.09%at 100μg/mL and the inhibitory rate of d15 against Botrytis cinerea was 86.19%at 100μg/mL.The EC₅₀ of compound d14 against Botrytis cinerea was 19.58μg/mL.2:Design,synthesis,and antifungal activity evaluation of 2,8-bis（trifluoromethyl）-4-quinolinol derivatives with hydrazine as synthon.In order to further improve the antifungal effect and expand the antifungal spectrum,a series of 2,8-bis（trifluoromethyl）-4-quinolinol derivatives with hydrazine as the synthon were successfully designed and synthesized.Phenylhydrazines,phenylhydrazones,thiadiazoles,oxadiazoles,dihydrazides,and sulfonyl hydrazides were introduced to explore their inhibition against plant fungi.Tests showed that the introduction of phenylhydrazines significantly improved the antifungal activity,especially the EC₅₀ of compound h12 against Botrytis cinerea was 0.50μg/mL.The antifungal activity of most phenylhydrazine derivatives was not only improved,but also the inhibition spectrum was expanded.3:Preliminary study on the antifungal mechanism of compound h12.Through activity screening,we found that compound h12 exhibited excellent antifungal activity and could be selected as a candidate to study antifungal mechanism.The experimental results showed that h12 could reduce the number of spores and hyphae.Not only the cell membrane of fungi was badly damaged,but also the hyphae was suffered from destructive changes.Besides,compound h12 had comparably therapeutic activity to the positive control boscalid.These results suggested that compound h12 could be regarded as a novel and promising agent for its valuable potency.