Synthesis Of Methylphosphinic Acid Derivatives As Fosmidomicin Anologs And Their Biological Activity Evaluation

Herbicides play an important role in weeds control and food security.With the intensification of environmal protection regulations and the increasingly worsening problem of weed reistance,developing new herbicides with new modes of actions has become an urgent need.The mevalonate pathway(MEP pathway)is a route for the biosynthesis of isoprenoid compounds characterized with 2-methylerythritol phosphate(MEP)as an intermediate.This pathway widely exists in bacteria and plants,but not in mammals.There are seven key enzymes involved in the MEP pathway and all have proven to be possible herbicidal and fungicidal targets.Therefore,developing new lead compounds that can target the enzymes is of great significance for the development of new herbicides and fungicides.The natural product fosmidomycin is an inhibitor of the IspC enzyme in the MEP pathway and possesses bactericidal and herbicidal activity.In this dissertation,α-substituted methylphosphinic acid compounds,which have the structural patterns of fosmidomycin,were designed and synthesized,using fosmidomycin as the lead structure,and their biological activiies were also evaluated.The main work includes the following four parts:1.The first chapter overviews herbicidal targets and herbicide types,as well as the key enzymes of the MEP pathway and their inhibitors.The key enzyme IspC is also introduced in terms of its structure,function,and the development of its inhibitors as well as the research advances of fosmidomycin and its analogs.On the basis of this overview,the project design and research contents of this dissertation is probosed.2.With the natural product fosmidomycin as the lead structure,a total of 20α-substituted fosmidomycin analogues methylphosphinic acids were designed and synthesized.The synthetic route involves diethyl methylphosphite as the raw material and seven steps to obtain target compound,such as Abuzov reaction,acid hydrolysis,aldol condensation,amidation,catalytic hydrogenation,and alkaline hydrolysis.The structures of the compounds were confirmed by 1H NMR,13C NMR,31P NMR,19F NMR and HRMS.3.Similarly using fosmidomycin as the lead structure,a total of 16 a-substituted methylphosphinic acids with a structure pattern of trans fosmidomycin were designed and synthesized.The synthetic route used diethyl methylphosphite as the raw material and also included multiple steps of reaction such as Abuzov reaction,substitution,acid hydrolysis,oxidation,amidation,catalytic hydrogenation,alkaline hydrolysis to obtain the target compound.The structures of the compounds were confirmed by 1H NMR,13C NMR,31P NMR,19F NMR and HRMS.4.The bioactivities were tested on E.coli IspC enzyme,Plasmodium falciparum in vitro,and model plants for the target compounds.The results of the test showed that at 100 μM the α-substituted methylphosphinate compounds 1-7,1-8,1-9,1-10,1-11,1-13,1-14,1-16 had desirable activities with EcIspC inhibition higher than 70%.Among these compounds,the inhibitory activities of compounds 1-7 and 1-16 reached 83.37%and 83.06%,respectively,with the IC50 values measured to be 3.21 μM and 4.21 μM,slightly lower than fosmidomycin,which has an IC50 of 0.178 μM.On the other hand,theα-substituted trans-fosmidomycin analogue methylphosphinic acid had no inhibitory activity on EcIspC enzyme.Meanwhile,most of the α-substituted methylphosphinic acid compounds exhibited antimalarial activity against P.falciparum Dd2 in vitro.At a concentration of 1 μM,compounds 1-8 against P.falciparum Dd2 in vitro with an inhibitory activity of 80.72%,which is comparable to the antimalarial activity of fosmidomycin.The α-substituted methylphosphonic acid compounds with trans fosmidomycin structure had no in vitro antimalarial activity.The herbicidal activity results showed that a few compounds had a good inhibitory activity on the roots of model plant rape at a high concentration of 100 ppm,but overall,the compounds had poor herbicidal activity.