Preparation And Biological Activities Of Mono Quinoline Chelators As Potential Drugs Against Alzheimer’s Disease And Coupling Of Mono Quinoline With Atovaquone As Atokel Hybrid Molecules Against Malaria

“Alzheimer’s disease”（AD）and“Malaria”are world-wide medical problems.At present,the pathogenesis of AD is not clear.There are only seven drugs（6 approved by FDA and 1approved by NMAP）used to treat AD,but none of them can prevent the progress of AD.In addition,with the emergence of resistance of Plasmodium falciparum to the standard gold drug artemisinin and its partner drugs,which greatly threatens the global control of malaria.In this thesis,a series of N4-tetradentate quinoline small molecule chelators were designed and synthesized,and their activities against AD oxidative stress and Plasmodium falciparum were deeply studied.The main contents include the following two parts:1.The homeostasis imbalance of redox transition metal ions in AD brain and the induction of oxidative stress（OS）under the action of endogenous reductants are one of the main factors causing neuron death.In chapter 2,N4-tetradentate mono-8-aminoquinoline chelators“TDMQ”were designed and synthesized by linking polyamine flexible side chain at C2 position with quinoline as the skeleton.The ability of TDMQ regulate copper homeostasis and inhibit oxidative stress inducing by Cu^II-Aβ_1-16were studied by UV or fluorescence spectrophotometry.The results show that:（i）the selectivity of TDMQ-35-37 for copper with respect to zinc is about 10-12 orders of magnitude;（ii）with 1 hour incubation of TDMQ and active substances（vitamin B12,Cu,Zn-SOD,tyrosinase）,TDMQ-35-37 can not extract the metal ions from active substances and destroy their physiological activity;（iii）TDMQ-35-37 can extract Cu²⁺from Cu^II-Aβ_1-16 in vitro to form the complex of Cu^II-TDMQ under rich Zn²⁺conditions,and TDMQ can be released from Cu^II-TDMQ under 6.0-120.0mole equivelent of GSH,and then Cu（II）are reduced by GSH and transported in the form of Cu^I-GSH;（iv）only TDMQ-37 can inhibit the production of ROS induced by Cu^II-Aβ_1-16in vitro under the condition of rich Zn²⁺to prevent the oxidative stress,while TDMQ-35,-36can’t completely inhibit it.It shows that TDMQ-37 has the ability to regulate copper ion homeostasis and inhibit oxidative stress,which provides experimental basis and theoretical guidance for drug development of metal ion disorders related diseases.2.In the third chapter of this paper,new hybrid small molecules Atokel（atovaquone chelators）were designed and synthesized by targeting the mitochondria of Plasmodium.Namely,the pharmacophore“atovaquone”is covalently linked to the nitrogen atom at the end of the polyamine flexible side chain of TDMQ to develop dual fuctions hybrid small molecules“Atokel”,in which the pharmacophore“atovaquone”target the mitochondria of Plasmodium to inhibit its respiration,another pharmacophore“TDMQ”with endogenous Cu²⁺to form the complex of Cu^II-Atokel,which induce dioxygen reduction in enriched oxygen mitochondria in situ to produce lethal oxidative stress,with the synergistic action of the dual pharmacophores to kill Plasmodium.The antimalarial activity of Atokel in vitro was studied by UV spectrophotometry,fluorescence spectrophotometry and MMT.The results show that:（i）Atokel have good metal selectivity,and the log K_app[Cu^II-Atokel]of complexations value are in the range of 7-11;（ii）Cu^II-Atokel can chelate with Cu²⁺can induce dioxygen reduction to produce ROS and trigger oxidative stress in vitro in the presence of reductant;（iii）although the mechanism of action of Atokel follows the rational design of mitochondrial target and triggers destructive ROS in situ,but Atokel show deceptive antimalarial activity,the most antimalarial（F32-ART）activity compound Atokel-13 has an IC₅₀ about 622 n M,which is about 3 orders of magnitudes higher than the Atovaquone;（iv）IC₅₀ of Atokel-13 did not produce cytotoxicity to Vero cells at the concentration of 50μM,and the antimalarial activity/cytotoxicity selectivity index was more than 80（>50/0.6）.The lead compound Atokel-13 shows a weak but significant activity against Plasmodium falciparum,which is expected to provide ideas for the design of new Atokel derivatives.