The Designe, Synthesis And Antischistosomasis Activities Of Mefloquine Derivatives And The Designe, Synthesis And Activities Of Pantothenate Synthetase Inhibitor

This thesis includes two sections.The first section: the designe, synthesis and antischistosomasis activities of mefloquine derivatives.Schistosomasis is an acute and chronic disease caused by prarsitic worm, with 3 species(Schistosoma mansoni, S. haematobium, and S. japonicum). Praziquantel(PZQ) is the only drug being used to treat human schistosomiasis on a large scale. Having a single drug to treat a disease that affects hundred millions of people is a real dangerous.Antimalarial drug mefloquine, an amino alcohol compound, have exhibited potential effect against Schistosoma mansoni and Schistosoma japonicum. But in a clinical investigation, the results of monotherapy with mefloquine showed low cure rates. In this thesis, we choosed mefloquine as lead compound, to reduce its severe neuropsychiatric side-effects, considering the design of β- receptor antagonists, induced a O-CH2 group into the side chain of mefloquine, and varying the amine group and aromatic group to perform the SAR research.Fifty two new mefloquine derivatives were synthesized.Twenty four derivatives showed good activities(LD50 < 10μM) against 14-day-old juvenile schistosomes in vitro. Among them, LD50 values of ten compound were less than 5μM, which was equal with mefloquine and seven compounds showed good activities(LD50 < 10μM) against 35-day-old adult schistosomes in vitro. QC010105 showed better activities than mefloquine. Although these compound gave the negative results in the experiments in vivo, it has proved they were potential compounds against schistosomes, which were deserved further study. The varying aimed with the 2,8-bis(trifluoromethyl) quinoline group was feasible.The second section: the designe, synthesis and activities of pantothenate synthetase inhibitor.The increasing of MDR-TB cases and the epidemic of AIDS made tuberculosis become the focus of the drug researches. Although two drugs were approved for treatment MDR-TB in 2012-2014, the situation was still pressure, even there was no drug for the XDR-TB.The pantothenate synthetase(PS), coding with pan C gene, is the possible target for TB treatment. It was the new target different from all the first-line TB drugs, so the inhibitor of PS would not cause cross resistance. Notably, no whole cell activity against wild-type Mtb has yet been observed or disclosed for any previously described Pan C inhibitor.In this thesis, ten new pantoyl-adenylate intermediate mimics with the C-2 stereo center retaining the same configuration were synthesized. Kinetic studies to evaluate enzyme inhibition of inhibitors 4-8 toward Pan C were performed; the constants Ki of inhibitors were calculated. Computer modeling was applied for explaining the result of enzyme inhibition; Inhibitors 4-8 were also evaluated against wild-type Mtb and a Pan C depleted Mtb strain.Inhibitors 4-8 acted as competitive inhibitors towards the substrate pantoic acid. The most potent inhibitor 4 had Ki value of 0.27±0.04μM,while Ki value of the epimeric mixture 3j was 0.3μM. Although the methods of determining inhibition were different, the C-2 stereo center didn’t have obvious effect with the inhibitor. We modeled inhibitors 4-8 into Pan C binding site using compute modeling method. Inhibitor 4 was found it had nine hydrogen bonds with the target enzyme. It also explained its most potent activity. Other inhibitors have less hydrogen bonds with the enzyme, so the activities were decreased.Although inhibitors 4-8 showed good inhibition activities, none of them displayed any growth inhibition toward wild-type Mtb and a Pan C depleted Mtb strain, suggesting the compounds failed to accumulate intracellularly. This could be caused by poor cell penetration or active efflux. By now, no whole cell activity against wild-type Mtb has yet been observed or disclosed for any previously described Pan C inhibitor. Alternatively, Pan C may not represent an ideal target for development of new antitubercular agents.