Synthesis And Evaluation Of Anti-toxoplasma Gondii Of A Series Of Arctigenin Derivatives

Toxoplasma gondii can cause opportunistic zoonotic toxoplasmosis.It is an obligate intracellular parasite.The proliferation of Toxoplasma gondii depends on its ability to invade host cells,and its invasive ability is partly mediated by calcium-dependent protein kinase 1(CDPK1).At present,there are limitations in the use of therapeutic drugs for this disease due to severe toxic and side effects,so there is an urgent need to develop low toxicity and highly effective drugs.Arctigenin is an effective active ingredient in Arctium lappa.With Discovery Studio 2017 Server,a computer-aided drug design software,the molecular docking of Arctigenin and TgCDPK1,3T3V.pdb was simulationed.It was found that Arctigenin has a better binding effect with TgCDPK1 receptor protein.It shown that arctigenin has anti-parasitic activity,due to its low solubility and bioavailability,the role of arctigenin in clinical applications is limited.In order to increase the solubility of arctigenin,increase its bioavailability and enhance the antiparasitic activity,we have synthesized some new derivatives with arctigenin as a parent to obtain better pharmacological activity target derivatives.Amino acid derivatives have a variety of biological functions.The introduction of amino acids into the molecular structure of drugs on the one hand can increase the biological activity of drugs,reduce the toxic effects on cells,and on the other hand can increase the solubility of drugs and participate in active transport.Correspondingly enhance the bioavailability of drugs.Compounds containing triazole perssad enhance drug activity by interacting with many enzymes and receptors via non-covalent bonds.The amide group can increase the stability of the compound in vitro and in vivo,reduce the sensitivity of enzymatic hydrolysis,and can be used as a hydrogen donor.In this study,three aminoglycosides,amine heterocycles,and triazole derivative groups were used to structurally modify the structure of Arctigenin,and three series of Arctigenin derivatives were designed and synthesized.A total of 32 compounds were synthesized and identified by 1H-NMR,13C-NMR,IR and MS.All synthetic compounds were tested for their Toxoplasma activity by in vitro and in vivo experiments.The results showed that most of the compounds synthesized not only have activity against Toxoplasma gondii(IC50 b=17.09 to≥ 500 μM)but also have lower toxicity to host cell(IC50a=53.18 to≥500 μM).The results of in vitro experiments at drug gradient concentrations of 1～500 μmol/L showed that the effects of compound D4(SI=29.26)and E5(SI=12.33)against Toxoplasma gondii were particularly significant and could be effectively kill toxoplasma tachyzoites and improve the morphology of host cells.After all of the synthesized compounds were subjected to molecular modeling and protein structure processing were found that the binding of compounds D4 and E5 to Toxoplasma Calcium-dependent Protein Kinase 1 Receptor Protein(TgCDPK1,3T3V.)was superior to that of parental arctigenin.In vivo experiments further confirmed that Compounds D4 and E5 not only significantly reduced the number of tachyzoites in the peritoneal cavity of mice,but also resulted in partial tachyzoites malformation(P<0.05).The effects were superior to those of the positive control drug pyrimethamine.These compounds have similar or better activity than the positive control drug pyrimethamine and are expected to become potential antiparasitic drugs,pending further in-depth mechanistic studies.