New antiamlarial drug development research including mechanism analysis of drug-resistant Plasmodium falciparum

目前疟疾的形势越来越严峻，近年来，人类感染重症疟疾的抗药性恶性疟原虫增加了对恶性疟原虫的耐药性，我们的研究目标是开发针对耐药恶性疟原虫的抗疟新药，以期为疟疾的防治做出贡献。为了溶解抗疟疾的作用，我们使用了新的抗疟疾有机化合物，内氧化物，结合分子生物学和基于计算机的药物靶标技术。我们研究的最终目标是从地球上控制疟疾。本研究的研究结果如下：合成了150g的1，2，4，5-四氧杂环烷(N-)，包括改进合成步骤以供疟疾流行区廉价使用，并在合成步骤中研究适合良好生产实践的溶剂。对感染猴疟疾寄生虫的猴子进行了抗疟试验。结果表明，N-89对猴疟有较高的抗疟活性，且无任何细胞毒作用。最后，感染猴疟疾的寄生虫治愈为N-89治疗的口服途径。对N-89的药代动力学研究表明，N-89的血药浓度为1×10~(-7)~(-7)·g~(-1)M，且在给药5小时后仍保持此浓度。血液中N-89浓度足以杀死血液中的疟疾寄生虫。在药代动力学参数分析中，该化合物在血流中的半衰期较短(t_1；1/2&gt；=45min)，具有较高的生物利用度(BA=58.6%)。综上所述，我们的化合物有望成为一种新的抗疟疾药物。

Current situation of the malaria becomes serious more and more and recently, drug-resistant Plasmodium falciparum malaria parasites, human infected severe malaria, has increased drug-resistant P. falciparum malaria.Our research objective is development of new antiamalarial drug against drug-resistant P. falciparum and our study is advanced for the purpose of contributing to the malaria control. For the dissolve the antimalarial action, we used new antimalarial organic compounds, endoperoxides, with molecular biology and computor based drug-target techniques. Our final goal of research is control of malaria from the on earth.The research result of this study is shown at the following.We synthesized the 150 g of 1,2,4,5-tetraoxacycloalkane (N-89) including improvement of synthtic steps for supply of cheap price in the malaria endemic areas and research of suitable solvent for good manufactured practice during synthetic steps.It's antimalarial test for monkey malaria parasite infected monkey was done. As a result, N-89 has high antimalarial activities for monkey malaria with no any cytotoxic effect. Finally, malarial parasites infected monkey cured for N-89 treatment of oral route. Also our compound has no side effect treatment with 2,000 mg/kg of N-89, weight loss, biological composition of blood, behavior, against rat.Pharmacokinetic study of N-89, blood concentration level of N-89 was 1×10^<-7> M, and this concentration was also kept 5 hours after N-89 treatment. Blood level of N-89 concentration was sufficient for kill the malaria parasite in the blood. During pharmacokinetic parameter analysis, our compound have short half time in the blood stream (t_<1/2>=45 min) and shows the high bioavailability (BA=58.6%). In conclusion, Our compoud can be expected as a new antimalarial drug.