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

近年来，疟疾的现状越来越严重，耐药恶性疟原虫疟疾寄生虫，人感染重症疟疾，耐药恶性疟原虫有所增加。我们的研究目标是针对耐药恶性疟原虫开发新的抗疟药物，为疟疾的控制做出贡献。为了溶解抗疟作用，我们使用了新的抗疟有机化合物，内过氧化物，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：我们合成了150 g的1,2,4,5-四氧环烷（N-89），包括改进合成步骤以使其在疟疾流行地区价格便宜和研究合成步骤中适宜的溶剂以达到良好的生产规范。对感染猴疟原虫的猴子进行了抗疟试验。结果表明，N-89对猴疟具有较高的抗疟活性，且无细胞毒作用。最后，疟疾寄生虫感染的猴子治愈为口服N-89治疗途径。同时，我们的化合物对大鼠无副作用，用2000 mg/kg的N-89治疗，体重减轻，血液生物成分，行为，对大鼠无害。N-89的药代动力学研究表明，N-89的血药浓度水平为1×10^<-7> M，且该浓度在N-89治疗后仍保持5 h。血中N-89浓度足以杀死血中疟原虫。在药代动力学参数分析中，化合物在血流中半衰期短（t_<1/2>=45 min），生物利用度高（BA=58.6%）。综上所述，该化合物有望成为一种新的抗疟药物。

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.