Synthesis And Pharmacodynamic Studies Of New Antimalarial Naphthoquine Phosphate Derivatives

which is transmit by worm media. Malaria is one of the outstanding issues of public health, and also is the most prevalent and harmful parasitic diseases in the world. Ac-cording to the report from WHO, malaria is threaten to nearly half of the population in global of about 108 countries and regions. Such as sub-Saharan Africa, Asia, Latin America, the Middle East and Europe. In 2008 there were 274 million cases of mala-ria and nearly one million deaths-mostly among children living in African. In Africa a child dies every 45 seconds of Malaria, the disease accounts for 20% of all childhood deaths.Malaria had been widely outbroken in the early 1960s and 1970s in China, and the cases of malaria is more than 30 million. Recently, with the hard working of med-ical researchers, the malaria has been effectively controlled. But in some area malaria is still a threaten; The disease outbreak unstable and in point. According to reports of 2007 and 2008, malaria showed a downward trend, but the plasmodium resistance in-creasingly serious and diffusion fast, has severely affected the control of malaria. We should still focus on this disease.Phosphate naphthoquine is the class I anti-malaria new drug, and belong to the kind of 4-aminoquinoline anti-malarial drugs like chloroquine. In vivo anti-malarial experiments showed that phosphate naphthoquine has high anti-malarial activity. Re-sults of clinical trials showed that the half-life of phosphate naphthoquine is more than 255h. Advantage of Long half-life drug is short course in clinical medication and good compliance. But it accumulate in blood, so according to drugs with short half life, it easily causes resistance. So, we synthesized a group of phosphate naphthoquine derivatives with novel amine, to obtain the new drugs with powerful anti-malaria ac-tivity and low resistance. To establish background of deeply research on phosphate naphthoquine derivatives.Objective:1. With the different of choiced amine compounds as side chain, synthetic new phosphoric naphthoquine derivatives. 2. we synthesized a group of phosphate naphtha- quine derivatives with novel amine, to obtain the new drugs with powerful anti-malaria activity, To establish background of deeply research on phos-phate naphthoquine derivatives. 3. Because of the insolubility of phosphoric naph- thoquine in water, we used the beta amino alcohol as raw materials to synthesis new phosphoric naphthoquine derivatives with good solubility in water. 4. Simplified the preparation methods of intermediates II, and improved the yield, optimize preparation methods of these compounds. 5. Using K173 strains of P. falciparum, study the phar-macodynamics of new antimalarial drugs, guide future pharmacological studies on the selection of the side chain type according to this result of pharmacodynamics.Methods: 1. Optimize synthetic route, improved the experiment of which the yield is low through parallel test, to increase the yield of intermediate production. 2. Choosing 3 amine compounds not contain hydroxyl, to synthesize new phosphate naphthoquine derivatives through Mannich action. 3. Choosing seven compounds containing theβ-amino alcohols, to synthesize new phosphate naphthoquine deriva-tives through Mannich action. And separate and purify the compounds with the me-thod of column chromatography. 4. Analysist structures of the compounds using the methods of NMR, Q-FT-MS, melting point section. 5. Evaluate the activity of new compounds with the method of international general 4 days inhibition. 6. Evaluate the activity of new compounds with the K173 strains of P. falciparum, and guide the future work.Results: 1.Optimized the preparation method of internal II, the result show that the yield of this method is higher than the method reported. 2. There are 10 targets compounds were synthesized, which is not been reported in abroad and home. 3 of them are with side chain of amines without hydroxyl, and amine is respectively 4-methyl-piperidine, propylene amine and circum-propylamine. 7 of them are with side chain ofβ-amino alcohols, and they are respectively isobutanol amine, DL-aminopropanol and two chiral optics isomers, 2-amino-1-butanol, 2-amino-2- methyl-1-propanol, 3-amino-1,2-dipropanol. 3. According to 1H-NMR, Q-FT-MS spectra, we determined the structures consistent with the target compound. And we are also studied the property such as melting point and optical rotation. 4. According to the results of 4 days inhibition, for compounds with side chain without hydroxyl amine, the dose of inhibiting K173 strains of plasmodium falciparum is ED50=0.71 -0.88mg/kg, ED90 =2.67-3.96 mg/kg. For compounds with side chain withβ-amino alcohols, the dose of inhibiting K173 strains of plasmodium falciparum is ED50= 0.51-0.77mg/kg, ED90=1.16-3.35mg/kg. The ED50 of compound VIII is only 0.51 mg/kg, and ED90 of compound III is 1.16 mg/kg. Conclusion: The results of synthesisshouwed that, the yield can improve to 50% through improving the preparation method of intermediates II, and the time of the reaction is also shortening. In the preparation of intermediate IV, using compound with amine without hydroxyl groups as raw material, the reaction time is short, and product is easy to obtain and purified with high yield. using compound with beta amino alcohols as raw material, the reaction time is long, and the product need to be purified through column chromatography method which causes the low yield.The results of preliminary pharmacodynamic show that, anti-malaria activity in mice of compounds containingβ-amino alcohols as side chain were superior to com-pounds containing amino without hydroxyl amine as side chain. And the more alco-hols , the more active against malaria. It's reported that in 4-aminoquinoline, the li-posoluble of the 4-amino, the more active against malaria. But in our paper, 4-aminoquinoline derivatives with hydrosoluble compound as 4-amino has good acti-vitity against malaria, the result initiate a new tread of researches on this kind of compound.