新型抗疟药物磷酸萘酚喹衍生物的合成与药效学研究
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摘要
疟疾是世界上发病率和死亡率最高的虫媒传染病之一,是当今世界公共卫生的突出问题之一,是世界上流行最广、危害最大的寄生虫病。据WHO报道全球有约108各国家和地区,全球近半人口受到疟疾的危害,多数在撒哈拉以南非洲地区,并且亚洲、拉美、中东以及欧洲也受到影响。其中2008年全年就有2.74亿的临床报告病例,有近百万人死亡。在非洲,每45秒就有一名儿童死于疟疾,死于该病的儿童数目高达儿童死亡总数的20%。
我国60年代初及70年代初,都曾发生过大范围的流行,患病人数逾3 000万。近年来,经过医药工作者的努力工作,已经有效的控制了疟疾的大规模流行。但是在局部地区疟疾仍然很严重,疫情呈现不稳定,点状爆发的特点。据报道,2007年和2008年连续两年,全国的疟疾疫情都呈现下降的趋势,但疟原虫的抗药性日益严重且扩散极快,已经严重影响了疟疾的控制,我们仍然不能掉以轻心。
磷酸萘酚喹是我研究所研制的I类抗疟新药,与氯喹同属4-氨基喹啉类抗疟药。动物实验显示,磷酸萘酚喹具有很高的抗疟活性。临床实验显示磷酸萘酚喹消除半衰期长达255h以上。长半衰期药物的优点是临床用药疗程短、依从性好,缺点是由于血液中较长时间存在低浓度药物,故与短半衰期药物相比容易产生抗性。所以,我们用新型胺类化合物作为氨基侧链末端基团合成新型磷酸萘酚喹衍生物,以筛选出抗疟活性强且耐药性小的抗疟新药,为磷酸萘酚喹类衍生物的深入研究奠定基础。
目的:1、通过选择不同的胺类化合物作为侧链,合成新型磷酸萘酚喹衍生物;2、在新的目标化合物中发现抗疟效果比较好的化合物,为进行后续的研究工作奠定良好的科研基础;3、由于磷酸萘酚喹不易溶于水,所以通过以β-氨基醇为原料合成新型磷酸萘酚喹衍生物,得到易溶于水的磷酸萘酚喹衍生物化合物。4、简化中间体II的制备方法,提高中间II的收率,优化该类药物的制备方法;5、以伯氏疟原虫K173株,进行新型抗疟药物的药效学筛选工作,并结合药效学结果,指导今后该类化合物合成研究时氨基末端侧链类型的选择方向。
方法:1、优化合成路线,并在此基础上,通过平行实验对收率较低的反应步骤加以改进以提高中间体的产率。2、根据相关文献报道,选择3种不含有羟基的胺类化合物,利用Mannich反应合成新型磷酸萘酚喹衍生物目标化合物;3、选择了7种β-氨基醇类化合物,利用Mannich反应合成新型磷酸萘酚喹衍生物,并用柱层析的方法进行分离纯化;4、通过核磁共振、高分辨质谱、熔点测定等方法分析目标化合物的结构。5、使用国际通用的4日抑制法,对新合成的目标化合物进行药效学评价。6、使用伯氏疟原虫K173株,在昆明小鼠体内测试新化合物的抗疟活性,指导以后的药效学研究。
结果:1、对中间体II的制备方法进行了优化,结果显示该方法较文献报道的方法产率有较大的提高。2、合成了10个目标化合物,国内外均未见报道,其中3个为以不含羟基的胺类(4-甲基哌啶,丙烯胺,环丙胺)作为氨基侧链末端基团合成的新化合物,另外7个为以β-氨基醇类(异丁醇胺、氨基丙醇的外消旋体和手性旋光异构体、2-氨基-1-丁醇、2-氨基-2-甲基-1-丙醇、3-氨基-1,2-丙二醇)作为氨基侧链末端基团合成的新化合物。3、根据1H-NMR,Q-FT-MS等的结果,可以确定其结构特征与目标化合物一致。并对目标化合物的熔点和旋光度等理化性质进行了研究。4、4日抑制实验法的药效学结果显示,不含有羟基的胺类为侧链的化合物,对伯氏疟原虫K173株抑制剂量范围为ED50=1.75-2.02uM,ED90=6.58-9.08uM ;以β-氨基醇类为侧链的化合物的药效学结果为ED50=1.19-1.87uM,ED90=2.72-8.13uM。其中化合物V10的ED50仅为1.19uM,化合物V4的ED90=2.72uM。目标化合物均有进行深入研究的价值。
结论:药物合成研究结果显示,中间体II的制备方法优化后,产率可提高至50%左右,缩短了整条路线的反应时间。在中间体IV制备过程中,以不含羟基的胺类化合物作为Mannich反应原料时,反应时间短,反应迅速,产物易得,且纯化方法简单、收率高。而以β-氨基醇类化合物作为Mannich反应原料时,反应时间长,反应速度慢,产物需使用柱层析方法纯化,导致产物收率低。
初步药效学研究结果显示,含有β-氨基醇类侧链的磷酸萘酚喹衍生物在小鼠体内抗疟活性均优于以不含羟基的胺类为侧链的磷酸萘酚喹衍生物;作为侧链的β-氨基醇中含有的羟基的个数越多,抗疟活性越强。据文献报道4-氨基喹啉类化合物中4位氨基侧链末端的脂溶性越强其抗疟活性越强,但本论文的实验结果表明,以水溶性化合物作为4位氨基末端侧链的4-氨基喹啉类化合物也可以获得很好的抗疟效果,该研究结果为此类药物的研究开创了新的思路。
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.
我国60年代初及70年代初,都曾发生过大范围的流行,患病人数逾3 000万。近年来,经过医药工作者的努力工作,已经有效的控制了疟疾的大规模流行。但是在局部地区疟疾仍然很严重,疫情呈现不稳定,点状爆发的特点。据报道,2007年和2008年连续两年,全国的疟疾疫情都呈现下降的趋势,但疟原虫的抗药性日益严重且扩散极快,已经严重影响了疟疾的控制,我们仍然不能掉以轻心。
磷酸萘酚喹是我研究所研制的I类抗疟新药,与氯喹同属4-氨基喹啉类抗疟药。动物实验显示,磷酸萘酚喹具有很高的抗疟活性。临床实验显示磷酸萘酚喹消除半衰期长达255h以上。长半衰期药物的优点是临床用药疗程短、依从性好,缺点是由于血液中较长时间存在低浓度药物,故与短半衰期药物相比容易产生抗性。所以,我们用新型胺类化合物作为氨基侧链末端基团合成新型磷酸萘酚喹衍生物,以筛选出抗疟活性强且耐药性小的抗疟新药,为磷酸萘酚喹类衍生物的深入研究奠定基础。
目的:1、通过选择不同的胺类化合物作为侧链,合成新型磷酸萘酚喹衍生物;2、在新的目标化合物中发现抗疟效果比较好的化合物,为进行后续的研究工作奠定良好的科研基础;3、由于磷酸萘酚喹不易溶于水,所以通过以β-氨基醇为原料合成新型磷酸萘酚喹衍生物,得到易溶于水的磷酸萘酚喹衍生物化合物。4、简化中间体II的制备方法,提高中间II的收率,优化该类药物的制备方法;5、以伯氏疟原虫K173株,进行新型抗疟药物的药效学筛选工作,并结合药效学结果,指导今后该类化合物合成研究时氨基末端侧链类型的选择方向。
方法:1、优化合成路线,并在此基础上,通过平行实验对收率较低的反应步骤加以改进以提高中间体的产率。2、根据相关文献报道,选择3种不含有羟基的胺类化合物,利用Mannich反应合成新型磷酸萘酚喹衍生物目标化合物;3、选择了7种β-氨基醇类化合物,利用Mannich反应合成新型磷酸萘酚喹衍生物,并用柱层析的方法进行分离纯化;4、通过核磁共振、高分辨质谱、熔点测定等方法分析目标化合物的结构。5、使用国际通用的4日抑制法,对新合成的目标化合物进行药效学评价。6、使用伯氏疟原虫K173株,在昆明小鼠体内测试新化合物的抗疟活性,指导以后的药效学研究。
结果:1、对中间体II的制备方法进行了优化,结果显示该方法较文献报道的方法产率有较大的提高。2、合成了10个目标化合物,国内外均未见报道,其中3个为以不含羟基的胺类(4-甲基哌啶,丙烯胺,环丙胺)作为氨基侧链末端基团合成的新化合物,另外7个为以β-氨基醇类(异丁醇胺、氨基丙醇的外消旋体和手性旋光异构体、2-氨基-1-丁醇、2-氨基-2-甲基-1-丙醇、3-氨基-1,2-丙二醇)作为氨基侧链末端基团合成的新化合物。3、根据1H-NMR,Q-FT-MS等的结果,可以确定其结构特征与目标化合物一致。并对目标化合物的熔点和旋光度等理化性质进行了研究。4、4日抑制实验法的药效学结果显示,不含有羟基的胺类为侧链的化合物,对伯氏疟原虫K173株抑制剂量范围为ED50=1.75-2.02uM,ED90=6.58-9.08uM ;以β-氨基醇类为侧链的化合物的药效学结果为ED50=1.19-1.87uM,ED90=2.72-8.13uM。其中化合物V10的ED50仅为1.19uM,化合物V4的ED90=2.72uM。目标化合物均有进行深入研究的价值。
结论:药物合成研究结果显示,中间体II的制备方法优化后,产率可提高至50%左右,缩短了整条路线的反应时间。在中间体IV制备过程中,以不含羟基的胺类化合物作为Mannich反应原料时,反应时间短,反应迅速,产物易得,且纯化方法简单、收率高。而以β-氨基醇类化合物作为Mannich反应原料时,反应时间长,反应速度慢,产物需使用柱层析方法纯化,导致产物收率低。
初步药效学研究结果显示,含有β-氨基醇类侧链的磷酸萘酚喹衍生物在小鼠体内抗疟活性均优于以不含羟基的胺类为侧链的磷酸萘酚喹衍生物;作为侧链的β-氨基醇中含有的羟基的个数越多,抗疟活性越强。据文献报道4-氨基喹啉类化合物中4位氨基侧链末端的脂溶性越强其抗疟活性越强,但本论文的实验结果表明,以水溶性化合物作为4位氨基末端侧链的4-氨基喹啉类化合物也可以获得很好的抗疟效果,该研究结果为此类药物的研究开创了新的思路。
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.
引文
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[7]药理学人民卫生出版社2001
[8]郑虎,药物化学,人民卫生出版社,2002,4:373-376
[9]叶祖光,4-氨基喹啉类抗疟药的作用原理,国外医学、药学分册,1981(6):357-361
[10]徐勤丰,4-氨基喹啉类药物的研究进展,中国药物化学杂志,1994,4(1):68-73,78
[11] V.R. Solomon, W.Haq, M. Smilkstein, Kumkum Srivastava, Sunil K. Puri, S.B.Katti, 4-Aminoquinoline derived antimalarials: Synthesis, antiplasmodial ac-tivityand heme polymerization inhibition studies,European Journal of Medicinal Chemistry, 45(2010):4990-4996
[12] Naresh Sunduru, Moni Sharma, Kumkum Srivastava, S. Rajakumar, S. K. Puri, J. K. Saxena, Prem M. S. Chauhan, Synthesis of oxalamide and triazine deriva-tives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial ac-tivity, Bioorganic & Medicinal Chemistry, 17(2009):6451–6462
[13] Ashok Kumar, Kumkum Srivastava, S. Raja Kumar, S. K. Puri, Prem M. S. Chauhan, Synthesis of new 4-aminoquinolines and quinoline–acridine hybrids as antimalarial agents, Bioorganic & Medicinal Chemistry Letters, 20(2010):7059–7063
[14] Rodrigo Arancibia, Faustine Dubar, Bruno Pradines, Isabelle Forfar, Daniel Dive, A. Hugo Klahn, Christophe Biot Synthesis and antimalarial activities of rhenium bioorganometallics basedon the 4-aminoquinoline structure Bioorganic & Medi-cinal Chemistry, 18(2010):8085–8091
[15] Manolo Casagrande, Nicoletta Basilico, Chiara Rusconi, Donatella Taramelli, Anna Sparatore, Synthesis, antimalarial activity, and cellular toxicity of new arylpyrrolylaminoquinolines, Bioorganic & Medicinal Chemistry, 18(2010):6625–6633
[16] Eric M. Guantai, Kanyile Ncokazi, Timothy J. Egan, Jiri Gut, Philip J. Rosenthal, Peter J. Smith, Kelly Chibale, Design, synthesis and in vitro antimalarial evalua-tion of triazole-linked chalcone and dienone hybrid compounds Bioorganic & Medicinal Chemistry, 18(2010):8243–8256
[17]萘酚喹盐类的制备方法,CN93103887.1
[18]王红,磷酸萘酚喹抗药性机制的研究,军事医学科学院,2010
[19]王京燕,邬伯安,徐在海,孙国章等,复方萘酚喹对比格犬的长期毒性,军事医学科学院院刊,2003,27(3):196-199
[20]王京燕,单成启,符大东,庞学坚,复方萘酚喹片治疗恶性疟的临床观察,中国寄生虫病防治杂志,2003,16(3):134-136
[21]张立明,沈季华,王云玲,张洪北,王丽华,王俭,李福林,2-二烷氨甲基-4-杂环氨基-5,6,7,8-四氢萘酚衍生物的合成及抗疟活性,医药工业1985,16(2):8(52)~16(60)
[22]高守海,李福林,抗疟化合物含呱嗦侧链的四氢萘酚Mannich碱的合成,中国药物化学杂志1993,3(3):175~178
[23]李福林,王丽华,丁德本,杨俊德,高徐生,疟疾治疗药物——4-芳胺基-2-特丁胺甲基酚类化合物的合成,药学学报,1982,17(1):77-79
[24]李福林,王丽华,丁德本,杨俊德,高徐生,疟疾治疗药物-4-芳胺基-2-特丁胺甲基酚类化合物的合成,药学学报,1982,17(2):77-79
[25]抗疟新药磷酸萘酚喹,中国新技术新产品精选:65
[26]李春富,车立刚,杨从忠,陶定珍,磷酸蔡酚哇治疗疟疾的疗效观察,实用寄生虫病杂志,1998,16(2):58-59
[27]单成启,刘光裕,焦岫卿,磷酸萘酚喹治疗恶性疟的疗效初步观察,寄生虫与医学昆虫学报,2003,10(4):198-201
[28]舒文谊,车立刚,陈昕,岩嫩,磷酸萘酚喹治疗疟疾效果观察,中国寄生虫病防治杂志,1998,11(3):230
[29]忻祥法,磷酸萘酚喹治疗疟疾临床研究进展,上海医药,2004,25(4):160-161
[30]魏晓莉,苏瑞斌,喹啉类药物抗疟作用机制研究进展,军事医学科学院院刊,2002,26(3):228-230
[31] Gabay T, Krugliak M, Shalmiev G, et al. Inhibition by anti-malarial drugs of haemoglobin denaturation and iron release in acidified red blood cell lysates—a possible mechanism of their anti-malarial effect? Parasitology, 1994,108:371- 381
[32] Slater AF, Swiggard WJ, Orton BR, et al. An iron-carboxyl ate bond links the heme units of malaria pigment [J]. Proc Natl Acad Sci USA, 1991,88(2):325- 329
[33] Gabay T., Ginsburg H., Hemoglobin denaturation and iron release in acidified red blood cell lysate—a possible source of iron for intra erythrocytic malaria para-sites [J]. Exp Parasitol, 1993, 77(3):261-272
[34] Bray PG, Janneh O, Ward SA. Chloroquine uptake and activity is determined by binding to ferriprotoporphyrin IX in Plasmodium falciparum [C]. Novart is Found Symp, 1999, 226:252-260; discussion 260-264.
[35] Bachhawat K, Thomas CJ, Surolia N, et al. Interaction of chloroquine and its analogues with heme: an isothermal titration calorimetric study, [J]. Biochem Biophys Res Commun, 2000, 276(3): 1075-1079
[36] Raynes KJ, Bray PG, Ward SA. Altered binding of chloroquine to ferriprotopor-phyrin IX is the basis for chloroquine resistance [J]. Drug Resist Update, 1999, 2(2):97-103
[37]取代的噁嗪衍生物,CN93103883.6
[38]闫喜龙,手性邻氨基醇类化合物及相关药物的合成研究,天津大学,2004
[39] L. A. Mitscher, L. Kans, D. T. Chu, et al. Process for Preparation of Racemate and Optically Active Ofloxacin and Related Derivatives. US 4777253, 1988
[40] R. G. Wilkinson, M. B. Cantrall, R. G. Shepherd, (+)-2,2’-(Ethylenediimino)-di-1-butanol and Some Analogs, J. Med. Chem. 1962, 5:835-845
[41]孙同庆,石鸿昌,dl-麻黄碱和dl-伪麻黄碱的合成,中国医药工业杂志,2000, 31(12):534-535
[42] J. B. Koepfli, J. A. Brockman, J. Moffat, The Structure of Febrifugine and Isofe-brifugine J. Am. Chem. Soc. 1950, 72(7):3323
[43] S. Kobayashi, M. Ueno, R. Suzuki, et al. Catalytic Asymmetric Synthesis of Fe-brifugine and Isofebrifugine. Tetrahedron Lett. 1999, 40(11):2175-2178
[44]王红,王京燕,喹啉类抗疟药抗性机制研究进展,军事医学科学院院刊2009, 33(1):71-73
[45]胡晶莹,沈利,潘卫庆,恶性疟原虫氯喹抗性机制研究进展,中国热带医学,2009,9(12) : 2315-2317
[46]董莹,抗疟药的抗疟作用及恶性疟原虫药物抗性机制,中国寄生虫病防治杂志2002,15(4):254-256
[47]楚心唯,恶性疟的抗药性流行病学和治疗药物研究进展,国外医学寄生虫分册,2003,30(4):152-157
[48]李福林,王丽华,丁德本,杨俊德,高徐生,疟疾治疗药物——4-芳胺基-2-特丁胺甲基酚类化合物的合成,药学学报1982,17(1):77-79
[49]姚文莉,丁德本,杨俊德,李福林,三氟甲喹四氢萘酚类化合物的合成及其抗疟作用,军事医学科学院院刊,1989,13(5):354-357
[50]倪沛州,有机化学,人民卫生出版社,2002,4:374
[51]基础有机化学邢其毅裴伟伟徐瑞秋裴坚高等教育出版社2002
[52] US2475718A[1]
[1]周水森,王漪,房文,汤林华2007年全国疟疾形势中国寄生虫学与寄生虫病杂志2008年12月第26卷第6期
[2]周水森,王漪,房文,汤林华2008年全国疟疾形势中国寄生虫学与寄生虫病杂志2009年12月第27卷第6期455-457
[3]梁晓竟,谢贤桂氯喹抗疟研究概况预防医学情报杂志2002,18(3)
[4]张秀平近年来国内外抗疟药物研究进展医药工业,1982.3:13
[5]叶祖光. 4-氨基喹啉类抗疟药的作用原理.
[6]郑贤育,陈昌,黄兰孙抗疟药双咯喹及其类似物的合成中国医药工业杂志1990 21(5)
[7]李福林.药学学报. 17:27,1982
[8]王京燕,单成启.复方萘酚喹片治疗恶性疟的临床观察中国寄生虫病防治杂志2003年6月第16卷第3期:134-136
[9]王京燕,邬伯安,徐在海.复方萘酚喹对比格犬的长期毒性.军事医学科学院院刊2003年6月第27卷第3期:196-198,226
[10]V.R. Solomon, W.Haq, M. Smilkstein, Kumkum Srivastava, Sunil K. Puri, S.B.Katti 4-Aminoquinoline derived antimalarials: Synthesis, antiplasmodial ac-tivityand heme polymerization inhibition studies European Journal of Medicin-al Chemistry 45(2010) 4990-4996
[11] Naresh Sunduru, Moni Sharma, Kumkum Srivastava, S. Rajakumar, S. K. Puri, J. K. Saxena, Prem M. S. Chauhan, Synthesis of oxalamide and triazine deriva-tives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activ-ity, Bioorganic & Medicinal Chemistry 17 (2009) 6451–6462
[12] Ashok Kumar, Kumkum Srivastava, S. Raja Kumar, S. K. Puri, Prem M. S. Chauhan, Synthesis of new 4-aminoquinolines and quinoline–acridine hybrids as antimalarial agents, Bioorganic & Medicinal Chemistry Letters 20 (2010) 7059–7063
[13] Rodrigo Arancibia, Faustine Dubar, Bruno Pradines, Isabelle Forfar, Daniel Dive, A. Hugo Klahn,Christophe Biot Synthesis and antimalarial activities of rhe-nium bioorganometallics basedon the 4-aminoquinoline structure Bioorganic & Medicinal Chemistry 18 (2010) 8085–8091
[14] Manolo Casagrande, Nicoletta Basilico, Chiara Rusconi, Donatella Taramelli, Anna Sparatore Synthesis, antimalarial activity, and cellular toxicity of new arylpyrrolylaminoquinolines Bioorganic & Medicinal Chemistry 18 (2010) 6625–6633
[15] Eric M. Guantai, Kanyile Ncokazi, Timothy J. Egan, Jiri Gut, Philip J. Rosenthal, Peter J. Smith, Kelly Chibale Design, synthesis and in vitro antimalarial evalu-ation of triazole-linked chalcone and dienone hybrid compounds Bioorganic & Medicinal Chemistry 18 (2010) 8243–8256
[2]汤林华,国内外疟疾防治研究进展,疾病控制杂志,1998,2(2):97-100
[3]张丽茹,张丽娜,王晓蕙,蒋燕,国内疟疾治疗药物的进展,药物实践杂志,2001,19(5):259-262
[4]周水森,王漪,房文,汤林华,2007年全国疟疾形势,中国寄生虫学与寄生虫病杂志,2008,26(6):401-403
[5]周水森,王漪,房文,汤林华,2008年全国疟疾形势,中国寄生虫学与寄生虫病杂志,2009,27(6):455-457
[6]甘绍伯,防治疟疾药物的应用,中国感染与化疗杂志,2007,7(5):391-392
[7]药理学人民卫生出版社2001
[8]郑虎,药物化学,人民卫生出版社,2002,4:373-376
[9]叶祖光,4-氨基喹啉类抗疟药的作用原理,国外医学、药学分册,1981(6):357-361
[10]徐勤丰,4-氨基喹啉类药物的研究进展,中国药物化学杂志,1994,4(1):68-73,78
[11] V.R. Solomon, W.Haq, M. Smilkstein, Kumkum Srivastava, Sunil K. Puri, S.B.Katti, 4-Aminoquinoline derived antimalarials: Synthesis, antiplasmodial ac-tivityand heme polymerization inhibition studies,European Journal of Medicinal Chemistry, 45(2010):4990-4996
[12] Naresh Sunduru, Moni Sharma, Kumkum Srivastava, S. Rajakumar, S. K. Puri, J. K. Saxena, Prem M. S. Chauhan, Synthesis of oxalamide and triazine deriva-tives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial ac-tivity, Bioorganic & Medicinal Chemistry, 17(2009):6451–6462
[13] Ashok Kumar, Kumkum Srivastava, S. Raja Kumar, S. K. Puri, Prem M. S. Chauhan, Synthesis of new 4-aminoquinolines and quinoline–acridine hybrids as antimalarial agents, Bioorganic & Medicinal Chemistry Letters, 20(2010):7059–7063
[14] Rodrigo Arancibia, Faustine Dubar, Bruno Pradines, Isabelle Forfar, Daniel Dive, A. Hugo Klahn, Christophe Biot Synthesis and antimalarial activities of rhenium bioorganometallics basedon the 4-aminoquinoline structure Bioorganic & Medi-cinal Chemistry, 18(2010):8085–8091
[15] Manolo Casagrande, Nicoletta Basilico, Chiara Rusconi, Donatella Taramelli, Anna Sparatore, Synthesis, antimalarial activity, and cellular toxicity of new arylpyrrolylaminoquinolines, Bioorganic & Medicinal Chemistry, 18(2010):6625–6633
[16] Eric M. Guantai, Kanyile Ncokazi, Timothy J. Egan, Jiri Gut, Philip J. Rosenthal, Peter J. Smith, Kelly Chibale, Design, synthesis and in vitro antimalarial evalua-tion of triazole-linked chalcone and dienone hybrid compounds Bioorganic & Medicinal Chemistry, 18(2010):8243–8256
[17]萘酚喹盐类的制备方法,CN93103887.1
[18]王红,磷酸萘酚喹抗药性机制的研究,军事医学科学院,2010
[19]王京燕,邬伯安,徐在海,孙国章等,复方萘酚喹对比格犬的长期毒性,军事医学科学院院刊,2003,27(3):196-199
[20]王京燕,单成启,符大东,庞学坚,复方萘酚喹片治疗恶性疟的临床观察,中国寄生虫病防治杂志,2003,16(3):134-136
[21]张立明,沈季华,王云玲,张洪北,王丽华,王俭,李福林,2-二烷氨甲基-4-杂环氨基-5,6,7,8-四氢萘酚衍生物的合成及抗疟活性,医药工业1985,16(2):8(52)~16(60)
[22]高守海,李福林,抗疟化合物含呱嗦侧链的四氢萘酚Mannich碱的合成,中国药物化学杂志1993,3(3):175~178
[23]李福林,王丽华,丁德本,杨俊德,高徐生,疟疾治疗药物——4-芳胺基-2-特丁胺甲基酚类化合物的合成,药学学报,1982,17(1):77-79
[24]李福林,王丽华,丁德本,杨俊德,高徐生,疟疾治疗药物-4-芳胺基-2-特丁胺甲基酚类化合物的合成,药学学报,1982,17(2):77-79
[25]抗疟新药磷酸萘酚喹,中国新技术新产品精选:65
[26]李春富,车立刚,杨从忠,陶定珍,磷酸蔡酚哇治疗疟疾的疗效观察,实用寄生虫病杂志,1998,16(2):58-59
[27]单成启,刘光裕,焦岫卿,磷酸萘酚喹治疗恶性疟的疗效初步观察,寄生虫与医学昆虫学报,2003,10(4):198-201
[28]舒文谊,车立刚,陈昕,岩嫩,磷酸萘酚喹治疗疟疾效果观察,中国寄生虫病防治杂志,1998,11(3):230
[29]忻祥法,磷酸萘酚喹治疗疟疾临床研究进展,上海医药,2004,25(4):160-161
[30]魏晓莉,苏瑞斌,喹啉类药物抗疟作用机制研究进展,军事医学科学院院刊,2002,26(3):228-230
[31] Gabay T, Krugliak M, Shalmiev G, et al. Inhibition by anti-malarial drugs of haemoglobin denaturation and iron release in acidified red blood cell lysates—a possible mechanism of their anti-malarial effect? Parasitology, 1994,108:371- 381
[32] Slater AF, Swiggard WJ, Orton BR, et al. An iron-carboxyl ate bond links the heme units of malaria pigment [J]. Proc Natl Acad Sci USA, 1991,88(2):325- 329
[33] Gabay T., Ginsburg H., Hemoglobin denaturation and iron release in acidified red blood cell lysate—a possible source of iron for intra erythrocytic malaria para-sites [J]. Exp Parasitol, 1993, 77(3):261-272
[34] Bray PG, Janneh O, Ward SA. Chloroquine uptake and activity is determined by binding to ferriprotoporphyrin IX in Plasmodium falciparum [C]. Novart is Found Symp, 1999, 226:252-260; discussion 260-264.
[35] Bachhawat K, Thomas CJ, Surolia N, et al. Interaction of chloroquine and its analogues with heme: an isothermal titration calorimetric study, [J]. Biochem Biophys Res Commun, 2000, 276(3): 1075-1079
[36] Raynes KJ, Bray PG, Ward SA. Altered binding of chloroquine to ferriprotopor-phyrin IX is the basis for chloroquine resistance [J]. Drug Resist Update, 1999, 2(2):97-103
[37]取代的噁嗪衍生物,CN93103883.6
[38]闫喜龙,手性邻氨基醇类化合物及相关药物的合成研究,天津大学,2004
[39] L. A. Mitscher, L. Kans, D. T. Chu, et al. Process for Preparation of Racemate and Optically Active Ofloxacin and Related Derivatives. US 4777253, 1988
[40] R. G. Wilkinson, M. B. Cantrall, R. G. Shepherd, (+)-2,2’-(Ethylenediimino)-di-1-butanol and Some Analogs, J. Med. Chem. 1962, 5:835-845
[41]孙同庆,石鸿昌,dl-麻黄碱和dl-伪麻黄碱的合成,中国医药工业杂志,2000, 31(12):534-535
[42] J. B. Koepfli, J. A. Brockman, J. Moffat, The Structure of Febrifugine and Isofe-brifugine J. Am. Chem. Soc. 1950, 72(7):3323
[43] S. Kobayashi, M. Ueno, R. Suzuki, et al. Catalytic Asymmetric Synthesis of Fe-brifugine and Isofebrifugine. Tetrahedron Lett. 1999, 40(11):2175-2178
[44]王红,王京燕,喹啉类抗疟药抗性机制研究进展,军事医学科学院院刊2009, 33(1):71-73
[45]胡晶莹,沈利,潘卫庆,恶性疟原虫氯喹抗性机制研究进展,中国热带医学,2009,9(12) : 2315-2317
[46]董莹,抗疟药的抗疟作用及恶性疟原虫药物抗性机制,中国寄生虫病防治杂志2002,15(4):254-256
[47]楚心唯,恶性疟的抗药性流行病学和治疗药物研究进展,国外医学寄生虫分册,2003,30(4):152-157
[48]李福林,王丽华,丁德本,杨俊德,高徐生,疟疾治疗药物——4-芳胺基-2-特丁胺甲基酚类化合物的合成,药学学报1982,17(1):77-79
[49]姚文莉,丁德本,杨俊德,李福林,三氟甲喹四氢萘酚类化合物的合成及其抗疟作用,军事医学科学院院刊,1989,13(5):354-357
[50]倪沛州,有机化学,人民卫生出版社,2002,4:374
[51]基础有机化学邢其毅裴伟伟徐瑞秋裴坚高等教育出版社2002
[52] US2475718A[1]
[1]周水森,王漪,房文,汤林华2007年全国疟疾形势中国寄生虫学与寄生虫病杂志2008年12月第26卷第6期
[2]周水森,王漪,房文,汤林华2008年全国疟疾形势中国寄生虫学与寄生虫病杂志2009年12月第27卷第6期455-457
[3]梁晓竟,谢贤桂氯喹抗疟研究概况预防医学情报杂志2002,18(3)
[4]张秀平近年来国内外抗疟药物研究进展医药工业,1982.3:13
[5]叶祖光. 4-氨基喹啉类抗疟药的作用原理.
[6]郑贤育,陈昌,黄兰孙抗疟药双咯喹及其类似物的合成中国医药工业杂志1990 21(5)
[7]李福林.药学学报. 17:27,1982
[8]王京燕,单成启.复方萘酚喹片治疗恶性疟的临床观察中国寄生虫病防治杂志2003年6月第16卷第3期:134-136
[9]王京燕,邬伯安,徐在海.复方萘酚喹对比格犬的长期毒性.军事医学科学院院刊2003年6月第27卷第3期:196-198,226
[10]V.R. Solomon, W.Haq, M. Smilkstein, Kumkum Srivastava, Sunil K. Puri, S.B.Katti 4-Aminoquinoline derived antimalarials: Synthesis, antiplasmodial ac-tivityand heme polymerization inhibition studies European Journal of Medicin-al Chemistry 45(2010) 4990-4996
[11] Naresh Sunduru, Moni Sharma, Kumkum Srivastava, S. Rajakumar, S. K. Puri, J. K. Saxena, Prem M. S. Chauhan, Synthesis of oxalamide and triazine deriva-tives as a novel class of hybrid 4-aminoquinoline with potent antiplasmodial activ-ity, Bioorganic & Medicinal Chemistry 17 (2009) 6451–6462
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