Drugs Targeting Erthrocytic and Exoerythrocytic Stages of Malaria

针对疟疾红细胞和红细胞外阶段的药物

• 批准号: 8850457
• 负责人: Roman Manetsch
• 金额: $ 23.84万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850457
• 关键词: Accounting; Action Potentials; Affinity; Africa South of the Sahara; Age-Years; Aminoquinolines; Antimalarials; Avian Malaria; Biological; Blood; Cessation of life; Chemicals; Child; Culicidae; Development; Disease; Drug Kinetics; Drug Targeting; Drug or chemical Tissue Distribution; Drug resistance; Erythrocytes; Esters; Evaluation; Falciparum Malaria; Future; Glucosephosphate Dehydrogenase; Gold; Health; Human; In Vitro; Individual; International; Lead; Liver; Macaca mulatta; Malaria; Mammals; Metabolic; Modeling; Multi-Drug Resistance; Parasites; Parasitic Diseases; Patients; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Population; Pregnant Women; Preventive; Primaquine; Property; Public Health; Quinolones; Relapse; Resistance; Resistance development; Series; Solubility; Staging; Structure; analog; aqueous; biochemical tools; combat; drug development; drug discovery; high risk; human disease; in vitro activity; in vivo; killings; man; novel; preclinical efficacy; prevent; prophylactic; transmission process

DESCRIPTION (provided by applicant): Malaria is the most important parasitic disease of man, with over 1 million deaths per year and more than 300 million cases annually. New drugs are urgently required to combat this deadly disease. Due to a limited number of chemotypes and documented resistance to the available drugs, there is renewed international effort aimed to discover and develop new leads with potential to prevent or treat malaria. Most antimalarial drug discovery focuses on the erythrocytic stages of malaria that cause disease, yet to eliminate malaria compounds are required to kill liver stages as well as the infective stages for mosquitoes. The only approved drug with these combined properties is primaquine, an 8-aminoquinoline (8AQ) that has weak erythrocytic stage activity and is toxic in glucose-6-phosphate dehydrogenase deficient individuals. Therefore, the most significant need for future malaria elimination efforts is a compound that is safe and effective at killing parasites at all stages of development in the patient. With the exception of 8AQs, very few compound series have demonstrated activity against the exo-erythrocytic (EE) stages in the liver as well as erythrocytic and gametocyte stages. Endochin and 4(1H)-quinolones are known to possess causal prophylactic activity (kill growing EE stage parasites) and potent erythrocytic stage inhibition in avian malaria models, but not against malaria parasites in mammals. Furthermore, a quinolone ester ICI56,780 has been shown to produce a radical cure in P. cynomologi infected rhesus monkeys (eradicate dormant EE parasites); however, rapid development of resistance hampered its further development. Many of these studies were conducted over 20 years ago without an adequate evaluation in current preclinical efficacy models or without assessing the compounds' physicochemical properties. The broad long term objectives of this proposal are to progress 3-alkyl and 3-(hetero)aryl-4(1H)- quinolones, tetrahydroacridones, and 7-(2-phenoxyethoxy)-4(1H)-quinolones as antimalarial agents and to determine their mechanism of action and potential for resistance by utilizing chemical and biochemical tools. The three chemotypes possess in vivo liver stage activity, in vivo blood stage activity, gametocytocidal activity, and/or activity in the mosquitoes.

描述（由申请人提供）：疟疾是人类最重要的寄生疾病，每年死亡超过100万，每年超过3亿例。迫切需要新药才能打击这种致命的疾病。由于数量有限的化学型和对可用药物的抗药性，因此有新的国际努力旨在发现和发展具有预防或治疗疟疾的新潜在客户。大多数抗疟药发现都集中在引起疾病的疟疾的红细胞阶段，但要消除疟疾化合物以杀死肝脏阶段以及蚊子的感染阶段。唯一具有这些联合特性的药物是Primaquine，Primaquine是一种8-氨基喹啉（8AQ），具有弱红细胞阶段活性，并且在6-磷酸葡萄糖-6-磷酸脱氢酶缺陷酶中有毒。因此，对未来疟疾消除努力的最重要需求是一种可以安全有效地在患者发育阶段杀死寄生虫的化合物。除8AQ以外，很少有复合系列显示出对肝脏中的外肉眼（EE）阶段以及红细胞和配子细胞阶段的活性。众所周知，内胆素和4（1H） - 喹诺酮具有因果性预防活性（杀死EE阶段的寄生虫生长）和有效的红细胞抑制，在禽类疟疾模型中，但不反对哺乳动物中的疟疾人寄生虫。此外，已证明一种喹诺酮酯ICI56,780可在受感染的鼠李疟原虫感染的鼠尾草（根除休眠的EE寄生虫）中产生根治性的治疗。但是，抗药性的快速发展阻碍了其进一步的发展。这些研究中的许多研究是在20年前进行的，没有在当前的临床前疗效模型中进行适当的评估，也没有评估化合物的理化特性。该提议的长期长期目标是进步3-烷基和3-（杂种）芳基-4（1H） - 喹诺酮，四氢丙酮酸酮，以及7-（2-苯氧乙氧基氧基）-4（1H）-Quinolonon-喹诺酮作为抗疟疾剂，并确定其动作和抗抗化学机构的机制，并确定其能力和uCHEM的可能性机制。这三种化学型具有体内肝脏阶段活性，体内血液阶段活性，子志摄入活性和/或蚊子中的活性。

项目成果

Synthesis, antimalarial activity, and structure-activity relationship of 7-(2-phenoxyethoxy)-4(1H)-quinolones.

• DOI: 10.1021/jm200718m
• 发表时间: 2011-12-22
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Cross, R. Matthew;Namelikonda, Niranjan K.;Mutka, Tina S.;Luong, Lisa;Kyle, Dennis E.;Manetsch, Roman
• 通讯作者: Manetsch, Roman

Progress in the Optimization of 4(1H)-Quinolone Derivatives as Antimalarials Targeting the Erythrocytic, the Exoerythrocytic and the Transmitting Stages of the Malaria Parasite.

• DOI: 10.2533/chimia.2017.213
• 发表时间: 2017-04-26
• 期刊: Chimia
• 影响因子: 1.2

Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies.

• DOI: 10.1021/acs.jmedchem.7b00738
• 发表时间: 2018-02-22
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Neelarapu R;Maignan JR;Lichorowic CL;Monastyrskyi A;Mutka TS;LaCrue AN;Blake LD;Casandra D;Mashkouri S;Burrows JN;Willis PA;Kyle DE;Manetsch R
• 通讯作者: Manetsch R

Metal-free arylation of ethyl acetoacetate with hypervalent diaryliodonium salts: an immediate access to diverse 3-aryl-4(1H)-quinolones.

• DOI: 10.1021/jo5023958
• 发表时间: 2015-03-06
• 期刊: The Journal of organic chemistry
• 作者: Monastyrskyi A;Namelikonda NK;Manetsch R
• 通讯作者: Manetsch R

ICI 56,780 Optimization: Structure-Activity Relationship Studies of 7-(2-Phenoxyethoxy)-4(1H)-quinolones with Antimalarial Activity.

• DOI: 10.1021/acs.jmedchem.6b00759
• 发表时间: 2016-07-28
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Maignan, Jordany R.;Lichorowic, Cynthia L.;Giarrusso, James;Blake, Lynn D.;Casandra, Debora;Mutka, Tina S.;LaCrue, Alexis N.;Burrows, Jeremy N.;Willis, Paul A.;Kyle, Dennis E.;Manetsch, Roman
• 通讯作者: Manetsch, Roman