Orally Bioavailable 4(1H)-Quinolones with Multi-Stage Antimalarial Activity

具有多阶段抗疟活性的口服生物可利用 4(1H)-喹诺酮类药物

• 批准号: 9913468
• 负责人: DENNIS E KYLE
• 金额: $ 71.38万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913468
• 关键词: Affect; African; Aminoquinolines; Antimalarials; Area; Artemisinins; Avian Malaria; Bioavailable; Biological Availability; Blood; Cause of Death; Cessation of life; Child; Chloroquine resistance; Combined Modality Therapy; Contracts; Country; Culicidae; Cytochrome bc1 Complex; Data; Development; Disease; Dose; Drug resistance; Elements; Erythrocytes; Evaluation; Falciparum Malaria; Future; Glucosephosphate Dehydrogenase; Gold; In Vitro; Individual; Infection; Investigation; Lead; Liver; Macaca mulatta; Malaria; Mammals; Medicine; Modeling; Multi-Drug Resistance; New Agents; Oral; Parasite resistance; Parasites; Parasitic Diseases; Performance; Pharmaceutical Preparations; Phase; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium vivax; Population; Prevalence; Primaquine; Prodrugs; Property; Public Health; Pyridones; Quinolones; Regimen; Relapse; Reporting; Research; Research Personnel; Resistance; Resort; Rhesus; Risk; Series; Solubility; Southeastern Asia; Structure; Therapeutic Index; Toxic effect; Traditional Medicine; Work; World Health Organization; analog; aqueous; base; combat; drug development; improved; in vivo; inhibitor/antagonist; malaria infection; mouse model; novel therapeutics; phase 1 study; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; prevent; prophylactic; resistant Plasmodium falciparum; scaffold; service member; transmission process

Project Summary / Abstract Malaria remains among the most significant public health problems in the world. Since 40% of the world’s population living in malaria endemic areas, malaria is one of the most devastating parasitic diseases. More than 200 million infections and over 0.4 million of deaths were reported in 2015. Importantly, commonly used antimalarials lose potency at an alarming rate due to widespread prevalence of drug resistant parasites. For example, resistance to chloroquine, one of the most commonly used antimalarials, has been confirmed in nearly all regions affected by malaria. Artemisinin combination therapies (ACTs) have arisen to combat malaria resistant to traditional medicines, and presently serve as a last-resort treatment. Unfortunately, a recent WHO report indicates that resistance to artemisinin has emerged in more than five countries of South-East Asia. Due to the limited number of antimalarial chemotypes and rising P. falciparum resistance to most available medicines, new drugs are urgently required to combat this deadly disease. Herein, we propose the evaluation and optimization of two 4(1H)-quinolone chemotypes, namely the phenoxyethoxy-4(1H)-quinolones (PEQs) and the 1,2,3,4- tetrahydroacridin-9(10H)-ones (THAs), for their activity against the blood, liver, and transmission stages of the parasite. The PEQs and THAs are structurally related to 4(1H)-quinolone ELQ-300, whose advancement towards Phase I studies was deferred due to poor oral bioavailability, limiting preclinical safety and toxicity studies. Our preliminary data demonstrate that a variety of structural elements, which we identified, render the PEQs and THAs a better aqueous solubility than ELQ-300 without significantly reducing the antimalarial activity. Furthermore, the use of a solubilizing prodrug moiety has also shown to improve the 4(1H)-quinolone’s antimalarial activity in vivo. Based on this preliminary data, we hypothesize that increase of PEQ’s and THA’s aqueous solubility will improve the overall performance of 4(1H)-quinolone antimalarials and possibly provide entrance to preclinical development. Specifically, we propose to further optimize our PEQs and THAs as we identified specific substituents, which significantly increase aqueous solubility, while also maintain or improve antimalarial activity. Furthermore, we will also continue the optimization of a general prodrug approach. The proposed research has potential to provide orally bioavailable 4(1H)-quinolone-based malaria prophylactic regimens that (a) target blood, liver, and transmitting stages of the malaria parasites, (b) act against relapsing malaria including P. vivax, (c) encourage higher compliance in deployed service members, and (d) possibly optimize the application of existing malaria drugs reducing the impact of artemisinin resistant P. falciparum.

项目摘要 /摘要 疟疾仍然是世界上最重大的公共卫生问题之一。自世界的40％以来 疟疾中生活在疟疾内人体地区的人口是最毁灭性的寄生虫疾病之一。多于 2015年报告了2亿感染和超过40万人的死亡。重要的是，通常使用 由于抗药性寄生虫的广泛流行，抗疟疾剂以惊人的速度失去了效力。为了 例如，对氯喹的抗性是最常用的抗疟药之一，几乎已经证实 所有受疟疾影响的地区。青蒿素联合疗法（ACTS）已经出现了抗疟疾的抗药性 进行传统药物，目前作为最后的治疗方法。不幸的是，最近的一个人报告 表明在五个以上的东南亚国家中出现了对青蒿素的抵抗。由于 有限数量的抗疟疾化学型和对大多数可用药物的恶性疟原虫耐药性的增加，新的 迫切需要药物来应对这种致命疾病。在此，我们提出评估和优化 在两个4（1H） - 喹诺酮化学型中，即苯氧基-4（1H）-Quinolones（PEQ）和1,2,3,4-- 四氢基质-9（10H）-ONS（THAS），因为它们对血液，肝脏和传播阶段的活性 寄生虫。 PEQ和THA在结构上与4（1H）-Quinolone ELQ-300相关，其进步向 I期研究由于口服生物利用度差而推迟，限制了临床前的安全性和毒性研究。我们的 初步数据表明，我们确定的各种结构元素使PEQ和PEQS和 与ELQ-300更好的水溶性，而没有显着降低抗性活性。 此外，使用可溶性前药部分还显示出可改善4（1H）-Quinolone的 体内抗疟疾活性。基于此初步数据，我们假设PEQ和THA的增加 水溶性将改善4（1H） - 喹诺酮抗疟药的整体性能，并可能提供 企业家发展。特别是，我们建议进一步优化我们的PEQ和THA 确定了特定的子接头，这显着提高了水溶性，同时还保持或改进 抗疟疾活性。此外，我们还将继续优化一般前药方法。这 拟议的研究有可能提供口服生物利用4（1H） - 基于奎诺酮的疟疾预防性疟疾 （a）靶向血液，肝脏和疟原虫的传播阶段的方案，（b）针对接力的行为 疟疾在内，包括Vivax，（c）鼓励更高的部署服务成员遵守更高的依从性，（d）可能 优化现有疟疾药物的应用，以减少青蒿素耐药性恶性疟原虫的影响。