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: 10598072
• 负责人: DENNIS E KYLE
• 金额: $ 70.1万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598072
• 关键词: Affect; African; Aminoquinolines; Antimalarials; Area; Artemisinins; Avian Malaria; 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 Deficiency; 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; Persons; Pharmaceutical Preparations; Phase; Plasmodium cynomolgi; Plasmodium falciparum; Plasmodium vivax; Population; Populations at Risk; Prevalence; Primaquine; Prodrugs; Property; Public Health; Pyridones; Quinolones; Regimen; Relapse; Reporting; Research; Research Personnel; Resistance; Rhesus; Series; Solubility; Southeastern Asia; Therapeutic Index; Toxic effect; Traditional Medicine; Work; World Health Organization; analog; aqueous; combat; drug action; drug development; improved; in vivo; inhibitor; mouse model; novel therapeutics; phase 1 study; preclinical development; preclinical efficacy; preclinical safety; preclinical toxicity; prevent; prophylactic; resistant Plasmodium falciparum; scaffold; service member; transmission blocking; 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.

项目概要/摘要 疟疾仍然是世界上最严重的公共卫生问题之一，因为世界上有 40% 的人患有疟疾。 对于居住在疟疾流行地区的人口来说，疟疾是最具破坏性的寄生虫病之一。 2015 年报告了 2 亿例感染病例和超过 40 万人死亡。重要的是，常用的 由于耐药寄生虫的广泛流行，抗疟药以惊人的速度失去效力。 例如，对最常用的抗疟药之一氯喹的耐药性已在近 所有受疟疾影响的地区都出现了青蒿素联合疗法（ACT）来对抗疟疾耐药性。 不幸的是，世界卫生组织最近的一份报告称，传统药物目前已成为最后的治疗手段。 表明东南亚已有五个以上国家出现了对青蒿素的耐药性。 抗疟化学型数量有限，恶性疟原虫对大多数可用药物的耐药性不断上升，新 迫切需要对抗这种致命疾病的药物在此，我们提出评估和优化。 两种 4(1H)-喹诺酮化学型，即苯氧基乙氧基-4(1H)-喹诺酮 (PEQ) 和 1,2,3,4- 四氢吖啶-9(10H)-酮 (THAs)，因其对血液、肝脏和病毒传播阶段的活性 PEQ 和 THA 在结构上与 4(1H)-喹诺酮 ELQ-300 相关，其进展方向是 由于口服生物利用度差，限制了我们的临床前安全性和毒性研究，第一阶段研究被推迟。 初步数据表明，我们确定的各种结构元素使 PEQ 和 TH 的水溶性比 ELQ-300 更好，且不会显着降低抗疟活性。 此外，增溶前药部分的使用也被证明可以改善 4(1H)-喹诺酮的 根据这些初步数据，我们追求 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 具体来说，我们建议进一步优化我们的 PEQ 和 THA。 确定了特定的取代基，显着增加水溶性，同时还保持或改善 此外，我们还将继续优化通用前药方法。 拟议的研究有可能提供口服生物可利用的 4(1H)-喹诺酮类疟疾预防药物 (a) 针对疟疾寄生虫的血液、肝脏和传播阶段，(b) 预防复发的治疗方案 包括间日疟在内的疟疾，(c) 鼓励已部署的军人提高依从性，以及 (d) 可能 优化现有疟疾药物的应用，减少青蒿素耐药性恶性疟原虫的影响。

项目成果

Synthesis of Mono- and Bisperoxide-Bridged Artemisinin Dimers to Elucidate the Contribution of Dimerization to Antimalarial Activity.

• DOI: 10.1021/acsinfecdis.1c00066
• 发表时间: 2021-07-09
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Lichorowic, Cynthia L.;Zhao, Yingzhao;Maher, Steven P.;Padin-Irizarry, Vivian;Mendiola, Victoria C.;de Castro, Sagan T.;Worden, Jacob A.;Casandra, Debora;Kyle, Dennis E.;Manetsch, Roman
• 通讯作者: Manetsch, Roman

Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures.

• DOI: 10.1021/acs.jmedchem.0c01104
• 发表时间: 2021-05-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Monastyrskyi A;Brockmeyer F;LaCrue AN;Zhao Y;Maher SP;Maignan JR;Padin-Irizarry V;Sakhno YI;Parvatkar PT;Asakawa AH;Huang L;Casandra D;Mashkouri S;Kyle DE;Manetsch R
• 通讯作者: Manetsch R