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

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40%的 对于生活在疟疾流行区的人口来说，疟疾是最具破坏性的寄生虫病之一。超过 2015年报告了2亿例感染和40多万例死亡。重要的是，通常使用 由于抗药性寄生虫的广泛流行，抗疟药以惊人的速度失去效力。为 例如，对最常用的抗疟药之一氯喹的耐药性已在近100个国家得到证实， 所有受疟疾影响的地区。青蒿素联合疗法（ACTs）已经出现，以对抗耐药性疟疾。 传统药物，目前作为最后的治疗手段。不幸的是，最近世卫组织的一份报告 报告指出，对青蒿素的抗药性已在东南亚五个以上的国家出现。由于 抗疟化学型数量有限，恶性疟原虫对大多数现有药物的耐药性不断上升， 迫切需要药物来防治这种致命的疾病。在此，我们提出了评估和优化 两种4（1H）-喹诺酮化学型，即苯氧基乙氧基-4（1H）-喹诺酮（PEQs）和1，2，3，4- 四氢吖啶-9（10H）-酮（THA），因为它们对血液，肝脏和传播阶段的活性， 寄生虫PEQs和THA在结构上与4（1H）-喹诺酮ELQ-300相关，其向 由于口服生物利用度差，限制了临床前安全性和毒性研究，I期研究被推迟。我们 初步数据表明，我们确定的各种结构要素使PEQ和 THA具有比ELQ-300更好的水溶性，而不显著降低抗疟活性。 此外，增溶前药部分的使用也显示出改善4（1H）-喹诺酮的 体内抗疟活性。基于这些初步数据，我们假设PEQ和THA的增加 水溶性将改善4（1H）-喹诺酮抗疟药的总体性能，并可能提供 进入临床前开发阶段。具体来说，我们建议进一步优化临屋区和临屋区， 确定的特定取代基，其显著增加水溶性，同时还保持或改善水溶性。 抗疟疾活性。此外，我们还将继续优化一般前药方法。的 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 治疗方案（a）针对疟原虫的血液、肝脏和传播阶段，（B）防止复发， 包括间日疟原虫在内的疟疾，（c）鼓励部署的服务人员更高的依从性，以及（d）可能 优化现有疟疾药物的应用，减少青蒿素耐药恶性疟原虫的影响。

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.