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首页> 外文学位 >Synthesis and Evaluation of 3-Aryl-4(1H)-Quinolones as Orally Active Antimalarials: Overcoming Challenges in Solubility, Metabolism, and Bioavailability.
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Synthesis and Evaluation of 3-Aryl-4(1H)-Quinolones as Orally Active Antimalarials: Overcoming Challenges in Solubility, Metabolism, and Bioavailability.

机译：合成和评估3-芳基-4（1H）-喹诺酮类药物作为口服活性抗疟药：克服溶解性，代谢和生物利用度方面的挑战。

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摘要

Infectious diseases are the second leading cause of deaths in the world with malaria being responsible for approximately the same amount of deaths as cancer in 2012. Despite the success in malaria prevention and control measures decreasing the disease mortality rate by 45% since 2000, the development of single-dose therapeutics with radical cure potential is required to completely eradicate this deadly disease. Targeting multiple stages of the malaria parasite is becoming a primary requirement for new candidates in antimalarial drug discovery and development. Recently, 4(1H)-pyridone, 4(1H)-quinolone, 1,2,3,4-tetrahydroacridone, and phenoxyethoxy-4(1H)-quinolone chemotypes have been shown to be antimalarials with blood stage activity, liver stage activity, and transmission blocking activity. Advancements in structure-activity relationship and structure-property relationship studies, biological evaluation in vitro and in vivo, as well as pharmacokinetics of the 4(1H)-pyridone and 4(1H)-quinolone chemotypes is discussed in the first chapter of the dissertation.;Convenient synthetic approaches to 3-aryl-4(1H)-quinolones via metal-catalyzed and metal-free arylation of beta-keto carbonyl compounds is addressed in Chapter 2. A clean arylation protocol of ethyl acetoacetate was developed by using hypervalent diaryl iodonium salts under mild and metal-free conditions. The scope of the reaction, using symmetric and unsymmetric iodonium salts varying in sterics and electronics was examined. This method has been applied for the synthesis of antimalarial compound ELQ-300, which is currently in preclinical development. Additionally, a first gram scale synthesis of ELQ-300 and its structurally related 4(1H)-quinolone P4Q-391 using operationally simple and highly yielding metal-catalyzed conditions have been shown.;Despite 3-aryl-4(1H)-quinolone chemotypes displaying potent antimalarial activities against Plasmodium species in vitro and in vivo, their development is also associated with risks. 4(1H)-quinolones are known to be poorly soluble and thus represent challenging drug candidates for pharmacokinetic and bioavailability reasons. Disrupting of molecular crystal packing and prodrug approaches were employed to overcome solubility and bioavailability issues in current series. Quantum mechanics torsion profile calculations, 13C T1 spin-lattice relaxation experiments as well as X-ray studies were conducted with the objective to determine possible effects improving key physicochemical properties such as solubility and stability.;As a backup strategy, a prodrug approach was developed enabling the 4(1H)-quinolone scaffold to be functionalized at the quinolone's oxygen. In order to avoid any enzymatic dependences, an approach was developed in which the prodrug moiety was removed via a pH-triggered decay. Additionally, phosphate prodrugs regenerating the active compound via extrahepatic enzymes such as the ubiquitous alkaline phosphatase were investigated. The development of orally bioavailable prodrugs enabled an advance overcoming in vivo efficacy limitations and has been confirmed by pharmacokinetic profiling studies. The herein presented approaches present viable options for any pyridone quinolone antimalarial chemotype which are currently studied.
机译：传染病是世界上第二大死亡原因，2012年疟疾导致的死亡人数与癌症几乎相同。尽管疟疾预防和控制措施取得了成功，但自2000年以来，疾病死亡率降低了45％。要彻底根除这种致命疾病，就需要有大量具有根本治愈潜力的单剂量治疗药物。针对疟疾寄生虫的多个阶段，已成为抗疟疾药物发现和开发新候选人的主要要求。最近，已显示4（1H）-吡啶酮，4（1H）-喹诺酮，1,2,3,4-四氢ac啶酮和苯氧基乙氧基-4（1H）-喹诺酮化学型是抗疟疾药物，具有血液阶段活性，肝脏阶段活性和传输阻止活动。论文的第一章讨论了结构-活性关系和结构-性质关系的研究进展，体内外生物学评价以及4（1H）-吡啶酮和4（1H）-喹诺酮化学型的药代动力学。 。;在第2章中介绍了通过金属催化和无金属的β-酮羰基化合物芳基合成3-芳基-4（1H）-喹诺酮的简便方法。使用超价二芳基化合物开发了乙酰乙酸乙酯的纯芳基化方案在温和且不含金属的条件下形成碘鎓盐。研究了使用在空间和电子方面变化的对称和不对称碘鎓盐的反应范围。该方法已用于合成抗疟疾化合物ELQ-300，该药物目前正在临床前开发中。此外，还显示了使用操作简单且高产率的金属催化条件对ELQ-300及其结构相关的4（1H）-喹诺酮P4Q-391进行第一克规模的合成;尽管有3-芳基-4（1H）-喹诺酮。在体外和体内对疟原虫物种表现出有效抗疟活性的化学型，其发展也与风险相关。已知4（1H）-喹诺酮类药物难溶，因此由于药代动力学和生物利用度原因，代表了具有挑战性的候选药物。破坏分子晶体堆积和前药方法被用来克服当前系列中的溶解度和生物利用度问题。进行了量子力学扭转轮廓计算，13C T1自旋晶格弛豫实验以及X射线研究，目的是确定改善关键物理化学性质（如溶解度和稳定性）的可能影响。作为一种后备策略，开发了一种前药方法使4（1H）-喹诺酮骨架在喹诺酮的氧上被官能化。为了避免任何酶依赖性，开发了一种方法，其中通过pH触发的衰变除去前药部分。另外，还研究了通过肝外酶（如普遍存在的碱性磷酸酶）再生活性化合物的磷酸盐前药。口服生物可利用的前药的开发使得能够克服体内功效的局限性，并且已经通过药代动力学分析研究得到证实。本文提出的方法为目前研究的任何吡啶酮喹诺酮抗疟化学型提供了可行的选择。

著录项

  • 作者

    Monastyrskyi, Andrii.;

  • 作者单位

    University of South Florida.;

  • 授予单位 University of South Florida.;
  • 学科 Organic chemistry.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 100 p.
  • 总页数 100
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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