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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria
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Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria

机译：针对恶性疟原虫线粒体呼吸链的喹诺酮类抗疟药的产生，用于治疗和预防疟疾

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摘要

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreduc-tase (Plasmodium falciparum NDH2) and cytochrome bc_1,. Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimi-dine metabolism and parasite death. Several analogs also display activity against liver-stage parasites {Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium ber-ghei mouse malaria model associated with favorable pharmacoki-netic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria.
机译：迫切需要具有新颖作用机制的新型抗疟疾药物，以提供有效的控制和根除计划。在其临床使用期间，据报道对所有现有抗疟药类（包括青蒿素）具有寄生虫抗药性。无法产生具有新颖作用机制的新抗疟疾药物来克服当前的抗药性挑战，将导致该疾病的复发，这将代表全球卫生紧急情况。在这里，我们介绍了独特的喹诺酮铅抗疟药，它具有针对两种呼吸酶NADH：泛醌氧化还原酶（恶性疟原虫NDH2）和细胞色素bc_1的双重作用机制。可以通过在2或3位上特权的喹诺酮核心的操作来巧妙地控制两种酶的抑制剂特异性。抑制剂对寄生虫酶和对多药耐药的恶性疟原虫寄生虫均表现出强大的（纳摩尔级）活性，这可通过寄生虫线粒体膜电位的快速选择性除极化来证明，从而导致嘧啶-丁酮代谢中断和寄生虫死亡。几种类似物还显示出针对肝阶段寄生虫（食蟹疟原虫）的活性以及阻断传输的特性。铅优化分子在恶性疟原虫小鼠疟疾模型中还显示出有效的口服抗疟活性，并具有与单剂量治疗一致的良好药代学特征。这些抑制剂的合成简便易行，成本低廉，可满足目标产品的要求，可生产出有效，安全且价廉的药物，并有可能在控制和根除恶性疟疾中最终用于临床。

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    Giancarlo A. Biagini; Nicholas Fisher; Alison E. Shone; Murad A. Mubaraki; Abhishek Srivastava; Alisdair Hill; Thomas Antoine; Ashley J. Warman; Jill Davies; Chandrakala Pidathala; Richard K. Amewu; Suet C. Leung; Raman Sharma; Peter Gibbons; David W. Hong; Benedicte Pacorel; Alexandre S. Lawrenson; Sitthivut Charoensutthivarakul; Lee Taylor; Olivier Berger; Alison Mbekeani; Paul A. Stocks; Gemma L. Nixon; James Chadwick; Janet Hemingway; Michael J. Delves; Robert E. Sinden; Anne-Marie Zeeman; Clemens H. M. Kocken; Neil G. Berry; Paul M. ONeill; Stephen A. Ward;

  • 作者单位

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

    Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom;

    Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom;

    Department of Parasitology, Biomedical Primate Research Centre, 2280 GH, Rijswijk, The Netherlands;

    Department of Parasitology, Biomedical Primate Research Centre, 2280 GH, Rijswijk, The Netherlands;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom;

    Molecular and Biochemical Parasitology, Liverpool School of Tropical Medicine, University of Liverpool, Liverpool L3 5QA, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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