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DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites.
ACS Central Science ( IF 12.7 ) Pub Date : 2019-11-27 , DOI: 10.1021/acscentsci.9b00874 Flore Nardella 1 , Ludovic Halby 2 , Elie Hammam 1, 3 , Diane Erdmann 2, 4 , Véronique Cadet-Daniel 2 , Roger Peronet 1 , Didier Ménard 1, 5 , Benoit Witkowski 5 , Salah Mecheri 1 , Artur Scherf 1 , Paola B Arimondo 2
ACS Central Science ( IF 12.7 ) Pub Date : 2019-11-27 , DOI: 10.1021/acscentsci.9b00874 Flore Nardella 1 , Ludovic Halby 2 , Elie Hammam 1, 3 , Diane Erdmann 2, 4 , Véronique Cadet-Daniel 2 , Roger Peronet 1 , Didier Ménard 1, 5 , Benoit Witkowski 5 , Salah Mecheri 1 , Artur Scherf 1 , Paola B Arimondo 2
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Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in Plasmodium, we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline-quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show in vivo activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins.
中文翻译：
DNA甲基化双底物抑制剂是抗青蒿素抗性恶性疟原虫寄生虫的速效药物。
疟疾是最致命的寄生虫病，影响全世界2亿多人。东南亚由于多重耐药性寄生虫而导致治疗失败的人数不断增加，这阻碍了消除疟疾的努力。因此，迫切需要开发新的抗疟药来包含这些抗药性寄生虫。根据先前的报告显示疟原虫中存在DNA甲基化，我们产生了针对疟疾寄生虫的新型DNA甲基化抑制剂。基于喹啉-喹唑啉的抑制剂可在低纳摩尔范围内杀死寄生虫，包括适于培养的青蒿素抗药性田间分离株。这些化合物的目标是在6小时的治疗期内无性循环的所有阶段，包括早期的环。它们减少了寄生虫中的DNA甲基化，并以10 mg / kg的剂量显示了体内活性。
更新日期：2020-01-23
中文翻译：
DNA甲基化双底物抑制剂是抗青蒿素抗性恶性疟原虫寄生虫的速效药物。
疟疾是最致命的寄生虫病，影响全世界2亿多人。东南亚由于多重耐药性寄生虫而导致治疗失败的人数不断增加，这阻碍了消除疟疾的努力。因此，迫切需要开发新的抗疟药来包含这些抗药性寄生虫。根据先前的报告显示疟原虫中存在DNA甲基化，我们产生了针对疟疾寄生虫的新型DNA甲基化抑制剂。基于喹啉-喹唑啉的抑制剂可在低纳摩尔范围内杀死寄生虫，包括适于培养的青蒿素抗药性田间分离株。这些化合物的目标是在6小时的治疗期内无性循环的所有阶段，包括早期的环。它们减少了寄生虫中的DNA甲基化，并以10 mg / kg的剂量显示了体内活性。
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