Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.
Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen.
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二氨基萘醌具有有效的恶性疟原虫配子细胞杀灭活性，二氨基萘醌是抗疟化合物筛选中鉴定出的主要抗疟化学型。
DOI：
10.1128/aac.01930-13
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发表时间：
2015
影响因子：
4.9
通讯作者：
Williamson,KimC
中科院分区：
文献类型：
--
作者：
Tanaka,TakeshiQ;Guiguemde,WArmand;Barnett,DavidS;Maron,MaximI;Min,Jaeki;Connelly,MicheleC;Suryadevara,PraveenKumar;Guy,RKiplin;Williamson,KimC
世界上40%的人口受到疟疾的威胁，疟疾是由疟疾寄生虫引起的，估计每年导致2亿临床病例和65万人死亡。据报道，所有常用的抗疟疾药物都出现了耐药性，并促使筛查确定新的候选药物。然而，这些新的候选者中有许多还没有针对负责传播的寄生虫阶段--配子体--进行评估。如果恶性疟原虫配子体不被消灭，患者在无性寄生虫清除后继续传播疟疾数周。没有症状的个体也可以携带足以传播的配子体负担，安全、有效的配子体杀伤剂也可以用于社区范围的疟疾控制计划。在这里，我们识别了15个具有纳摩尔活性的小分子，这些小分子对晚期配子体具有活性。其中14个是二氨基萘醌(DANQ)，1个是2-亚氨基苯并[d]咪唑(IBI)。已确定的DANQ之一SJ000030570是主要的抗疟疾候选药物。相比之下，在测试的650种化合物中，94%对晚期配子体没有活性。与大多数已批准的抗疟药对配子细胞的无效一致，在19个具有抗无性生殖阶段已知靶标活性的新化合物中，只有3个化合物对配子细胞的活力有任何强烈的影响。这些数据显示了传播阶段的不同生物学特征，并强调了筛选配子体杀灭活性的重要性。DANQ和IBI具有强大的杀配子体活性，再加上它们对无性寄生虫的有效性，为开发具有预防疟疾症状和传播潜力的抗疟疾药物提供了线索。
Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria.