Aguiar Anna Caroline C, Figueiredo Flávio Jr B, Neuenfeldt Patrícia D, Katsuragawa Tony H, Drawanz Bruna B, Cunico Wilson, Sinnis Photini, Zavala Fidel, Krettli Antoniana U
Centro de Pesquisas René Rachou-Fiocruz, Av. Augusto de Lima 1715, Belo Horizonte, MG, 30190-002, Brazil.
Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil.
Malar J. 2017 Mar 9;16(1):110. doi: 10.1186/s12936-017-1755-6.
Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission. However, PQ metabolites cause haemolysis in patients deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). Fifteen PQ-thiazolidinone derivatives, synthesized through one-post reactions from primaquine, arenealdehydes and mercaptoacetic acid, were evaluated in parallel in several biological assays, including ability to block malaria transmission to mosquitoes.
All primaquine derivatives (PQ-TZs) exhibited lower cell toxicity than primaquine; none caused haemolysis to normal or G6PD-deficient human erythrocytes in vitro. Sera from mice pretreated with the test compounds thus assumed to have drug metabolites, caused no in vitro haemolysis of human erythrocytes, whereas sera from mice pretreated with primaquine did cause haemolysis. The ability of the PQ-TZs to block malaria transmission was evaluated based on the oocyst production and percentage of mosquitoes infected after a blood meal in drug pre-treated animals with experimental malaria caused by either Plasmodium gallinaceum or Plasmodium berghei; four and five PQ-TZs significantly inhibited sporogony in avian and in rodent malaria, respectively. Selected PQ-TZs were tested for their inhibitory activity on P. berghei liver stage development, in mice and in vitro, one compound (4m) caused a 3-day delay in the malaria pre-patent period.
The compound 4m was the most promising, blocking malaria transmissions and reducing the number of exoerythrocytic forms of P. berghei (EEFs) in hepatoma cells in vitro and in mice in vivo. The same compound also caused a 3-day delay in the malaria pre-patent period.
伯氨喹是一种抗疟药物，用于预防间日疟原虫复发和疟疾传播。然而，伯氨喹代谢产物会导致葡萄糖-6-磷酸脱氢酶（G6PD）缺乏的患者发生溶血。通过伯氨喹、芳烃醛和巯基乙酸的一步反应合成了15种伯氨喹噻唑烷酮衍生物，并在包括阻断疟疾传播给蚊子的能力在内的几种生物学试验中进行了平行评估。
所有伯氨喹衍生物（PQ-TZs）的细胞毒性均低于伯氨喹；在体外，它们均未导致正常或G6PD缺乏的人类红细胞发生溶血。用测试化合物预处理的小鼠血清（因此假定含有药物代谢产物）不会导致人类红细胞发生体外溶血，而用伯氨喹预处理的小鼠血清则会导致溶血。基于鸡疟原虫或伯氏疟原虫引起的实验性疟疾的药物预处理动物在血餐后的卵囊产生和感染蚊子的百分比，评估了PQ-TZs阻断疟疾传播的能力；分别有4种和5种PQ-TZs显著抑制禽疟和啮齿动物疟疾的孢子生殖。在小鼠体内和体外测试了选定的PQ-TZs对伯氏疟原虫肝期发育的抑制活性，一种化合物（4m）使疟疾潜伏期延长了3天。
化合物4m最具前景，它能阻断疟疾传播，并减少体外肝癌细胞和体内小鼠中伯氏疟原虫的红细胞外期（EEFs）数量。同一化合物还使疟疾潜伏期延长了3天。
