Vasconcelos Mariela Ferreira de, Cunha-Júnior Edézio Ferreira da, Andrade-Neto Valter Viana de, Siqueira Larissa Moreira, d'Avila-Levy Cláudia Masini, Moreth Marcele, Cunico Wilson, Souza Marcus Vinícius Nora de, Gomes Cláudia Regina Brandão, Torres-Santos Eduardo Caio
Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil.
Int J Parasitol Drugs Drug Resist. 2014 Nov 8;4(3):210-3. doi: 10.1016/j.ijpddr.2014.10.005. eCollection 2014 Dec.
Pentavalent antimonials have saved the lives of thousands of Leishmania-infected patients more than seventy years but, unfortunately, they are highly toxic and require parenteral delivery. Therefore, the search for safer and orally delivered alternative is a need. This paper describes the antileishmanial properties of PMIC4, a novel hydroxyethylpiperazine analogue. PMIC4 showed potent activity against intracellular amastigotes of Leishmania amazonensis, with IC50 of 1.8 μM and selectivity index higher than 100-fold, calculated in relation to the toxicity on the host cell. Following laboratory animal welfare policies, we analyzed the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and calculated the Lipinski's rule of five of PMIC4 before proceeding to in vivo tests. PMIC4 satisfied Lipinski's rule of five and presented high probability of human intestinal absorption, suggesting a good chance of druglikeness and oral bioavailability. For in vivo studies, PMIC4 was administered via intralesional injection (3.4 mg/kg/day, three times a week) or orally (34.0 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout the 98 day experiments. At the end of the treatment period, serum markers of toxicity were measured. When administered orally, PMIC4 controlled the lesions in L. amazonensis-infected BALB/c mice without altering serological markers of toxicity. These results demonstrate that PMIC4 is a promising molecular scaffold, orally effective against experimental leishmaniasis.
七十多年来，五价锑已挽救了数千名利什曼原虫感染患者的生命，但不幸的是，它们毒性很强，需要肠胃外给药。因此，寻找更安全的口服替代药物很有必要。本文描述了一种新型羟乙基哌嗪类似物PMIC4的抗利什曼原虫特性。PMIC4对亚马逊利什曼原虫的细胞内无鞭毛体显示出强效活性，IC50为1.8 μM，相对于对宿主细胞的毒性计算，选择性指数高于100倍。遵循实验动物福利政策，在进行体内试验之前，我们分析了PMIC4的吸收、分布、代谢、排泄和毒性（ADMET）特性，并计算了其Lipinski五规则。PMIC4符合Lipinski五规则，具有较高的人体肠道吸收可能性，表明具有良好的类药性质和口服生物利用度。在为期98天的实验中，通过病灶内注射（3.4 mg/kg/天，每周三次）或口服（34.0 mg/kg/天，每周五次）将PMIC4给予感染亚马逊利什曼原虫的BALB/c小鼠。在治疗期结束时，测量毒性血清标志物。口服PMIC4时，可控制感染亚马逊利什曼原虫的BALB/c小鼠的病灶，而不改变毒性血清学标志物。这些结果表明，PMIC4是一种有前景的分子骨架，对实验性利什曼病口服有效。
