Cavalcanti de Queiroz Aline, Alves Marina Amaral, Barreiro Eliezer Jesus, Lima Lídia Moreira, Alexandre-Moreira Magna Suzana
Laboratório de Farmacologia e Imunologia- Universidade Federal de Alagoas, Laboratório de Farmacologia e Imunidade, Instituto de Ciências Biológicas e da Saúde, Av. Lourival Melo Mota, s/n, Tabuleiro do Martins, CEP:57072-900, Maceió - AL, Brazil; Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR)(3). Universidade Federal do Rio de Janeiro, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio(®))(4) CCS, Cidade Universitária, P.O. Box 68024, ZIP, 21941-971, Rio de Janeiro-RJ, Brazil; Universidade Federal de Alagoas, Campus Arapiraca, Av. Manoel Severino Barbosa, Bom Sucesso, CEP: 57309-005, Arapiraca-AL, Brazil.
Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR)(3). Universidade Federal do Rio de Janeiro, Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio(®))(4) CCS, Cidade Universitária, P.O. Box 68024, ZIP, 21941-971, Rio de Janeiro-RJ, Brazil; Programa de Pós-graduação em Química- Instituto de Química- UFRJ, Brazil.
Exp Parasitol. 2019 Jun;201:57-66. doi: 10.1016/j.exppara.2019.04.003. Epub 2019 Apr 17.
In the present study, we investigated the in vitro and in vivo leishmanicidal activity of synthetic compounds, containing a semicarbazone scaffold as a peptide mimetic framework. The leishmanicidal effect against amastigotes of Leishmania amazonensis was also evaluated at concentration of 100 μM-0.01 nM. The derivatives 2e, 2f, 2g and 1g, beyond the standards miltefosine and pentamidine, significantly diminished the number of L. amazonensis amastigotes in macrophages. These derivatives were also active against amastigotes of L. braziliensis. As 2g presented potent leishmanicidal activity against the amastigotes of L. amazonensis in macrophages, we also investigated the in vivo leishmanicidal activity of this compound against L. amazonensis. Approximately 10L. amazonensis promastigotes were subcutaneously inoculated into the dermis of the right ear of BALB/c mice, which were subsequently treated with 2g (p.o. or i.p.), miltefosine (p.o.) or glucantime (i.p.) at 30 μmol/kg/day x 28 days. Thus, a similar reduction in the lesion size was observed after the administration of 2g through oral (63.7 ± 10.1%) and intraperitoneal (61.8 ± 3.7%) routes. A larger effect was observed after treatment with miltefosine (97.7 ± 0.4%), and glucantime did not exhibit activity at the dose administered. With respect to the ear parasite load, 2g diminished the number of parasites by p.o. (30.5 ± 5.1%) and i.p. (33.3 ± 4.3%) administration. In addition, 2g induced in vitro apoptosis, autophagy and cell cycle alterations on L. amazonensis promastigotes. In summary, the derivative 2g might represent a lead candidate for antileishmanial drugs, as this compound displayed pronounced leishmanicidal activity.
在本研究中，我们研究了含有氨基脲支架作为肽模拟框架的合成化合物的体外和体内杀利什曼原虫活性。还在100μM - 0.01 nM的浓度下评估了对亚马逊利什曼原虫无鞭毛体的杀利什曼原虫作用。除标准药物米替福新和喷他脒外，衍生物2e、2f、2g和1g显著减少了巨噬细胞中亚马逊利什曼原虫无鞭毛体的数量。这些衍生物对巴西利什曼原虫的无鞭毛体也有活性。由于2g对巨噬细胞中亚马逊利什曼原虫的无鞭毛体具有强大的杀利什曼原虫活性，我们还研究了该化合物对亚马逊利什曼原虫的体内杀利什曼原虫活性。将约10个亚马逊利什曼原虫前鞭毛体皮下接种到BALB/c小鼠右耳的真皮中，随后用2g（口服或腹腔注射）、米替福新（口服）或葡糖胺（腹腔注射）以30μmol/kg/天×28天进行治疗。因此，通过口服（63.7±10.1%）和腹腔注射（61.8±3.7%）途径给予2g后，观察到病变大小有类似程度的减小。用米替福新治疗后观察到更大的效果（97.7±0.4%），并且葡糖胺在所给剂量下未表现出活性。关于耳部寄生虫负荷，2g通过口服（30.5±5.1%）和腹腔注射（33.3±4.3%）给药减少了寄生虫数量。此外，2g在体外诱导亚马逊利什曼原虫前鞭毛体发生凋亡、自噬和细胞周期改变。总之，衍生物2g可能代表抗利什曼原虫药物的潜在候选物，因为该化合物表现出显著的杀利什曼原虫活性。
