Kaplum Vanessa, Cogo Juliana, Sangi Diego Pereira, Ueda-Nakamura Tânia, Corrêa Arlene Gonçalves, Nakamura Celso Vataru
Programa de Pós Graduação em Ciências Farmacêuticas, Universidade Estadual de Maringá, Maringá, PR, Brazil.
Instituto de Ciências Exatas, Universidade Federal Fluminense, Volta Redonda, RJ, Brazil Laboratório de Síntese de Produtos Naturais, Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil.
Antimicrob Agents Chemother. 2016 May 23;60(6):3433-44. doi: 10.1128/AAC.02582-15. Print 2016 Jun.
Leishmaniasis is endemic in 98 countries and territories worldwide. The therapies available for leishmaniasis have serious side effects, thus prompting the search for new therapies. The present study investigated the antileishmanial activities of 2,3-diarylsubstituted quinoxaline derivatives against Leishmania amazonensis The antiproliferative activities of 6,7-dichloro-2,3-diphenylquinoxaline (LSPN329) and 2,3-di-(4-methoxyphenyl)-quinoxaline (LSPN331) against promastigotes and intracellular amastigotes were assessed, and the cytotoxicities of LSPN329 and LSPN331 were determined. Morphological and ultrastructural alterations were examined by electron microscopy, and biochemical alterations, reflected by the mitochondrial membrane potential (ΔΨm), mitochondrial superoxide anion (O2·(-)) concentration, the intracellular ATP concentration, cell volume, the level of phosphatidylserine exposure on the cell membrane, cell membrane integrity, and lipid inclusions, were evaluated. In vivo antileishmanial activity was evaluated in a murine cutaneous leishmaniasis model. Compounds LSPN329 and LSPN331 showed significant selectivity for promastigotes and intracellular amastigotes and low cytotoxicity. In promastigotes, ultrastructural alterations were observed, including an increase in lipid inclusions, concentric membranes, and intense mitochondrial swelling, which were associated with hyperpolarization of ΔΨm, an increase in the O2·(-) concentration, decreased intracellular ATP levels, and a decrease in cell volume. Phosphatidylserine exposure and DNA fragmentation were not observed. The cellular membrane remained intact after treatment. Thus, the multifactorial response that was responsible for the cellular collapse of promastigotes was based on intense mitochondrial alterations. BALB/c mice treated with LSPN329 or LSPN331 showed a significant decrease in lesion thickness in the infected footpad. Therefore, the antileishmanial activity and mitochondrial mechanism of action of LSPN329 and LSPN331 and the decrease in lesion thickness in vivo brought about by LSPN329 and LSPN331 make them potential candidates for new drug development for the treatment of leishmaniasis.
利什曼病在全球98个国家和地区呈地方性流行。现有的利什曼病治疗方法有严重的副作用，因此促使人们寻找新的治疗方法。本研究调查了2,3 - 二芳基取代喹喔啉衍生物对亚马逊利什曼原虫的抗利什曼活性。评估了6,7 - 二氯 - 2,3 - 二苯基喹喔啉（LSPN329）和2,3 - 二 -（4 - 甲氧基苯基）- 喹喔啉（LSPN331）对前鞭毛体和细胞内无鞭毛体的抗增殖活性，并测定了LSPN329和LSPN331的细胞毒性。通过电子显微镜检查形态学和超微结构改变，并评估由线粒体膜电位（ΔΨm）、线粒体超氧阴离子（O2·(-)）浓度、细胞内ATP浓度、细胞体积、细胞膜上磷脂酰丝氨酸暴露水平、细胞膜完整性和脂质包涵体反映的生化改变。在小鼠皮肤利什曼病模型中评估体内抗利什曼活性。化合物LSPN329和LSPN331对前鞭毛体和细胞内无鞭毛体表现出显著的选择性且细胞毒性低。在前鞭毛体中，观察到超微结构改变，包括脂质包涵体增加、同心膜和强烈的线粒体肿胀，这与ΔΨm超极化、O2·(-)浓度增加、细胞内ATP水平降低和细胞体积减小有关。未观察到磷脂酰丝氨酸暴露和DNA片段化。处理后细胞膜保持完整。因此，导致前鞭毛体细胞崩溃的多因素反应基于强烈的线粒体改变。用LSPN329或LSPN331处理的BALB/c小鼠感染足垫病变厚度显著降低。因此，LSPN329和LSPN331的抗利什曼活性、线粒体作用机制以及LSPN329和LSPN331在体内引起的病变厚度降低使其成为治疗利什曼病新药开发的潜在候选药物。
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