Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice
Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice
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DOI：
10.1371/journal.pone.0142386
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发表时间：
2015-11-10
期刊：
影响因子：
3.7
通讯作者：
Schurigt, Uta
中科院分区：
文献类型：
--
作者：
Masic, Anita;Hernandez, Ana Maria Valencia;Schurigt, Uta
人类利什曼病涵盖了广泛的临床表现，从自愈性皮肤利什曼病到严重和致命的内脏利什曼病，这些利什曼病分别在其他物种中由硕大利什曼原虫或杜氏利什曼原虫引起。一些候选药物正在进行临床试验，以取代目前的治疗方法，这些方法正面临着伴随严重副作用的新的耐药性。在此，评价了两种肉桂酸正丙基酯衍生物（1和2）的抗利什曼病活性。3-苯基丙酸正丁酯（2）体外良好的选择性和抗利什曼原虫活性促进了体内抗利什曼原虫评价。为此目的，用硕大利什曼原虫前鞭毛体感染BALB/c小鼠，并用三个剂量的50 mg/kg/天的化合物2处理。治疗预防了感染部位的特征性肿胀，并与减少寄生虫负担相关。利什曼原虫主要前鞭毛体的透射光显微镜和透射电子显微镜显示，化合物1和2诱导线粒体肿胀。随后对大型利什曼原虫前鞭毛体的研究表明，线粒体跨膜电位（Delta psi（m））的丧失是一种推定的作用模式。由于肉桂酸正戊酯衍生物1和2在体外表现出抗利什曼原虫活性，化合物2在体内表现出抗利什曼原虫感染的BALB/c小鼠的活性，它们可以被认为是开发新的抗利什曼原虫治疗方法的可能的先导结构。
Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (Delta psi(m)) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.