鉴定多种吲哚-2-甲酰胺作为有效的抗利什曼原虫化学类型。
Identification of a diverse indole-2-carboxamides as a potent antileishmanial chemotypes.
作者信息
Pandey Shashi, Chauhan Shikha S, Shivahare Rahul, Sharma Abhisheak, Jaiswal Swati, Gupta Suman, Lal Jawahar, Chauhan Prem M S
机构信息
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India.
出版信息
Eur J Med Chem. 2016 Mar 3;110:237-45. doi: 10.1016/j.ejmech.2016.01.028. Epub 2016 Jan 20.
A novel series of highly diverse indole-2-carboxamides was synthesized utilizing the isocyanide based multicomponent reaction (IMCR)-post modification approach and were identified as potential antileishmanial chemotype. Among the synthesized 18 analogues, 12 analogues exhibited better antileishmanial activity against intracellular amastigotes form of Leishmania donovani (IC50 values of 0.6-7.5 μM) as compared to standard drugs miltefosine and sodium stibogluconate. The compounds were also non-toxic towards Vero cells. Compounds 2b, 2m and 2p with significant in vitro activity were then evaluated for their in vivo efficacy following intraperitoneal route. These three compounds at a concentration of 50 mg/kg/day for 5 consecutive days showed 70.0, 63.5 and 63.4% inhibition of Leishmania amastigotes, respectively at day 7 post treatment in hamster model of visceral leishmaniasis.
利用基于异腈的多组分反应（IMCR）-后修饰方法合成了一系列新型的高度多样的吲哚-2-甲酰胺，并将其鉴定为潜在的抗利什曼原虫化学类型。在合成的18个类似物中，与标准药物米替福新和葡萄糖酸锑钠相比，12个类似物对杜氏利什曼原虫的细胞内无鞭毛体形式表现出更好的抗利什曼原虫活性（IC50值为0.6-7.5 μM）。这些化合物对Vero细胞也无毒。然后对具有显著体外活性的化合物2b、2m和2p进行腹腔注射后的体内疗效评估。在内脏利什曼病仓鼠模型中，这三种化合物以50 mg/kg/天的浓度连续给药5天，在治疗后第7天分别显示出70.0%、63.5%和63.4%的利什曼原虫无鞭毛体抑制率。
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