Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents.
Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents.
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DOI：
10.1021/acs.jmedchem.1c00813
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发表时间：
2021-08-26
影响因子：
7.3
通讯作者：
Guy RK
中科院分区：
文献类型：
--
作者：
Hammill JT;Sviripa VM;Kril LM;Ortiz D;Fargo CM;Kim HS;Chen Y;Rector J;Rice AL;Domagalska MA;Begley KL;Liu C;Rangnekar VM;Dujardin JC;Watt DS;Landfear SM;Guy RK
利什曼病是一种由利什曼原虫引起的疾病，全世界约有 1200 万人受其困扰。大多数现有的治疗利什曼病的药物有毒、昂贵、难以施用并且容易产生耐药性。我们报告了一类新的抗利什曼原药，即 3-芳基喹啉，它能有效阻止利什曼原虫巨噬细胞内无鞭毛体形式的增殖，相对于宿主巨噬细胞具有良好的选择性。早期的 34 号先导药物作用迅速，对墨西哥利什曼原虫具有良好的效力（EC50 = 120 nM），相对于巨噬细胞，该寄生虫的选择性是巨噬细胞的 30 倍（EC50 = 3.7 μM），并且还可以阻断对锑药物具有抗性的杜氏利什曼原虫寄生虫的增殖。最后，另一个早期先导药物27表现出合理的体内耐受性，在皮肤利什曼病小鼠模型的给药期间损害了疾病进展。这些结果表明芳基喹啉为新型抗利什曼病药物的开发提供了富有成效的起点。
Leishmaniasis, a disease caused by protozoa of the Leishmania species, afflicts roughly 12 million individuals worldwide. Most existing drugs for leishmaniasis are toxic, expensive, difficult to administer, and subject to drug resistance. We report a new class of antileishmanial leads, the 3-arylquinolines, that potently block proliferation of the intramacrophage amastigote form of Leishmania parasites with good selectivity relative to the host macrophages. Early lead 34 was rapidly acting and possessed good potency against L. mexicana (EC50 = 120 nM), 30-fold selectivity for the parasite relative to the macrophage (EC50 = 3.7 μM), and also blocked proliferation of Leishmania donovani parasites resistant to antimonial drugs. Finally, another early lead, 27, which exhibited reasonable in vivo tolerability, impaired disease progression during the dosing period in a murine model of cutaneous leishmaniasis. These results suggest that the arylquinolines provide a fruitful departure point for the development of new antileishmanial drugs.
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影响因子：
120.1
作者：
Katsuno, Kei;Burrows, Jeremy N.;Slingsby, B. T.
通讯作者：
Slingsby, B. T.
影响因子：
4.9
作者：
Ortiz, Diana;Forquer, Isaac;Landfear, Scott M.
通讯作者：
Landfear, Scott M.
影响因子：
3.2
作者：
Laurent, Thierry;Rijal, Suman;Dujardin, Jean-Claude
通讯作者：
Dujardin, Jean-Claude
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
DOI：
10.1016/j.trstmh.2006.03.009
发表时间：
2006-12-01
影响因子：
2.2
作者：
Croft, Simon L.;Engel, Juergen
通讯作者：
Engel, Juergen