SAR refinement of antileishmanial N(2),N(4)-disubstituted quinazoline-2,4-diamines.
SAR refinement of antileishmanial N(2),N(4)-disubstituted quinazoline-2,4-diamines.
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DOI：
10.1016/j.bmc.2015.02.020
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发表时间：
2015-08-15
影响因子：
3.5
通讯作者：
Werbovetz KA
中科院分区：
文献类型：
--
作者：
Zhu X;Van Horn KS;Barber MM;Yang S;Wang MZ;Manetsch R;Werbovetz KA
内脏利什曼病是一种被忽视的寄生虫病，在没有治疗的情况下死亡率很高。廉价、口服有效的新药可能是对抗这种疾病的有用工具。我们先前表明，N2，N4-二取代的喹唑啉-2，4-二胺显示出低至亚微摩尔的抗细胞内利什曼原虫的效力，并且先导化合物N4-（呋喃-2-基甲基）-N2-异丙基-7-甲基喹唑啉-2，4-二胺（4）在内脏利什曼病的急性鼠模型中显示出适度的效力。在目前的工作中，31个N2，N4-二取代喹唑啉-2，4-二胺，以前没有被检查其抗利什曼原虫活性的效力和选择性进行了评估，对杜氏利什曼原虫，内脏利什曼病的致病寄生虫。在N2和N4处具有芳族取代基的喹唑啉-2，4-二胺表现出有效的体外抗利什曼原虫活性，但选择性相对较低，而在N2或N4处被小烷基取代的化合物通常表现出较低的抗利什曼原虫效力，但对鼠巨噬细胞系的毒性较小。基于其体外抗利什曼病效力，选择N4-苄基-N2-（4-氯苄基）喹唑啉-2，4-二胺（15）和N2-苄基-N4-异丙基喹唑啉-2，4-二胺（40）用于体内评价其药代动力学和抗利什曼病性质。虽然15显示出比40更长的血浆半衰期和更大的曲线下面积，但两种化合物在急性鼠内脏利什曼病模型中均显示出低功效。虽然本研究没有发现新的喹唑啉-2，4-二胺具有良好的体内疗效，但在N2或N4处具有小烷基的衍生物的体外毒性降低可能为设计安全有效的抗利什曼病喹唑啉提供线索。
Visceral leishmaniasis is a neglected parasitic disease that has a high fatality rate in the absence of treatment. New drugs that are inexpensive, orally active, and effective could be useful tools in the fight against this disease. We previously showed that N2,N4-disubstituted quinazoline-2,4-diamines displayed low- to sub-micromolar potency against intracellular Leishmania, and lead compound N4-(furan-2-ylmethyl)-N2-isopropyl-7-methylquinazoline-2,4-diamine (4) exhibited modest efficacy in an acute murine model of visceral leishmaniasis. In the present work, thirty-one N2,N4-disubstituted quinazoline-2,4-diamines that had not previously been examined for their antileishmanial activity were evaluated for their potency and selectivity against Leishmania donovani, the causative parasite of visceral leishmaniasis. Quinazoline-2,4-diamines with aromatic substituents at both N2 and N4 exhibited potent in vitro antileishmanial activity but relatively low selectivity, while compounds substituted with small alkyl groups at either N2 or N4 generally showed lower antileishmanial potency but were less toxic to a murine macrophage cell line. Based on their in vitro antileishmanial potency, N4-benzyl-N2-(4-chlorobenzyl)quinazoline-2,4-diamine (15) and N2-benzyl-N4-isopropylquinazoline-2,4-diamine (40) were selected for in vivo evaluation of their pharmacokinetic and antileishmanial properties. While 15 displayed a longer plasma half-life and a greater area under the curve than 40, both compounds showed low efficacy in an acute murine visceral leishmaniasis model. Although the present study did not identify new quinazoline-2,4-diamines with promising in vivo efficacy, the reduced in vitro toxicity of derivatives bearing small alkyl groups at either N2 or N4 may provide clues for the design of safe and effective antileishmanial quinazolines.