化学
广告
体外
细胞毒性
生物信息学
杜氏利什曼原虫
利什曼病
立体化学
利什曼原虫
效力
组合化学
对映体
IC50型
体外毒理学
手性(物理)
结构-活动关系
药理学
内脏利什曼病
免疫学
生物
生物化学
基因
万维网
物理
寄生虫寄主
量子力学
手征对称破缺
计算机科学
Nambu–Jona Lasinio模型
夸克
作者
Freddy A. Bernal,Marcel Gerhards,Marcel Kaiser,Bernhard Wünsch,Thomas Schmidt
标识
DOI:10.1016/j.ejmech.2020.112493
摘要
Leishmaniasis, a neglected tropical disease caused by parasites of the genus Leishmania, causes a serious burden of disease around the world, represents a threat to the life of millions of people, and therefore is a major public health problem. More effective and non-toxic new treatments are required, especially for visceral leishmaniasis, the most severe form of the disease. On the backdrop that dihydrobenzofurans have previously shown antileishmanial activity, we present here the synthesis of a set of seventy trans-2-phenyl-2,3-dihydrobenzofurans and evaluation of their in vitro activity against Leishmania donovani as well as a discussion of structure-activity relationships. Compounds 8m-o and 8r displayed the highest potency (IC50 < 2 μmol/L) and interesting selectivity of the antileishmanial activity over cytotoxicity against mammalian cells (SI > 4.6). Nonetheless, structural optimization as further requirement was inferred from the high clearance of the most potent compound (8m) observed during determination in vitro of its metabolic stability. On the other hand, chiral separation of 8m and subsequent biological evaluation of its enantiomers demonstrated no effect of chirality on activity and cytotoxicity. Holistic analysis of in silico ADME-like properties and ligand efficiency metrics by a simple scoring function estimating druglikeness highlighted compounds 16c, 18 and 23 as promising candidates for further development. Overall, the potential of trans-2-phenyl-2,3-dihydrobenzofurans as leishmanicidal agents was confirmed.
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