New antimalarials identified by a cell-based phenotypic approach: Structure?activity relationships of 2,3,4,9-tetrahydro-1H-β-carboline derivatives possessing a 2-((coumarin-5-yl)oxy)alkanoyl moiety
New antimalarials identified by a cell-based phenotypic approach: Structure?activity relationships of 2,3,4,9-tetrahydro-1H-β-carboline derivatives possessing a 2-((coumarin-5-yl)oxy)alkanoyl moiety
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通过基于细胞的表型方法鉴定的新型抗疟药：具有 2-((香豆素-5-基)氧基)烷酰基部分的 2,3,4,9-四氢-1H-β-咔啉衍生物的结构与活性关系
DOI：
10.1016/j.bmc.2022.116830
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Koyama Hiroo
中科院分区：
文献类型：
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作者：
Cho Nobuo;Kikuzato Ko;Futamura Yushi;Shimizu Takeshi;Hayase Hiroki;Kamisaka Kikuko;Takaya Daisuke;Yuki Hitomi;Honma Teruki;Niikura Mamoru;Kobayashi Fumie;Watanabe Nobumoto;Osada Hiroyuki;Koyama Hiroo
描述了由2，3，4，9-四氢-1H-β-咔啉核、香豆素环和氧烷酰基连接体组成的新型抗疟药的鉴定、构效关系（SAR）和生物学效应。一种基于细胞的表型方法被用于寻找具有独特作用模式的新型抗疟药物。我们对RIKEN化合物库的筛选活动成功地鉴定了已知的四氢-β-咔啉衍生物（4 e）作为显示显著体外活性的热门化合物。对该化学系列的SAR研究导致发现在氧乙酰基接头上具有（R）-甲基的化合物4 h，其具有对寄生虫生长的有效抑制（IC 50 = 2.0 nM）。还发现化合物4 h在小鼠模型中表现出显着的体内抗疟作用。此外，对4 e、4 h及其非对映体（4j）的分子模拟研究表明，4 h的（R）-甲基迫使优先采用被认为是活性构象异构体的特定构象异构体。
The identification, structure–activity relationships (SARs), and biological effects of new antimalarials consisting of a 2,3,4,9-tetrahydro-1H-β-carboline core, a coumarin ring, and an oxyalkanoyl linker are described. A cell-based phenotypic approach was employed in this search for novel antimalarial drugs with unique modes of action. Our screening campaign of the RIKEN compound library succeeded in the identification of the known tetrahydro-β-carboline derivative (4e) as a hit compound showing significantin vitroactivity. SAR studies on this chemical series led to the discovery of compound4hhaving a (R)-methyl group on the oxyacetyl linker with potent inhibition of parasite growth (IC50= 2.0 nM). Compound4hwas also found to exhibit significantin vivoantimalarial effects in mouse models. Furthermore, molecular modeling studies on4e,4h, and its diastereomer (4j) suggested that the (R)-methyl group of4hforces the preferential adoption of a specific conformer which is considered to be an active conformer.