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Synthesis and Evaluation of 4-Hydroxycoumarin Imines as Inhibitors of Class II Myosins.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-07 , DOI: 10.1021/acs.jmedchem.0c01062 Jhonnathan Brawley 1 , Emily Etter 2 , Dante Heredia 3 , Amarawan Intasiri 1, 4 , Kyle Nennecker 2 , Joshua Smith 2 , Brandon M Welcome 2 , Richard K Brizendine 2 , Thomas W Gould 3 , Thomas W Bell 1 , Christine Cremo 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-07 , DOI: 10.1021/acs.jmedchem.0c01062 Jhonnathan Brawley 1 , Emily Etter 2 , Dante Heredia 3 , Amarawan Intasiri 1, 4 , Kyle Nennecker 2 , Joshua Smith 2 , Brandon M Welcome 2 , Richard K Brizendine 2 , Thomas W Gould 3 , Thomas W Bell 1 , Christine Cremo 2
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Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation. The lead compound for this study ((3-(N-butylethanimidoyl)ethyl)-4-hydroxy-2H-chromen-2-one; BHC) was previously discovered to inhibit skeletal myosin II. BHC and 34 analogues were synthesized to explore structure–activity relationships. The properties of analogues, including solubility, stability, and toxicity, suggest that the BHC scaffold may be useful for developing therapeutics. Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity were measured. Several analogues with aromatic side arms showed improved potency (half-maximal inhibitory concentration (IC50) <1 μM) and selectivity (≥12-fold) for skeletal myosin versus cardiac myosin compared to BHC. Several analogues blocked neurotransmission, suggesting that they are selective for nonmuscle myosin II over skeletal myosin. Competition and molecular docking studies suggest that BHC and blebbistatin bind to the same site on myosin.
中文翻译：
作为 II 类肌球蛋白抑制剂的 4-羟基香豆素亚胺的合成和评价。
需要肌肉肌球蛋白 ATP 酶抑制剂来治疗可通过促进肌肉松弛来改善的病症。本研究的先导化合物 ((3-( N-丁基乙亚胺基)乙基)-4-羟基-2 H -chromen-2-one；BHC) 先前被发现可抑制骨骼肌球蛋白 II。合成了 BHC 和 34 种类似物以探索结构-活性关系。类似物的特性，包括溶解度、稳定性和毒性，表明 BHC 支架可能有助于开发治疗方法。测量了快速骨骼肌和心肌肌球蛋白 II 的肌动蛋白激活的 ATP 酶活性的抑制、离体骨骼肌收缩力的抑制以及体外肌动蛋白滑动速度的减慢。与 BHC 相比，具有芳香侧臂的几种类似物对骨骼肌球蛋白与心脏肌球蛋白的效力（半最大抑制浓度 (IC 50 ) <1 μM）和选择性（≥12 倍）有所改善。几种类似物阻断神经传递，表明它们对非肌肉肌球蛋白 II 的选择性高于骨骼肌球蛋白。竞争和分子对接研究表明，BHC 和 blebbistatin 与肌球蛋白上的同一位点结合。
更新日期：2020-10-08
中文翻译：
作为 II 类肌球蛋白抑制剂的 4-羟基香豆素亚胺的合成和评价。
需要肌肉肌球蛋白 ATP 酶抑制剂来治疗可通过促进肌肉松弛来改善的病症。本研究的先导化合物 ((3-( N-丁基乙亚胺基)乙基)-4-羟基-2 H -chromen-2-one；BHC) 先前被发现可抑制骨骼肌球蛋白 II。合成了 BHC 和 34 种类似物以探索结构-活性关系。类似物的特性，包括溶解度、稳定性和毒性，表明 BHC 支架可能有助于开发治疗方法。测量了快速骨骼肌和心肌肌球蛋白 II 的肌动蛋白激活的 ATP 酶活性的抑制、离体骨骼肌收缩力的抑制以及体外肌动蛋白滑动速度的减慢。与 BHC 相比，具有芳香侧臂的几种类似物对骨骼肌球蛋白与心脏肌球蛋白的效力（半最大抑制浓度 (IC 50 ) <1 μM）和选择性（≥12 倍）有所改善。几种类似物阻断神经传递，表明它们对非肌肉肌球蛋白 II 的选择性高于骨骼肌球蛋白。竞争和分子对接研究表明，BHC 和 blebbistatin 与肌球蛋白上的同一位点结合。
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