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6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-28 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00196 Amy S. T. Tong 1 , Peter J. Choi 1 , Adrian Blaser 1 , Hamish S. Sutherland 1 , Sophia K. Y. Tsang 1 , Jerome Guillemont 2 , Magali Motte 2 , Christopher B. Cooper 3 , Koen Andries 4 , Walter Van den Broeck 4 , Scott G. Franzblau 5 , Anna M. Upton 3 , William A. Denny 1 , Brian D. Palmer 1 , Daniel Conole 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-09-28 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00196 Amy S. T. Tong 1 , Peter J. Choi 1 , Adrian Blaser 1 , Hamish S. Sutherland 1 , Sophia K. Y. Tsang 1 , Jerome Guillemont 2 , Magali Motte 2 , Christopher B. Cooper 3 , Koen Andries 4 , Walter Van den Broeck 4 , Scott G. Franzblau 5 , Anna M. Upton 3 , William A. Denny 1 , Brian D. Palmer 1 , Daniel Conole 1
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Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.
中文翻译：
贝达喹啉的6-氰基类似物对结核病的亲脂性和潜在的安全性比二芳基喹啉少
Bedaquiline（1）是一种用于结核病的新药，是二芳基喹啉类药物中的第一个。它显示出优异的抗结核功效，但在高剂量时可引起磷脂酰肌病，具有长的末端消除半衰期（由于其高亲脂性），并具有有效的hERG通道抑制作用，从而导致临床QTc间隔延长。已经制备了许多苯达喹啉的结构环A类似物，并对其抗M.tb活性（MIC 90）进行了评估，以考虑其作为亲脂性较低的第二代化合物的可能应用。这是以前观察到的范围内的6-取代的类似物的1表现出阳性效价之间（MIC相关90）朝向M.tb和药物亲脂性。与此趋势相反，我们通过clogP / M.tb分数发现，6-氰基（CN）取代基可大大降低亲脂性，而对MIC值的影响仅适度，这表明该取代基可作为一种有用的工具用于寻找有效和更安全的类似物1。
更新日期：2017-09-28
中文翻译：
贝达喹啉的6-氰基类似物对结核病的亲脂性和潜在的安全性比二芳基喹啉少
Bedaquiline（1）是一种用于结核病的新药，是二芳基喹啉类药物中的第一个。它显示出优异的抗结核功效，但在高剂量时可引起磷脂酰肌病，具有长的末端消除半衰期（由于其高亲脂性），并具有有效的hERG通道抑制作用，从而导致临床QTc间隔延长。已经制备了许多苯达喹啉的结构环A类似物，并对其抗M.tb活性（MIC 90）进行了评估，以考虑其作为亲脂性较低的第二代化合物的可能应用。这是以前观察到的范围内的6-取代的类似物的1表现出阳性效价之间（MIC相关90）朝向M.tb和药物亲脂性。与此趋势相反，我们通过clogP / M.tb分数发现，6-氰基（CN）取代基可大大降低亲脂性，而对MIC值的影响仅适度，这表明该取代基可作为一种有用的工具用于寻找有效和更安全的类似物1。
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