Tong Amy S T, Choi Peter J, Blaser Adrian, Sutherland Hamish S, Tsang Sophia K Y, Guillemont Jerome, Motte Magali, Cooper Christopher B, Andries Koen, Van den Broeck Walter, Franzblau Scott G, Upton Anna M, Denny William A, Palmer Brian D, Conole Daniel
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France.
ACS Med Chem Lett. 2017 Sep 22;8(10):1019-1024. doi: 10.1021/acsmedchemlett.7b00196. eCollection 2017 Oct 12.
Bedaquiline () 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- activity (MIC), 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 demonstrated a positive correlation between potency (MIC) toward and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/ 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 .
贝达喹啉（）是一种用于治疗结核病的新药，也是二芳基喹啉类药物中的首个药物。它对结核病显示出优异的疗效，但在高剂量时会诱导磷脂沉积症，具有较长的终末消除半衰期（由于其高亲脂性），并表现出对人乙醚 - 去极化钾通道（hERG通道）的强效抑制作用，导致临床QTc间期延长。已经制备了贝达喹啉的一些结构A环类似物，并对其抗活性（最低抑菌浓度，MIC）进行了评估，以期它们作为亲脂性较低的第二代化合物的可能应用。之前观察到一系列的6 - 取代类似物显示出对的效力（MIC）与药物亲脂性之间存在正相关。与这一趋势相反，我们通过计算 clogP / 值发现，一个6 - 氰基（CN）取代基可大幅降低亲脂性，而对MIC值的影响较小，这表明该取代基是寻找有效且更安全的类似物的有用工具。
