Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei

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• 作者：Lori Ferrins ; Michelle Gazdik ; Rapha毛l Rahmani ; Swapna Varghese ; Melissa L. Sykes ; Amy J. Jones ; Vicky M. Avery ; Karen L. White ; Eileen Ryan ; Susan A. Charman ; Marcel Kaiser ; Christel A. S. Bergstr枚m ; Jonathan B. Baell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6393-6402
• 全文大小：423K
• ISSN：1520-4804

文摘

A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC₅₀ of 12聽渭M, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure鈥揳ctivity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC₅₀ of 0.045 渭M against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.