Drug Discovery Unit, Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee, UK.
ChemMedChem. 2012 Jan 2;7(1):95-106. doi: 10.1002/cmdc.201100420. Epub 2011 Dec 8.
Trypanothione synthetase (TryS) is essential for the survival of the protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis. It is one of only a handful of chemically validated targets for T. brucei in vivo. To identify novel inhibitors of TbTryS we screened our in-house diverse compound library that contains 62,000 compounds. This resulted in the identification of six novel hit series of TbTryS inhibitors. Herein we describe the SAR exploration of these hit series, which gave rise to one common series with potency against the enzyme target. Cellular studies on these inhibitors confirmed on-target activity, and the compounds have proven to be very useful tools for further study of the trypanothione pathway in kinetoplastids.
硫醇嘌呤核苷合成酶（TryS）对于引起人类非洲锥虫病的原生动物寄生虫布氏锥虫的存活至关重要。它是体内仅少数几个经过化学验证的针对 T. brucei 的靶标之一。为了鉴定新的 TbTryS 抑制剂，我们筛选了我们内部包含 62,000 种化合物的多样化化合物库。这导致了六种新型 TbTryS 抑制剂的发现。本文描述了这些命中系列的 SAR 探索，这导致了一种针对酶靶标具有效力的常见系列。对这些抑制剂的细胞研究证实了靶标活性，并且这些化合物已被证明是进一步研究动基体生物中硫醇嘌呤途径的非常有用的工具。
