Orban Oliver C F, Korn Ricarda S, Benítez Diego, Medeiros Andrea, Preu Lutz, Loaëc Nadège, Meijer Laurent, Koch Oliver, Comini Marcelo A, Kunick Conrad
Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany.
Group Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Mataojo 2020, CP 11400 Montevideo, Uruguay.
Bioorg Med Chem. 2016 Aug 15;24(16):3790-800. doi: 10.1016/j.bmc.2016.06.023. Epub 2016 Jun 13.
Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.
锥虫硫醇合成酶是动基体寄生虫的一种必需酶，这类寄生虫会在人类和动物中引发严重致残和致命的疾病。受N(5)-取代的保罗酮抑制相关寄生虫婴儿利什曼原虫的锥虫硫醇合成酶这一观察结果的启发，我们设计并合成了一系列新的衍生物。尽管这些新化合物均未对布氏锥虫的锥虫硫醇合成酶表现出强烈抑制作用，但其中几种化合物对培养的布氏锥虫血流型产生了显著的生长抑制作用。最有效的同系物3a在纳摩尔浓度达到两位数时表现出抗锥虫活性，并且相对于鼠巨噬细胞的选择性指数达到三个数量级。
