Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
Laboratory for Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610 Wilrijk, Belgium.
Bioorg Med Chem Lett. 2019 May 15;29(10):1232-1235. doi: 10.1016/j.bmcl.2019.03.009. Epub 2019 Mar 7.
A series of eleven double prodrug derivatives of a fosmidomycin surrogate were synthesized and investigated for their ability to inhibit in vitro growth of P. falciparum and M. tuberculosis. A pivaloyloxymethyl (POM) phosphonate prodrug modification was combined with various prodrug derivatisations of the hydroxamate moiety. The majority of compounds showed activity comparable with or inferior to fosmidomycin against P. falciparum. N-benzyl substituted carbamate prodrug 6f was the most active antimalarial analog with an IC value of 0.64 µM. Contrary to fosmidomycin and parent POM-prodrug 5, 2-nitrofuran and 2-nitrothiophene prodrugs 6i and 6j displayed promising antitubercular activities.
合成了一系列 11 种福米霉素类似物的双前药衍生物，并研究了它们抑制疟原虫和结核分枝杆菌体外生长的能力。将特戊酰氧甲基（POM）膦酸酯前药修饰与各种羟肟酸部分的前药衍生化相结合。大多数化合物的活性与福米霉素相当或低于福米霉素。N-苄基取代的氨基甲酸酯前药 6f 是最有效的抗疟类似物，IC 值为 0.64 µM。与福米霉素和母体 POM-前药 5 相反，2-硝基呋喃和 2-硝基噻吩前药 6i 和 6j 显示出有希望的抗结核活性。
