Synthesis of α-substituted fosmidomycin analogues as highly potent Plasmodium falciparum growth inhibitors
- 作者：Timothy Haemers ; Jochen Wiesner ; Sara Van Poecke ; Jan Goeman ; Dajana Henschker ; Edwald Beck ; Hassan Jomaa and Serge Van Calenbergh
- 关键词：Fosmidomycin ; 2C-Methyl-d-erithrytol 4-phosphate pathway ; 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2006
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 April 2006
- 卷：16
- 期：7
- 页码：1888-1891
- 文件大小：119 K
摘要
In view of the promising antimalarial activity of fosmidomycin or its N-acetyl homologue FR900098, the objective of this work was to investigate the influence of aromatic substituents in the α-position of the phosphonate moiety. The envisaged analogues were prepared using a linear route involving a 3-aryl-3-phosphoryl propanal intermediate. The activities of all compounds were evaluated on Eschericia coli 1-deoxy-d-xylulose 5-phosphate reductoisomerase and against two Plasmodium falciparum strains. Compared with fosmidomycin, several analogues displayed enhanced activity towards the P. falciparum strains. Compound 1e with a 3,4-dichlorophenyl substitution in the α-position of fosmidomycin emerged as the most potent analogue of this series. It is approximately three times more potent in inhibiting the growth of P. falciparum than FR900098, the most potent representative of this class reported so far.