Synthesis of β- and γ-oxa isosteres of fosmidomycin and FR900098 as antimalarial candidates

Abstract

To expand the structure-activity relationships of fosmidomycin and FR900098, two potent antimalarials interfering with the MEP-pathway, we decided to replace a methylene group in β-position of the phosphonate moiety of these leads by an oxygen atom. β-oxa-FR900098 (11) proved equally active as the parent compound.When applied to 4-[hydroxyl(methyl)amino]-4-oxobutyl phosphonic acid, featuring a hydroxamate instead of the retrohydroxamate moiety, a β-oxa modification yielded a derivative (13) with superior activity against a 3D7 P. falciparum strain than fosmidomycin, while a γ-oxa modification resulted in less active derivatives.A bis(pivaloyloxymethyl)ester of phosphonate 13 proved twice as active in inhibiting cultured parasites than a similar prodrug of FR900098.

Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

“…These limitations have led to substantial efforts to develop more cell-permeable analogs of FSM or its highly related analog FR900098 (30)(31)(32)(33)(34)(35). Because many FSM derivatives are prodrugs that require intracellular activation, it is often impossible to test the efficacy of these compounds directly on the Dxr target enzyme in vitro.…”

“…Because of this impermeability, FSM is ineffective against many potential pathogens, such as Toxoplasma gondii (29) and M. tuberculosis (10). Thus, substantial efforts have been made to develop more cell-permeable analogs of FSM or its highly related analog, FR900098 (30)(31)(32)(33)(34)(35).…”

Preparation of gem-difluorinated retrohydroxamic-fosmidomycin

“…The unique property of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the DOXP pathway, can therefore be considered as a remarkable and safe target for the discovery of new herbicides. The fosmidomycin 1a isolated from Streptomyces lavendulae in the seventies, has been referenced as an inhibitor of the DXR enzyme, 5,7 as well as N-acetyl homologue FR900098 1b, 8,9 fosmidomycin and FR900098 retrohydroxamic acids 1c-d 10,11 and phosphate analogues, namely fosfoxacin 1e 12 or acetyl analogue 1f 12 ( Figure 1). Fosmidomycin 1a has been positively evaluated for the treatment of uncomplicated falciparum malaria in combination with clindamycin, [13][14][15] as well as for its herbicide activities, by use alone in combination with commercial triazine or urea herbicides.…”

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

“…It has an anti-malarial action and well tolerated in the human beings. Modification in the simple structure of the fosmidomycin derivative to improve its drug characteristics has been challenging (Kurz et al 2007;Ortmann et al 2007;Tahar & Basco 2007;Wiesner et al 2007;Haemers et al 2008). In the current era of drug design and discovery, bridging the gap between the computational and a medicinal chemist is indispensable for synthesizing a blockbuster drug molecule.…”