Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098

Divergent Strategy for the Synthesis of α-Aryl-Substituted Fosmidomycin Analogues

“…15,16 The α-methyl and phenyl analogues proved almost equipotent and the 3,4-difluorophenyl analogue slightly better than the FR900098 prodrug in inhibiting growth of a 3D7 P. falciparum strain. 15 Incorporation of an arylmethyl moiety in -position generally resulted in a marked decrease in activity. 16 Unfortunately, the strategy used to synthesize the α-aryl substituted analogues involved a de novo synthetic approach, which permitted only to synthesize a limited number of examples.…”

“…Lately, Kurz and coworkers evaluated the effect of α-substituents on pivaloyloxymethyl ester prodrugs of fosmidomycin and FR900098. 15,16 The α-methyl and phenyl analogues proved almost equipotent and the 3,4-difluorophenyl analogue slightly better than the FR900098 prodrug in inhibiting growth of a 3D7 P. falciparum strain. 15 Incorporation of an arylmethyl moiety in -position generally resulted in a marked decrease in activity.…”

Synthesis and evaluation of α,β-unsaturated α-aryl-substituted fosmidomycin analogues as DXR inhibitors

“…10,11 Based on a reported prodrug approach, 6 Kurz et al systematically investigated the effect of introduction of different substituents in α-position of the bis(pivaloyloxymethyl) esters of fosmidomycin or FR900098. 12,13,14 Introduction of an -methyl or -phenyl substituent afforded analogues, which exhibited antiplasmodial activities that came close to that of the FR900098 prodrug, while a 3,4-difluorophenylsubstituted analogue was slightly more potent. Consistent with our findings, -aryl-substituted fosmidomycin analogues were generally superior to their FR900098 homologues.…”

“…The introduction of an ethyl, propyl, isopropyl, dimethyl and hydroxymethyl group was associated with a considerable drop in antimalarial activity. 12 Also -arylmethyl 13 or phenylethyl 14 analogues failed to surpass the activities of the -aryl prodrugs. Furthermore, rigidification of the carbon spacer by the introduction of a cyclopropane 15 (as in 2) or cyclopentane 11 ring, indicated a preferred trans geometry for the substituents on these rings for binding DXR.…”

New N-Acetyltransferase Fold in the Structure and Mechanism of the Phosphonate Biosynthetic Enzyme FrbF

“…Although fosmidomycin and FR-900098 differ only by the presence of an additional methyl decoration on the hydroxamate, FR-900098 has significantly more potent activity both in vitro and in vivo (10,11). Consequently, significant research efforts have focused on the characterization of FR-900098 and its derivatives.…”