α-Phenylethyl Substituted Bis(pivaloyloxymethyl) Ester Analogues of Fosmidomycin and FR900098

Abstract

α-Phenylethyl substituted bis(pivaloyloxymethyl) ester analogues of the natural products Fosmidomycin and FR900098 have been synthesized, and their in vitro antimalarial activity determined. The α-phenylethyl substituted Fosmidomycin analogue displays moderate in vitro antimalarial activity against the chloroquine-sensitive strain 3D7 of Plasmodium falciparum.

IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters

“…Fosmidomycin ( 1 ), a phosphonate antibiotic with a hydroxamate pharmacophore that was originally isolated from Streptomyces lavendulae , , is known to have antibacterial and herbicidal activity and was more recently shown to be active against the Plasmodium species causing malaria. , Its molecular target, IspC, catalyzes the first committed step in the non-mevalonate isoprenoid biosynthesis pathway that is essential in Plasmodium spp. but absent in mammals (Scheme ). , 1 can cure human malaria and has a favorable toxicity profile but has shortcomings with regard to pharmacokinetic aspects, which prompted structural modifications in several laboratories. − Also of note, 1 and its analogs are expected to be exempt from target-related toxicity and from cross-resistance with established antimalarials and may even be able to target the malaria liver stages that are insufficiently addressed by current antimalarials. , We report the synthesis of thia isosters of reversed hydroxamic acid analogs of 1 and their enzymatic, antiparasite, and structural biology features. Furthermore, we show that IspC has a high degree of enantioselectivity for a reverse α-aryl derivative of 1 .…”

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.…”