Reverse hydroxamate-based inhibitors of IspC, a key enzyme of the non-mevalonate pathway of isoprenoid biosynthesis and a validated antimalarial target, were synthesized and biologically evaluated. The binding mode of one derivative in complex with EcIspC and a divalent metal ion was clarified by X-ray analysis. Pilot experiments have demonstrated in vivo potential.
The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.
Delving into digallides: The characteristics of the chemical bonding of the digallides of the alkaline‐earth metals (see figure) have been studied by application of experimental methods, such as single‐crystal X‐ray diffraction and solid‐state NMR spectroscopy, in combination with quantum mechanical calculations. Combined application of 69,71Ga NMR spectroscopy and quantum mechanical calculations reveals the chemical bonding in the digallides of Ca, Sr, and Ba. An analysis of the electron localization function (ELF) shows honeycomb‐like 63 nets of the Ga atoms as the most prominent structural features in SrGa2 and BaGa2. For CaGa2 a description of a 3+1‐coordinated Ga atom is revealed by the ELF and by an analysis of interatomic distances. The NMR spectroscopic signal shift is mainly due to the Knight shift and is almost equal for the investigated digallides, whereas the anisotropy of the signal shift decreases with the radius of the alkaline‐earth metals. Calculated and observed values of the electric field gradient (EFG) are in good agreement for CaGa2 and BaGa2 but differ by about 21 % for SrGa2 indicating structural instability. Better agreement is achieved by considering a puckering of the Ga layers. For BaGa2 an instability of the structure is indicated by a peak in the density of states at the Fermi level, which is shifted to lower energies when taking puckering of the Ga layers into account. Both structural modifications are confirmed by crystallographic information. The Fermi velocity of the electrons is strongly anisotropic and is largest in the (001) plane of the crystal structure. This results in an alignment of the crystallites with the [001] axis perpendicular to the magnetic field as observed in 69,71Ga NMR spectroscopy and magnetic susceptibility experiments. The electron transport is predominantly mediated by the Ga–Ga px‐ and py‐like electrons in the (001) plane. The specific heat capacity of BaGa2 was determined and indicated the absence of phase transitions between 1.8 and 320 K.
1-Deoxy-d-xylulose 5-phosphate reductoisomerase of Plasmodium falciparum (PfIspC, PfDxr), believed to be the rate-limiting enzyme of the nonmevalonate pathway of isoprenoid biosynthesis (MEP pathway), is a clinically validated antimalarial target. The enzyme is efficiently inhibited by the natural product fosmidomycin. To gain new insights into the structure activity relationships of reverse fosmidomycin analogs, several reverse analogs of fosmidomycin were synthesized and biologically evaluated. The 4-methoxyphenyl substituted derivative 2c showed potent inhibition of PfIspC as well as of P. falciparum growth and was more than one order of magnitude more active than fosmidomycin. The binding modes of three new derivatives in complex with PfIspC, reduced nicotinamide adenine dinucleotide phosphate, and Mg(2+) were determined by X-ray structure analysis. Notably, PfIspC selectively binds the S-enantiomers of the study compounds.
Fosmidomycin inhibits IspC (Dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in Plasmodium falciparum. The drug has been used successfully to treat malaria patients in clinical studies, thus validating IspC as an antimalarial target. However, improvement of the drug's pharmacodynamics and pharmacokinetics is desirable. Here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxymethyl groups can increase the in vitro activity against asexual blood stages of P. falciparum by more than 1 order of magnitude. We also synthesized double prodrugs by additional esterification of the hydroxamate moiety. Prodrugs with modified hydroxamate moieties are subject to bioactivation in vitro. All prodrugs demonstrated improved antiplasmodial in vitro activity. Selected prodrugs and parent compounds were also tested for their cytotoxicity toward HeLa cells and in vivo in a Plasmodium berghei malaria model as well as in the SCID mouse P. falciparum model.
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