Synthesis and Antiplasmodial Activity of Highly Active Reverse Analogues of the Antimalarial Drug Candidate Fosmidomycin

Abstract

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.

Inhibition Studies on Enzymes Involved in Isoprenoid Biosynthesis. Focus on Two Potential Drug Targets: DXR and IDI-2 Enzymes

“…Additional structural variations around the phosphonate anchor and the spacer of this compound gave new whose structures are given in Fig. 8 and IC 50 are presented in Table 3 [56, 57]. Indeed, a new highly active and selective pf -DXR inhibitor with a unique chemical structure (compound 28 ) was developed by Behrendt et al .…”

“…Indeed, a new highly active and selective pf -DXR inhibitor with a unique chemical structure (compound 28 ) was developed by Behrendt et al . [57]. Molecule 28 is an α-phenyl phosphonic acid derivative of 17 .…”

Crystal Structure of Brucella abortus Deoxyxylulose-5-phosphate Reductoisomerase-like (DRL) Enzyme Involved in Isoprenoid Biosynthesis

“…Interestingly, both FSM and FR900098 inhibited BaDRL with less efficiency than EcDXR (Fig. 5A), resulting in IC 50 values for BaDRL that were ϳ10-fold higher than those reported in the literature for DXR (39,41). This might be due to the structural differences between the two types of enzymes since the large size of the pocket around the hydroxamic acid tail of both FSM and FR900098 in BaDRL is predicted to result in looser binding compared with DXR enzymes (Fig.…”

“…1) are excellent DXR inhibitors that consistently fit well into the active site of EcDXR (supplemental Fig. S4C) (39,40). However, positioning of compounds 3 and 4 into the BaDRL structure revealed that, for the two possible stereoisomers of both compounds, the ␣-phenyl group would either crash against the side chain of Phe-223 (supplemental Fig.…”

Structure-guided design and biosynthesis of a novel FR-900098 analogue as a potent Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr) inhibitor

“…16, 17 At the other end of the molecule, reversal of the hydroxamate moiety has also been shown to improve antimalarial properties, particularly in tandem with the aforementioned efforts. 18 …”