[PMC free article] [PubMed] [Google Scholar] (20) Bjorkelid C; Bergfors T; Unge T; Mowbray SL; Jones TA Structural studies on Mycobacterium tuberculosis DXR in complex with the antibiotic FR-900098. of malaria with 216 million new malaria cases as well as 0.4 million deaths, 64% of which are children under 5 years of age.1 Malaria is caused by a group of parasites, with causing the majority of deaths and severe infections.2 Parasites are transmitted to humans via the bites of female mosquitoes.3 After growing and replicating initially in human liver cells, the parasites reach the blood and cause malarial symptoms such as fever, headache, chills, Cefazedone or even death. 4 Artemisinin-based combination therapy (ACT) is currently the best treatment for malaria and is typically highly effective.3 Resistance to artemisinin, however, has already spread in the Greater Mekong subregion.5 Thus, there is a pressing need for new therapeutics for malaria with novel modes of action that could provide alternate chemotherapies to combat sensitive and drug-resistant parasites. uses the methyl erythritol phosphate (MEP) pathway for the biosynthesis of isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP), the C5 precursors of isoprenoids (Figure 1).6,7 Humans, however, use an alternate acetate/mevalonate pathway exclusively to synthesize these C5 isoprene building blocks.8 Blocking the MEP pathway terminates the biosynthesis of such important metabolites and results in cell death of DXR (IC50 = 0.034 DXR IC50 = 0.024 growth (IC50 = 0.09C0.35 malaria in combination therapies.18,19 Thus, we selected fosmidomycin as the parent structure from which to design analogues that would effectively inhibit Pf DXR, have improved pharmacokinetic properties and lead to promising drug candidates against malaria. Open in a separate window Figure 2. Fosmidomycin and selected previously reported analogues. We and others have previously evaluated the structureactivity relationships (SAR) of fosmidomycin and FR-900098 as inhibitors of several DXR homologues as well as various microbial pathogens.20C29 Fosmidomycin binds to DXR competitively with substrate DOXP and uncompetitively with cofactor NADPH.30 SAR studies on fosmidomycin analogues reveal that the retrohydroxamate or hydroxamate moiety should be retained to mimic the crucial interaction of fosmidomycin with the divalent metal cation.21,24,25,27C29,31 Similarly, the phosphonate moiety should be retained as it forms numerous hydrogen bonds with neighboring amino acid residues.32C34 A three-carbon linker between the two moieties is also found to be crucial for DXR inhibition.24 As we reported earlier, the unsaturated FR-900098 analogue (Figure 2, 2) gained a 2-fold increase in potency against (Mtb) DXR (IC50 = 1.07 growth with an IC50 value of 18.3 nM,35 nearly as potent as artemisinin (IC50 = 10.4 nM),35 a current Cefazedone first-line antimalarial drug. As expected, prodrug 3 displays potent in vivo antimalarial activity.35 Since it was found that the NADPH-binding pocket of DXR is druggable,36 and because this pocket is adjacent to the cavity where the retrohydroxamate moiety of fosmidomycin binds,37 we previously synthesized analogues with extended aromatic groups on the DXR by Phosphonic Acid Rabbit Polyclonal to MAST4 Salts Open in a separate window DXR IC50 [DXR inhibitor is 12a, with an IC50 value of 92 nM, slightly more potent than parent unsaturated compound 2. Within the DXR, respectively. This result shows that electronic effects on the following reported procedures (Table 2).35 This data indicates the inhibitory concentration of compound required to decrease growth of by 50% (IC50). Table 2. Growth Inhibition of the Analogues against DXR IC50 [growth Because of the penetrable cell membrane of eukaryotic parasite parasites. Compound 12a is the most active compound of the phosphonate salts, with an activity surpassing that of parent compound (and clinically evaluated candidate) fosmidomycin (1a). The data also shows that the inhibition of growth corresponds well to the activities of these compounds against the enzyme target DXR. Of the salts, compounds 12a and 16e were the most active DXR inhibitors. These compounds are also the most active inhibitors of growth among the salts. The cellular activity of the POM prodrugs is also shown in Table 2. As was the case with the phosphonic acid salts, several of the Cefazedone POM prodrugs are highly active against DXR inhibitor. Its prodrug, compound 18a, is the most potent prodrug inhibitor of (IC50 = 13 nM) from the POM series. In the parasites. Interestingly, addition of the prodrug did not improve the activity of this compound. As is evident from the data in Table 2, several compounds show potent antimalarial activity. Much of our work focuses on analogues of fosmidomycin, which is itself a reasonably potent inhibitor of growth (1a, IC50 = 1.087 inhibitor with an IC50 value of 19 nM. Its prodrug 18a also potently inhibits with an IC50 value of 13 nM..

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