Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane

We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that <i>trans</i>-3″-substituted trioxolanes would exhibit Fe­(II) reactivity and antiparasitic activity similar to that achieved with canonical <i>cis</i>-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the <i>trans</i>-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their <i>cis</i>-4″ comparators. In contrast, efficacy in the <i>Plasmodium berghei</i> mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., <b>12i</b>) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe­(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials

Design, Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2<i>R</i>,3<i>S</i>)‑<i>N</i>‑Benzoyl-3-phenylisoserine

A series of hybrid compounds based on (2<i>R</i>,3<i>S</i>)-<i>N</i>-benzoyl-3-phenylisoserine, artemisinin, and quinoline moieties was synthesized and tested for in vitro antiplasmodial activity against erythrocytic stages of K1 and W2 strains of <i>Plasmodium falciparum.</i> Two hybrid compounds incorporating (2<i>R</i>,3<i>S</i>)-<i>N</i>-benzoyl-3-phenylisoserine and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin, with nanomolar IC₅₀ values against <i>Plasmodium falciparum</i> K1 strain

Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane

We describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. Conformational analysis suggested that <i>trans</i>-3″-substituted trioxolanes would exhibit Fe­(II) reactivity and antiparasitic activity similar to that achieved with canonical <i>cis</i>-4″ substitution. The chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria model. As predicted, the <i>trans</i>-3″ analogues exhibited in vitro antiplasmodial activity remarkably similar to that of their <i>cis</i>-4″ comparators. In contrast, efficacy in the <i>Plasmodium berghei</i> mouse model differed dramatically for some of the congeneric pairs. The best of the novel 3″ analogues (e.g., <b>12i</b>) outperformed arterolane itself, producing cures in mice after a single oral exposure. Overall, this study suggests new avenues for modulating Fe­(II) reactivity and the pharmacokinetic and pharmacodynamic properties of 1,2,4-trioxolane antimalarials

Synthesis, Antiplasmodial Activity, and β‑Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids

A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor <i>N</i>-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of <i>Plasmodium falciparum</i>. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium­(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were <b>8c</b> (0.13, 0.004, and 0.1 μM); <b>8d</b> (0.08, 0.01, and 0.02 μM); and <b>7g</b> (0.07, 0.03, and 0.08 μM)

Correlation of Phenotype with Genotype by Gender.

<p>Correlation of Phenotype with Genotype by Gender.</p

Effect of G6PD activity cut-off criteria on the association analysis of G6PD status and malaria incidence.

<p>NOTE: N, represents the total number of individuals who have a G6PD activity level below the specified cut-off point; RR, relative risk.</p><p>NOTE: Table depicts how the relative risk of malaria varies depending on the cut-off point for determining G6PD deficiency by enzymatic assay.</p>*<p>Sample sizes are too small for meaningful analysis of enzymatically deficient females in these categories.</p

Association of predictor variables with the incidence of malaria.

<p><b>NOTE</b> RR, relative risk.</p>a<p>Previously published results from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007246#pone-0007246-t001" target="_blank">Table 1</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007246#pone.0007246-Clark1" target="_blank">[8]</a>, showing results of regression analysis using G6PD deficiency defined by enzyme assay.</p>b<p>Repeat regression analysis using G6PD deficiency defined by genotype. Note that RR for other covariates remain constant.</p

Dot plot showing the distribution of G6PD enzyme activity stratified by genotype.

<p>Dot plot showing the distribution of G6PD enzyme activity stratified by genotype.</p

Distribution of G6PD enzyme activity (mU/10⁹ erythrocytes) in all individuals, males, and females.

<p>For the male and female distributions, G6PD A- genotype data are also displayed, with wild-type individuals represented by a dark gray bar and hemizygous, heterozygous, and homozygous individuals by a light gray bar.</p

Antimalarial effects of combinations of proteasome and falcipain inhibitors.

<p>Parasites were cultured in the presence of varied combinations of the indicated inhibitor, and the 50% inhibitory concentration of each combination was determined to calculate fractional inhibitory concentrations (FIC). FICs from three independent experiments, each carried out in duplicate were used to construct isobolograms as described in Materials and Methods section. Mean FICs (ΣFIC) 0.5-1.0, <0.5, and >1.5 are indicative of additive, synergistic and antagonistic interactions, respectively. <b>A</b>. The isobolograms indicate additive interactions for the indicated combinations.</p