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

Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

Clinical development of the antimalarial artefenomel was recently halted due to formulation challenges stemming from the drug’s lipophilicity and low aqueous solubility. The symmetry of organic molecules is known to influence crystal packing energies and by extension solubility and dissolution rates. Here we evaluate RLA-3107, a desymmetrized, regioisomeric form of artefenomel in vitro and in vivo, finding that the regioisomer retains potent antiplasmodial activity while offering improved human microsome stability and aqueous solubility as compared to artefenomel. We also report in vivo efficacy data for artefenomel and its regioisomer across 12 different dosing regimens

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

Demographic and clinical characteristics of caregivers and their enrolled children.

Demographic and clinical characteristics of caregivers and their enrolled children.</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

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

Identification of Novel Parasitic Cysteine Protease Inhibitors by Use of Virtual Screening. 2. The Available Chemical Directory

The incidence of parasitic infections such as malaria, leishmaniasis, and trypanosomiasis has been steadily increasing. Since the existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance, there is an urgent need for development of potent, mechanism-based antiparasitic agents against these diseases. Cysteine proteases have been established as valid targets for this purpose. The Available Chemical Directory consisting of nearly 355 000 compounds was screened in silico against the homology models of plasmodial cysteine proteases, falcipain-2, and falcipain-3, to identify structurally diverse non-peptide inhibitors. The study led to identification of 22 inhibitors of parasitic cysteine proteases out of which 18 compounds were active against falcipain-2 and falcipain-3. Eight compounds exhibited dual activity against both enzymes. Additionally, four compounds were found to inhibit L. donovani cysteine protease. While one of the cysteine protease inhibitors also exhibited in vitro antiplasmodial activity with an IC50 value of 9.5 μM, others did not show noticeable antiplasmodial activity up to 20 μM. A model identifying important pharmacophoric features common to the structurally diverse falcipain-2 inhibitors has also been developed. Very few potent non-peptide inhibitors of the parasitic cysteine proteases have been reported so far, and identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat protozoal infections

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