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

1,4-Naphthoquinone Cations as Antiplasmodial Agents: Hydroxy‑, Acyloxy‑, and Alkoxy-Substituted Analogues

Cations of hydroxy-substituted 1,4-naphthoquinones were synthesized and evaluated as antiplasmodial agents against Plasmodium falciparum. The atovaquone analogues were found to be inactive as antagonists of parasite growth, which was attributed to ionization of the acidic hydroxyl moiety. Upon modification to an alkoxy substituent, the antiplasmodial activity was restored in the sub-100 nM range. Optimal inhibitors were found to possess IC50 values of 17.4–49.5 nM against heteroresistant P. falciparum W2

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

Dark field macroscopic imaging apparatus and computer application.

<p>The video camera is positioned below the microtiter plate and the plate is recorded using the WormAssay software.</p

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)

Dose-response curves of anthelmintic compounds used for validation.

<p> of (A) albendazole (), (B) ivermectin () and (C) fenbendazole () determined using the proposed method with compounds at concentrations of , , , , and .</p

Simplified state machine of the plate detection and tracking logic.

<p>The nodes indicate distinct states (or the start/end pseudostates) and the edges indicate transition conditions.</p

Microtiter plate images and application real-time preview.

<p>(A) Video frames of 24-well plates of <i>Brugia malayi</i> were recorded using the apparatus. (B) Screen capture of the software's real-time preview user interface. Green circles indicate that the wells have been detected and that the program is ready to begin recording data. The blue outline in each well is the worm (or other well artifacts) and the red color indicates the worm's movements. Mean movement units are measured in real-time and are shown for each well using the Lucas-Kanade Optical Flow algorithm. Canonical well labels determined by the well finding algorithm are drawn in teal in the preview image by the application. (There is no movement in the 2 left columns because the worms are dead due to high drug concentrations.)</p

<i>Schistosoma mansoni</i> adult worms can also be assayed in 24- or 96-well plates using the WormAssay visual imaging system.

<p>(A) Unprocessed video frame in a 96-well plate. (B) Screen capture of the software's user interface for those plates using the Consensus Voting Luminance Difference algorithm (see caption for <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001494#pntd-0001494-g002" target="_blank">Figure 2b</a>).</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