Effects of monepantel and albendazole on <i>A. suum in vivo</i>.

<p>SD = standard deviation.</p>§<p>Mann-Whitney U test comparing the median of the worm burdens of control and treated mice.</p

Effects of monepantel and albendazole on <i>N. americanus in vivo</i>.

<p>SD = standard deviation.</p><p>*Kruskal Wallis test comparing the median of the worm burdens of control and treated hamsters (all doses versus control).</p

Discovery of novel antischistosomal scaffolds from the open access Pandemic Response Box

Treatment and control of schistosomiasis rely on a single drug, praziquantel. New orally active antischistosomals featuring novel molecular scaffolds are urgently needed to prevent the emergence of resistance. We screened 400 drug-like compounds contained in the open-access Pandemic Response Box (PRB) against newly transformed schistosomula (NTS) at a concentration of 10 µM scoring death, changes in motility, and morphological alterations. Compounds displaying an activity ≥66% at 72 h underwent testing against adult Schistosoma mansoni in vitro. Fast-acting (≥66% at 24 h), nontoxic drugs focusing on late-stage and approved drugs were investigated in the patent S. mansoni mouse model. We identified 26 hits active against NTS, of which 17 elicited ≥66% activity against adult S. mansoni following 24 h of drug exposure. The highest activity against adult S. mansoni was observed with MMV1581558 (EC50 value of 0.18 ± 0.01 µM) and nitazoxanide (0.47 ± 0.07 µM). Of the five compounds tested in vivo, MMV1581558 and the approved drug ozanimod reduced average worm burden versus controls by 42 % and 36 %, respectively, after a single oral dose of 200 mg/kg bodyweight in mice harboring a chronic S. mansoni infection. MMV1581558 discovered from screening the PRB represents a novel antischistosomal scaffold with high in vitro antischistosomal activity amenable to chemical modification for drug development.</p

Analysis of the Physicochemical Properties of Anti-Schistosomal Compounds to Identify Next-Generation Leads

To investigate the physicochemical properties of anti-schisto­somal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schisto­somal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schisto­somal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schisto­somal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ’s anti-schisto­somal activity make PZQ an essential medicine for the treatment of schisto­somiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 μM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 μM) to provide high-quality hits and/or leads for the discovery of new oral anti-schisto­somal therapeutics

50% inhibitory concentrations of monepantel, albendazole, levamisole, and pyrantel pamoate on <i>A. ceylanicum</i>, <i>N. americanus</i>, and <i>T. muris</i>.

<p>IC₅₀s (µg/ml) were calculated for monepantel, albendazole, levamisole, and pyrantel pamoate after 72 h on L3 and adult stages of <i>A. ceylanicum</i>, <i>N. americanus</i>, and <i>T. muris</i>. r = linear correlation coefficient of the median-effect plot, indicating the goodness of fit. r≥0.85 indicates a satisfactory fit. n.d.: not determined, fitting not possible.</p

Analysis of the Physicochemical Properties of Anti-Schistosomal Compounds to Identify Next-Generation Leads

To investigate the physicochemical properties of anti-schisto­somal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schisto­somal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schisto­somal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schisto­somal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ’s anti-schisto­somal activity make PZQ an essential medicine for the treatment of schisto­somiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 μM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 μM) to provide high-quality hits and/or leads for the discovery of new oral anti-schisto­somal therapeutics

Effects of monepantel, albendazole, levamisole, and pyrantel pamoate on <i>T. muris in vivo</i>.

<p>SD = standard deviation.</p>§<p>Mann-Whitney U test comparing the median of the worm burdens of control and treated mice.</p

Ovicidal activity of monepantel, albendazole, levamisole, and pyrantel pamoate on <i>A. ceylanicum</i> eggs.

<p>SD = standard deviation.</p><p>*P-value <0.001 (Fisher's exact test).</p

Dose response relationships of monepantel, albendazole, levamisole, and pyrantel pamoate on <i>A. ceylanicum in vivo</i>.

<p>SD = standard deviation. The numbers in superscript refer to the corresponding control group.</p><p>*Kruskal Wallis test comparing the median of the worm burdens of control and treated hamsters (all doses versus control),</p>§<p>Mann-Whitney U-test comparing the median of the worm burdens of control and treated hamsters (one dose versus control).</p

Structure–Activity Relationship and <i>in Vitro</i> Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Studies of <i>N</i>‑aryl 3‑Trifluoromethyl Pyrido[1,2‑<i>a</i>]benzimidazoles That Are Efficacious in a Mouse Model of Schistosomiasis

We have previously reported on the antischistosomal activity of pyrido­[1,2-a]­benzimidazole (PBI) derivatives. As a follow-up, we designed and prosecuted further structure–activity relationship (SAR) studies that incorporate N-aryl substitutions on the PBI scaffold. Investigations into the in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms revealed several leads with promising potency. Active compounds with a good cytotoxicity profile were tested in vivo whereby 6 and 44 induced noteworthy reduction (62–69%) in the worm load in the Schistosoma mansoni mouse model. Pharmacokinetic analysis on 44 pointed to slow absorption, low volume of distribution, and low plasma clearance indicating the potential of these compounds to achieve a long duration of action. Overall, our work demonstrates that PBI chemotype is a promising scaffold in the discovery of new antischistosomal leads