Antischistosomal Activity of Trioxaquines: In Vivo Efficacy and Mechanism of Action on Schistosoma mansoni

Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents

In Vitro Activities of Trioxaquines against Schistosoma mansoni▿

We report the in vitro activities of trioxaquines against larval and adult-stage schistosomes at 5 and 50 μg/ml, respectively. Such activities are equivalent to that of praziquantel, the major and rather unique drug currently used for the treatment of schistosomiasis. In this range of concentrations, artemisinin derivatives (artesunate and artemether) have no activity

Synthesis of "Trioxaquantel"® derivates as potential new antischistosomal drugs

Over the past 20 years, praziquantel, a pyrazinoisoquinoline derivative, has become the mainstay for morbidity control of human and animal schistosomiasis. From early in their lives in vertebrate hosts, schistosomes ingest hemoglobin and aggregate the released heme as a dark pigment very similar to the hemozoin produced by Plasmodium in malaria infection. The antimalarial artemisinin derivatives have real, though low, schistosomicide activity. Because of the complementarity of the two drug classes – praziquantel and artemisinin deriv-atives – we designed new molecules, named trioxaquantels®, that combine the 1,2,4-trioxane unit responsible for the activity of artemisinin, and the pyrazinoisoquinoline moiety of praziquantel within a single drug. The synthesis of these new drugs and their preliminary evaluation in mice infected with Schistosoma mansoni is reported here

Preliminary Investigations of the Effect of Lipophilic Analogues of the Active Metabolite of Isoniazid Toward Bacterial and Plasmodial Strains

International audienceFive lipophilic analogues 1 –5 of the active metabolite of the antitubercular drug isoniazid (INH), selected as inhibitors of Mycobacterium smegmatis and Mycobacterium tuberculosis growth, were evaluated for their activity against Corynebacterium glutamicum (lacking in InhA activity), Escherichia coli (to test mycobacteria selectivity), and Plasmodium falciparum (as possible parasite target). Compound 3 was the only one that did not inhibit C. glutamicum growth. The poor InhA inhibitors 1 and 2 were able to inhibit C. glutamicum and their anti(myco)bacterial mechanisms of action involve targets other than InhA. For the effective InhA inhibitors 4 and 5 , also active against C. glutamicum and M. tuberculosis strains, more than one pathway should be envisaged to explain their actions. Pyridine‐base ring analogues (1 , 2, and 3 ) have no ability to inhibit the growth of E. coli even at a high concentration. Compound 3 thus exhibited a selective inhibitory action toward M. tuberculosis, while it was inactive on C. glutamicum and on E. coli growth. It presented an activity profile similar to that of INH suggesting InhA inhibition as one of the possible mechanisms of action. Finally, although a homologue of the reductase InhA exists in the FAS‐II system of P. falciparum , 3 was unable to display antiplasmodial activity

Copper Chelator Induced Efficient Episodic Memory Recovery in a Non-Transgenic Alzheimer’s Mouse Model

International audienceAlzheimer’s disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Ab amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Ab1–42 peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Ab42-1 peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinolinePA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model

Validation of the Aβ_1–42 injection model with memantine.

<p>Memory performances during the contextual fear memory assay show a significant variation [F(2,11) = 8.582; p = 0.006] due to the treatment factor (R² = 0.609). Control mice receiving a mixture of DMSO (icv) and vehicle (i.p.) exhibited standard levels of freezing scores. The icv injection of Aβ_1–42 (Aβ_1–42/Vehicle group) resulted in a highly significant decrease of freezing responses compared to controls (p = 0.005). Memantine (Aβ_1–42/MEM group) improved significantly the freezing scores of mice having received Aβ_1–42 (p = 0.004).</p

SDS-PAGE electrophoresis of amyloids Aβ_1–42 (central lane) and Aβ₄₂₋₁ (right lane) without β-mercapto-ethanol.

<p>The injected peptidic solutions were identified as trimeric and hexameric oligomer forms.</p

Injection site coordinates (a) and diffusion of fluorescent Aβ_1–42 (b) in the ventricles (Bregma = −1.22 mm).

<p>Injection site coordinates (a) and diffusion of fluorescent Aβ_1–42 (b) in the ventricles (Bregma  =  −1.22 mm).</p

Effect of PA1632 oral administration on episodic memory deficit.

<p>Memory performances during the contextual fear memory assay show a significant variation [F(2,12) = 8.114; p = 0.006] due to the treatment factor (R² = 0.575). Control mice receiving a mixture of DMSO (icv) and vehicle (oral) exhibited standard levels of freezing scores. The icv injection of Aβ_1–42 (Aβ_1–42/vehicle group) resulted in a highly significant decrease of freezing responses compared to controls (p = 0.008). PA1637 (Aβ_1–42/PA1637) improved significantly the freezing scores of mice having received Aβ_1–42 (p = 0.003).</p