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Pré-Publication, Document De Travail Année : 2022

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis

Valentin Buchter
Yih Ching Ong
François Mouvet
Abdallah Ladaycia
Elise Lepeltier
Ursula Rothlisberger
Jennifer Keiser

Résumé

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported 3 lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene‐containing (Fc‐CH2‐OXA), ruthenocene‐containing (Rc‐CH2‐OXA) and benzene‐containing (Ph‐CH2‐OXA). These derivatives showed excellent in vitro activity against both Schistosoma mansoni and S. haematobium larvae and adult worms, and in vivo against S. mansoni. Encouraged by these promising results, we followed a guided drug discovery process and report in this investigation on metabolic stability studies, in vivo studies, computational simulations, and formulation studies. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason as to why the promising in vitro activity did not translate to in vivo activity. This limitation could not be saved by the formulation of lipid nanocapsules as an intent to improve the in vivo activity. Further studies should focus on increasing the compound’s bioavailability, in order to reach an active concentration in the parasite’s microenvironment.
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Dates et versions

hal-03645191 , version 1 (19-04-2022)

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Valentin Buchter, Yih Ching Ong, François Mouvet, Abdallah Ladaycia, Elise Lepeltier, et al.. Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis. 2022. ⟨hal-03645191⟩
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