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Abstract
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.
Supplementary materials
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