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