Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis
| Autor: | Abdallah Ladaycia, Gilles Gasser, Ursula Rothlisberger, François Mouvet, Jennifer Keiser, Valentin Buchter, Yih Ching Ong, Elise Lepeltier |
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| Přispěvatelé: | Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), Europe ERC, European Project: 681679, H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),681679,PhotoMedMet(2017) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Drug
biology business.industry Drug discovery media_common.quotation_subject Schistosomiasis [CHIM.THER]Chemical Sciences/Medicinal Chemistry Pharmacology medicine.disease biology.organism_classification Molecular Dynamics In vitro Oxamniquine Praziquantel Medicinal Organometallic Chemistry In vivo Bioorganometallic Chemistry Metabolic Stability parasitic diseases medicine Schistosoma mansoni business medicine.drug media_common |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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