Abstract
We recently reported a series of compounds for a solubility-driven optimization campaign of antitrypanosomal compounds. Extending a parasite-hopping approach to the series, a subset of compounds from this library has been cross-screened for activity against the metazoan flatworm parasite, Schistosoma mansoni. This study reports the identification and preliminary development of several potently bioactive compounds against adult schistosomes, one or more of which represent promising leads for further assessment and optimization.
Highlights
Schistosomiasis, caused by trematode flatworms of the genus Schistosoma, is a debilitating and serious parasitic neglected tropical disease (NTD) that leads to chronic illhealth.[1]
Urogenital schistosomiasis is caused by S. hematobium, and intestinal schistosomiasis is caused by S. mansoni, S. japonicum, S. mekongi, and S. guineensis.[1]
A target class repurposing approach was undertaken in order to optimize the U.S Food and Drug Administration-approved drug lapatinib (Tykerb) (1) as an antitrypanosomal drug against Trypanosoma brucei brucei (Figure 1).[4]
Summary
Extension of the alkyl chain to an ethyl (8c) provided a similar phenotypic response, further extension to a propyl (8d) resulted in bioactivity being detected after 1 h, and a more severe phenotypic response was recorded after 24 h These compounds showed the greatest antischistosomal activity of the series, with 8b possessing >33,500-fold improvement in solubility compared to 8a; clearance increased 2-fold, and no toxicity improvement was observed. Four potent compounds of interest (5a, 5d, 6c, and 8a) were identified, with the most promising possessing an ortho-methylated quinoline core Compounds of this series were further explored, optimizing for antischistosomal activity, which resulted in 8b−a promising lead−with 8a, 8c, and 9e presenting as potential backup leads for further assessment and optimization as antischistosomal compounds. Details of biological assay protocols, chemistry experimental, in vitro ADME properties, and additional supplementary data (PDF)
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