Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 150, Issue -, Pages 698-718Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.03.024
Keywords
Malaria; Gametocytes; Plasmodium falciparum; Inhibition; Structure-activity relationships
Categories
Funding
- MIUR
- National Institutes of Health [Al-097119]
- COST Action [CM1307]
- Global Health Program of the Bill & Melinda Gates Foundation [OPP1040394]
- MIUR [20154JRJPP]
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Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba2+ current through Ca(v)1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite. (C) 2018 Elsevier Masson SAS. All rights reserved.
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