Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl) furan-2-yl]-N-Rpiperidin-4-yl)methyllmethanamine (MMV019918) and analogues

作者:Vallone Alessandra; D'Alessandro Sarah; Brogi Simone; Brindisi Margherita; Chemi Giulia; Alfano Gloria; Lamponi Stefania; Lee Soon Goo; Jez Joseph M; Koolen Karin J M; Dechering Koen J; Saponara Simona; Fusi Fabio; Gorelli Beatrice; Taramelli Donatella; Parapini Silvia; Caldelari Reto; Campiani Giuseppe*; Gemma Sandra*; Butini Stefania
来源:European Journal of Medicinal Chemistry, 2018, 150: 698-718.
DOI:10.1016/j.ejmech.2018.03.024

摘要

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.

  • 出版日期2018-4-25