Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 1, Pages 49-55Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00457
Keywords
Antimalarials; dioxonaphthoimidazoliums; quinones; drug resistant asexual parasites; gametocytocidal activity
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Funding
- Ministry of Education Academic Research Fund [R148000234114, R148000286114]
- South African Medical Research Council (MRC) Flagship Project MALTB-Redox
- National Treasury under its Economic Competitiveness and Support Package
- Ministry of Education Singapore
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Here we report the nanomolar potencies of N-1,N-3-dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant Plasmodium falciparum. Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N-1/N-3 alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC50 < 1 mu M. A representative analog with good solubility, limited PAMPA permeability, and microsomal stability demonstrated oral efficacy on a humanized mouse model of P. falciparum.
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