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ACS Med Chem Lett. 2019 Dec 11;11(1):49-55. doi: 10.1021/acsmedchemlett.9b00457. eCollection 2020 Jan 9.

Antimalarial N 1,N 3-Dialkyldioxonaphthoimidazoliums: Synthesis, Biological Activity, and Structure-activity Relationships.

Author information

1
Department of Pharmacy, Department of Microbiology and Immunology, and Department of Chemistry, National University of Singapore, 117543, Singapore.
2
Institute for Sustainable Malaria Control, Department of Biochemistry, Genetics and Microbiology, University of Pretoria, 0028 Pretoria, South Africa.
3
Swiss Tropical and Public Health Institute, 4051 Basel, Switzerland.
4
University of Basel, 4003 Basel, Switzerland.
5
Centre of Excellence for Pharmaceutical Sciences, North-West University, 2531 Potchefstroom, South Africa.

Abstract

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 N1/N3 alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC50 < 1 μM. A representative analog with good solubility, limited PAMPA permeability, and microsomal stability demonstrated oral efficacy on a humanized mouse model of P. falciparum.

PMID:
31938463
PMCID:
PMC6956359
[Available on 2021-01-09]
DOI:
10.1021/acsmedchemlett.9b00457

Conflict of interest statement

The authors declare no competing financial interest.

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