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

Stephen Ahenkorah; Dina Coertzen; Jie Xin Tong; Kevin Fridianto; Sergio Wittlin; Lyn-Marie Birkholtz; Kevin S W Tan; Yulin Lam; Mei-Lin Go; Richard K Haynes

doi:10.1021/acsmedchemlett.9b00457

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

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

Authors

Affiliations

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.