Antimalarial N¹,N³-Dialkyldioxonaphthoimidazoliums: Synthesis, Biological Activity, and Structure–activity Relationships

Abstract

Here we report the nanomolar potencies of N 1 ,N 3dialkyldioxonaphthoimidazoliums 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 IC 50 < 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.

Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against Mycobacterium tuberculosis

“…In an earlier investigation, we verified that several series 1 analogues generated hydrogen peroxide via redox cycling in an in vitro horseradish peroxidase-phenol red assay . To determine if this phenomenon also occurs in mycobacterial cultures, we monitored ROS production using CellROX Green Reagent (Invitrogen).…”

“…In all, 80 compounds were synthesized and their structures are presented in Table . Of these, several ( 4 – 37 in series 1, 66 – 70 in series 4) have been synthesized and screened for antiplasmodial activity . The reported synthetic pathways were employed to obtain the other compounds in series 1–4 (Scheme ).…”

“…We have previously reported several potent N , N -disubstituted dioxonaphthoimidazoliums against Plasmodium falciparum . These compounds were found to generate ROS in an in vitro redox cycling assay but were not followed up in plasmodia.…”

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…Following the identification of compound 77 as a potent multistage anti‐plasmodial agent, Haynes and co‐workers sought to explore whether related anti‐cancer agents including compound 78 , which are structurally related to sepantronium bromide, could be useful anti‐plasmodial lead compounds . A subsequent SAR study revealed that lipophilic alkyl N1/N3 substituents were critical for activity, with compound 79 displaying good in vitro activity with high water solubility and microsomal stability.…”

“…This translated into moderate in vivo activity following oral administration in a humanized mouse model of malaria. This low‐level activity was likely as a result of its relatively low oral bioavailability and a short biological half‐life, whose optimisation will likely constitute the next phase of advancement of this class …”