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


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 ?M. A representative analog with good solubility, limited PAMPA permeability, and microsomal stability demonstrated oral efficacy on a humanized mouse model of P. falciparum.

SUBMITTER: Ahenkorah S 

PROVIDER: S-EPMC6956359 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Antimalarial <i>N</i> <sup>1</sup>,<i>N</i> <sup>3</sup>-Dialkyldioxonaphthoimidazoliums: Synthesis, Biological Activity, and Structure-activity Relationships.

Ahenkorah Stephen S   Coertzen Dina D   Tong Jie Xin JX   Fridianto Kevin K   Wittlin Sergio S   Birkholtz Lyn-Marie LM   Tan Kevin S W KSW   Lam Yulin Y   Go Mei-Lin ML   Haynes Richard K RK  

ACS medicinal chemistry letters 20191211 1


Here we report the nanomolar potencies of <i>N</i> <sup>1</sup>,<i>N</i> <sup>3</sup>-dialkyldioxonaphthoimidazoliums against asexual forms of sensitive and resistant <i>Plasmodium falciparum</i>. Activity was dependent on the presence of the fused quinone-imidazolium entity and lipophilicity imparted by the N<sup>1</sup>/N<sup>3</sup> alkyl residues on the scaffold. Gametocytocidal activity was also detected, with most members active at IC<sub>50</sub> < 1 μM. A representative analog with good  ...[more]

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2019-11-12 | PXD010614 | Pride