Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines

Calas, Michele, Outtara, Mahama, Piquet, Giles, Ziora, Zyta, Bordat, Y., Ancelin, Marie L., Escale, Roger and Vial, Henri (2007) Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines. Journal of Medicinal Chemistry, 50 25: 6307-6315. doi:10.1021/jm0704752

Author Calas, Michele
Outtara, Mahama
Piquet, Giles
Ziora, Zyta
Bordat, Y.
Ancelin, Marie L.
Escale, Roger
Vial, Henri
Title Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
Publication date 2007-12-13
Sub-type Article (original research)
DOI 10.1021/jm0704752
Volume 50
Issue 25
Start page 6307
End page 6315
Total pages 9
Place of publication Washington, United States
Publisher American Chemical Society
Language eng
Formatted abstract
We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1H)-imino-heterocycle, bis-amidine, and bis-guanidine series. Bis-tertiary amines with a linker from 12 to 16 methylene groups were active against the in vitro growth of Plasmodium falciparum within the 10−6−10−7 M concentration range. IC50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC50 < 10 nM). Increasing the alkyl chain length from 6 to 12 methylene groups led to increased activity, while beyond this antimalarial activity decreased. Antimalarial activities appear to be strictly related to the basicity of the cationic head with an optimal pKa over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC50 values lower than 1 nM. In comparison to similar quaternary ammonium salts, amidinium compounds have distinct structural requirements for antimalarial activity and likely additional binding opportunities on account of their hydrogen-bond-forming properties.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Created: Thu, 17 Mar 2011, 20:20:27 EST by Susan Allen on behalf of Institute for Molecular Bioscience