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

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 -10 M concentration range. IC decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC < 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 pK over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC 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. © 2007 American Chemical Society.