Potent Antimalarial Activity of 2-Aminopyridinium Salts, Amidines, and Guanidines

Abstract

We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1 H)-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. IC 50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC 50 < 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 p K a over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC 50 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.

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

“…Compounds that mimic the structure of choline, the major malarial phospholipid necessary for the de novo biosynthesis of phosphatidylcholine, are potential substrates for the parasite choline carrier (6). Thus, the methylene (di)cationic lead compounds (compounds 13 to 15) and the piperidine derivatives compounds 5e to 5i (assuming that the piperidinyl nitrogen atom is charged at physiological pH) might possibly interfere with the parasite choline transporter, as reported previously for structurally related compounds bearing two polar heads separated by a methylene spacer (11). However, this hypothesis would need experimental confirmation.…”

“…On the other hand, Calas and colleagues have shown a positive relationship between the abilities of long-methylene-chain mono-and bisquaternary ammonium salts to inhibit P. falciparum growth in vitro and their inhibition of phosphatidylcholine biosynthesis (1,2). A recent report by that group on the antimalarial activity of 12-and 16-methylene chain biscationic compounds mimicking the structure of choline and structurally related to compounds 13 to 15 (e.g., bisamidines, bisguanidines) also points to a similar mechanism of action involving the inhibition of the phospholipid-related choline carrier (11). Compounds that mimic the structure of choline, the major malarial phospholipid necessary for the de novo biosynthesis of phosphatidylcholine, are potential substrates for the parasite choline carrier (6).…”

Quaternary Ammonium Salts and Their Antimicrobial Potential: Targets or Nonspecific Interactions?

“…Chain length-activity correlation of BQACs reported by Vial and colleagues. [64][65][66] bioavailability. [71,72] To circumvent the poor oral absorption of previous BQACs, the Vial group further replaced the quaternary ammonium heads by bioisosteric groups that are highly basic, charged at physiological pH, and capable of creating bonds with the target similar or stronger than those of conventional BQACs.…”

“…[71,72] To circumvent the poor oral absorption of previous BQACs, the Vial group further replaced the quaternary ammonium heads by bioisosteric groups that are highly basic, charged at physiological pH, and capable of creating bonds with the target similar or stronger than those of conventional BQACs. [65] Because of the equilibrium between protonated and unprotonated forms, these compounds are expected to diffuse more easily through cell barriers. Out of 60 new compounds, 2-aminopyridium salts, amidines, and guanidines showed the best antiplasmodial activities in the low nanomolar range.…”

“…Three lead compounds, the amidines M34, M38, and M40 (Figure 7), were identified, but the high flexibility of the linker was considered a drawback for membrane permeation. [65] In a subsequent study, hybrid biscationic salts were designed from efficient symmetrical derivatives (T3 or T4 and M34, 38, or M40). [66] However, the generation of hybrids did not result in any synergy between amidine and thiazolium cationic heads, and the oral absorption was still weak.…”