Antimalarial Activity of Compounds Interfering with Plasmodium falciparum Phospholipid Metabolism: Comparison between Mono- and Bisquaternary Ammonium Salts

Abstract

On the basis of a previous structure-activity relationship study, we identified some essential parameters, e.g. electronegativity and lipophilicity, required for polar head analogues to inhibit Plasmodium falciparum phospholipid metabolism, leading to parasite death. To improve the in vitro antimalarial activity, 36 cationic choline analogues consisting of mono-, bis-, and triquaternary ammonium salts with distinct substituents of increasing lipophilicity were synthesized. For monoquaternary ammonium salts, an increase in the lipophilicity around nitrogen was beneficial for antimalarial activity: IC(50) decreased by 1 order of magnitude from trimethyl to tripropyl substituents. Irrespective of the polar head substitution (methyl, ethyl, hydroxyethyl, pyrrolidinium), increasing the alkyl chain length from 6 to 12 methylene groups always led to increased activity. The highest activity was obtained for the N,N,N-tripropyl-N-dodecyl substitution of nitrogen (IC(50) 33 nM). Beyond 12 methylene groups, the antimalarial activities of the compounds decreased slightly. The structural requirements for bisquaternary ammonium salts in antimalarial activity were very similar to those of monoquaternary ammonium salts, i.e. polar head steric hindrance and lipophilicity around nitrogen (methyl, hydroxyethyl, ethyl, pyrrolidinium, etc.). In contrast, with bisquaternary ammonium salts, increasing the lipophilicity of the alkyl chain between the two nitrogen atoms (from 5 to 21 methylene groups) constantly and dramatically increased the activity. Most of these duplicated molecules had activity around 1 nM, and the most lipophilic compound synthesized exhibited an IC(50) as low as 3 pM (21 methylene groups). Globally, this oriented synthesis produced 28 compounds out of 36 with an IC(50) lower than 1 microM, and 9 of them had an IC(50) in the nanomolar range, with 1 compound in the picomolar range. This indicates that developing a pharmacological model for antimalarial compounds through choline analogues is a promising strategy.

Prodrugs of bisthiazolium salts are orally potent antimalarials

“…We have focused on mono-and bisquaternary ammonium compounds for their potent antimalarial activity in vitro and in vivo (6,7). These compounds mimic choline structure; they potently inhibit the low-affinity choline carrier related to phospholipid biosynthesis in eukaryotic cells and the high-affinity carrier involved in biosynthesis of the neurotransmitter acetylcholine in the CNS (8,9).…”

“…G25 [1,16-hexadecamethylenebis(N-methylpyrrolidinium) dibromide] and other drugs in this class possess a permanently charged cationic group (7,13) that is essential for activity but detrimental to oral absorption. This action prejudiced development for the clinic.…”

Synthesis of Novel Conjugates of Tetraoxane Endoperoxide with Bis(Quaternary Ammonium Salts)

“…15) Calas et al have also demonstrated that interference with de novo PC biosynthesis by bis(quaternary ammonium salts) was lethal to malaria parasites, including chloroquine-resistant species (Scheme 1). 16) Therefore, if we combine these two components via covalent binding, the conjugate should have a different nature from the originals. For example, the solubility of the tetraoxane moiety in water may be significantly improved by the introduction of the ammonium ion.…”

Quantification of Antimalarial Bisthiazolium Compounds and Their Neutral Bioprecursors in Plasma by Liquid Chromatography-Electrospray Mass Spectrometry

“…Compounds mimicking the structure of choline, a precursor required for phosphatidylcholine synthesis by the parasite, inhibit de novo phosphatidylcholine biosynthesis and are highly active against multiresistant P. falciparum malaria (3)(4)(5)(6)(7)(8)(9)(10). Three generations of compounds have been synthesized.…”

“…Three generations of compounds have been synthesized. The first two consist of mono-or bisquaternary ammonium salts (6,7 ) and ami-dine and guanidine compounds, respectively. These compounds have outstanding efficacy both in vitro and in vivo against P. falciparum and P. cynomolgi, a P. vivaxrelated parasite, with a high therapeutic index (3 ).…”