Antimalarial Activity of Molecules Interfering with Plasmodium falciparum Phospholipid Metabolism. Structure−Activity Relationship Analysis

Abstract

A series of 80 compounds, primary, secondary, and tertiary amines and quaternary ammonium and bisammonium salts, most of them synthesized as potential choline or ethanolamine analogs, were tested against the in vitro growth of Plasmodium falciparum, the human malaria parasite. They were active over the 10(-3)-10(-8) M concentration range. A structure-activity relationship study was carried out using autocorrelation vectors as structural descriptors, and multidimensional analysis. Principal component analysis, ascending hierarchical classification, and stepwise discriminant analysis showed that both the size and shape of the molecule were essential for antimalarial potency, making the lipophilicity and electronegativity distribution in the molecular space essential. Using the autocorrelogram describing the molecular shape and the electronegativity distribution on the molecular graph, 98% of the molecules were correctly classified either as poorly active or active with only three explanatory variables. The most active compounds were quaternary ammoniums salts whose nitrogen atom had only one long lipophilic chain of 11 or 12 methylene groups (E5, E6, E10, E13, E20, E21, E22, E23, F4, F8), or the bisammoniums whose polar heads were linked by linear alkyl chains of 10 to 12 carbon atoms (G4, G23). The hydroxyethyl group of choline was not very beneficial, whereas the charge and substitutions of nitrogen (aimed at increasing lipophilicity) were essential for optimal interactions. A crude topographic model of the ligand (choline) binding site was thus drawn up.

Prodrugs of bisthiazolium salts are orally potent antimalarials

“…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.…”

Potent Inhibitors of Plasmodium Phospholipid Metabolism with a Broad Spectrum of In Vitro Antimalarial Activities

“…Phosphatidylcholine (PC) is the major PL of infected erythrocytes, representing about 45% of total PL, much of which is provided by parasitedriven de novo biosynthesis from choline (4, 31). In the pathway, parasitic cholinephosphate cytidylyltransferase (38) and choline transport, which regulates the precursor supply, are a limiting and likely regulatory step (4, 33).More than 100 analogs of PL polar heads have been synthesized and tested in vitro for their activity against the intraerythrocytic stage of P. falciparum (2,8,9). More particularly, 36 compounds which possess one (or two) quaternary ammonium ions, such as choline and long lipophilic alkyl chains, were found to be very potent against P. falciparum, with a 50% inhibitory concentration (IC 50 ) within the micro-and picomolar range (8).…”

“…More than 100 analogs of PL polar heads have been synthesized and tested in vitro for their activity against the intraerythrocytic stage of P. falciparum (2,8,9). More particularly, 36 compounds which possess one (or two) quaternary ammonium ions, such as choline and long lipophilic alkyl chains, were found to be very potent against P. falciparum, with a 50% inhibitory concentration (IC 50 ) within the micro-and picomolar range (8).…”

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 ).…”