Modified quaternary ammonium salts as potential antimalarial agents
Introduction
Malaria is the most prevalent tropical disease in the world with 207 million estimated new cases in 2012 and an annual death toll of 627,000 people. At present, there are 104 countries in which malaria is considered endemic.1
The increasing drug resistance of Plasmodium falciparum (P. falciparum) responsible of the most lethal form of malaria and the resistance of mosquitoes to various pesticides stimulates the search for new weapons to fight this disease.
This is particularly urgent now that the resistance to the artemisinin derivatives, essential component of the combination treatments presently available, has been confirmed in SE Asia.2
Quaternary ammonium salts are known to play an active role inhibiting the growth of P. falciparum parasites and have gained attention as a new, effective, and relatively cheap anti-malarial drugs. Ancielin et al.3, 4 reported that the in vitro lethal effect of quaternary ammonium compounds on P. falciparum are predominantly related to the inhibition of phosphatidylcholine and phosphatidylethanolamine biosynthesis as a consequence of a reduced choline transport into infected erythrocytes. Choline cannot be synthesized by the parasites which relies on exogenous supply. The treatment with phospholipids polar head analogs interferes with natural phospholipids biosynthesis by competition or substitution.5, 6 From these observations, a series of bis-thiazolium compounds have been tested and shown to possess potent antimalarial activity.7, 8 The bis-thiazolium series provided the clinical candidate albitiazolium9 (albitiazolium bromide, SAR97276), that is in clinical phase II trials to treat severe malaria by the parenteral route.10
As widely reported in literature,11, 12 polyconjugated systems such as retinoids and carotenoids possess many biochemical and pharmacological properties including antioxidant and antimicrobial activities.
The retinol and some retinoid-like compounds are able to inhibit the in vitro growth of P. falciparum suggesting that this parasite is retinol-sensitive and that, in patients with malaria, adjunctive retinol therapy may accelerate parasite dysfunction and death.13 Moreover, it is also reported the high antiplasmodial activity of a marine carotenoid, fucoxanthin, extracted from marine brown seaweeds, macroalgae, diatoms and microalgae which activity could be related to its antioxidant properties.14
In the last decade our interest was turned on the synthesis of polyunsaturated molecules15, 16 whose structure is shown in Figure 1 which share with carotenoids and retinoids some structural features, antioxidant properties, effects on cell proliferation and antibacterial activity.17
These compounds are chemically homologous of sorbic acid (2E,4E-hexadienoic acid), a natural preservative used as antimicrobial agent especially in food, drinks and cosmetics.
From the preliminary biological evaluations18 (2E,4E,6E)-octatrien-1-ol, the corresponding acid and potassium salt showed interesting pharmacological properties. With the aim to develop a new class of compounds with potential antimalarial activity, in this work we describe the synthesis, the molecular characterization and the preliminary evaluation of the antimalarial activity in vitro of new quaternary ammonium salts derived from (2E,4E,6E)-octatrien-1-ol.
Section snippets
Chemistry
The compounds 4a–e and 6a–e were obtained following Scheme 1. Firstly, (2E,4E,6E)-octatrien-1-ol of industrial origin was oxidized to (2E,4E,6E)-octatrienal 1 with manganese dioxide and then reacted in anhydrous toluene with primary amines with long alkyl chain to give the corresponding Schiff bases 2a–e. The quantitative reduction of imines with sodium borohydride in refluxed anhydrous ethanol allowed to obtain the secondary amines 3a–e which were directly quaternized in a stainless steel
Conclusions
In this paper, two new series of quaternary ammonium salts derived from all trans 2,4,6-octatrienol have been synthesized and evaluated for their in vitro activity against D-10 (CQ-S) and W-2 (CQ-R) strains of P. falciparum. The most active of the tested compounds displayed a significant inhibitory activity with IC50 in the submicromolar range with no cross resistance with CQ and very low cytotoxicity against a human endothelial cell line, suggesting a high therapeutic index. Considering that
General
All commercial available solvents and reagents were used after distillation or treatment with drying agents. (2E,4E,6E)-octatrienol, a gift of Giuliani s.p.a. (Milan, Italy), was purified before use by dissolution in dichloromethane; the precipitate was filtered and the solution evaporated under reduced pressure. The residue was then recrystallized from petroleum ether.
All of the reactions that involved the use of reagents sensitive to oxygen or hydrolysis were carried out under an inert
Parasites cultures
Biological tests have been done on in vitro cultured P. falciparum parasites according to Trager and Jensen22 with slight modifications.23 The CQ-sensitive (D10) and the CQ-resistant (W2) strains were maintained at 5% haematocrit (human type A-positive red blood cells) in RPMI 1640 (EuroClone) medium supplemented with 1% AlbuMaxII (lipid-rich bovine serum albumin) (Invitrogen), 0.01% hypoxantine (Sigma), 20 mM Hepes (EuroClone), 2 mM glutamine (EuroClone). All the cultures were maintained at 37 °C
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Pyrrolyl-silicon compounds with different alkyl spacer lengths: Synthesis, electrochemical behavior and binding properties
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Both authors contributed equally to this work.