Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum
Graphical abstract
A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented.
Introduction
Malaria is a devastating infectious disease caused by the protozoan parasite Plasmodium.1 Four species of Plasmodium are known to infect humans: P. vivax, P. malariae, P. ovale, and P. falciparum, the latter being the most deadly. While the controversial use of polychlorinated biphenyl pesticides (e.g., DDT) has generally led to the eradication of malaria in North America and most European countries,2 the disease is still widespread in Africa, Central and South America, and Southeast Asia. Malaria continues to affect 200–500 million people and cause 1–2 million fatalities annually.3 As a result, malaria has produced devastating social and economic burdens on the countries most afflicted by it.1
The development of anti-malarial compounds continues to be a major focus of many laboratories,4 and as such, a variety of compounds have been explored in the prophylaxis and treatment of this disease (Fig. 1). The efficacy of quinine (1), a derivative of cinchona-bark, as an anti-malarial compound was recognized as early as the 1600 s. The earliest synthetic anti-malarial agent was quinacrine (2). Quinacrine was supplemented by chloroquine (3),5 along with various other 4- and 8-substituted quinolines, including mefloquine (4).6 Chloroquine was found to be highly effective against all four human-infecting species of Plasmodium, and its inexpensive production led it to quickly become a standard anti-malarial treatment.5 Unfortunately, over several decades this resulted in the development of chloroquine-resistant strains of Plasmodium, particularly of P. falciparum.7, 8 Certain substituted quinolines, including mefloquine (4), have been efficacious against chloroquine-resistant P. falciparum (CRPF), but this drug is also associated with a variety of neuropsychiatric side-effects.9 Another promising class of compounds with activity against CRPF are the artemisinins.10, 11, 12 The continuing exploration of compounds active against CRPF is an active pursuit of our laboratory.13, 14
In the context of exploring the 9-aminoacridine scaffold of quinacrine (3) to target the propagation of prions,15, 16, 17 we became interested in re-evaluating this class of molecules for anti-malarial activity, particularly against CRPF. Herein we report a parallel synthetic strategy to generate libraries of 9-aminoacridines based on the general structure of quinacrine, along with in vitro cell-based screening results against drug-sensitive and drug-resistant strains of P. falciparum. In addition to having anti-prion and anti-malarial properties, 9-aminoacridines are interesting for other types of biological activity. For example, 9-aminoacridines are known DNA intercalators,18 inhibitors of mammalian topoisomerase I19 and acetylcholinesterase,20 and these compounds are also active against African trypanosomes.21, 22, 23 Cancer chemotherapeutics based on the 9-aminoacridine scaffold have been developed24 (e.g., Ledakrin and Amascrine). Additionally, 9-aminoacridines have been explored as photoaffinity labels25 and as fluorescent probes used to detect cancer cells.26
Our general synthetic strategy to 9-aminoacridines is summarized in Figure 2. Derivatives of substituted salicylic acid chemset 5 were coupled to aniline chemset 6 to generate 9-chloroacridine chemset 7, as was previously introduced.27 The use of salicylic acid precursors, activated as triflates, is novel and deviates from an earlier approach to 9-chloroacridines based on the Ulmann coupling of anilines with 2-bromoaryl carboxylic acids,28, 29, 30 of which much fewer are commercially available. To approach the amine sidechain, 1,3-diaminopropane (8) was dually functionalized to generate a library of requisite diamine building block chemset 9. Finally, parallel coupling of 9-chloroacridines with the diamines was done to generate the desired 9-aminoacridine chemset 10. A notable feature of this strategy is that it allows quick access to variations of the tricyclic acridine heterocycle as well as the amine sidechain, which will allow probing of the cooperativity of these two structural features.
Section snippets
Chemistry
The synthesis of the 9-chloroacridine heterocycles is illustrated in Scheme 1. The salicylic acid chemset (5) was methylated and then activated for cross-coupling as the corresponding aryl triflate chemset (11), generally in near quantitative yield giving compounds of high purity. These species were coupled to substituted aniline chemset 6 to generate diarylamine chemset 12, using conditions developed by Buchwald et al.,31 which proceeded smoothly. Next, hydrolysis of the methyl ester groups
Conclusion
A parallel synthetic strategy to generate 9-aminoacridines is described. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in fairly diverse substitution patterns. Additionally, a procedure for the synthesis of disubstituted diaminoalkanes was presented. Two libraries were designed totaling 175 compounds, although only 93 of the final products had purities suitable for in vitro screening. Low purity was
General
NMR spectra were recorded on a Varian Model AS 400-MHz machine. The following abbreviations are used to describe peak splitting when appropriate: s, singlet, d, doublet, t, triplet, q, quartet, br s, broad singlet, and mult, multiplet. Reactions were carried out under an atmosphere of argon. Reagents were of commercial quality unless otherwise indicated. Analytical thin layer chromatography (TLC) was carried out using plastic plates coated with silica gel 60 F254 (Whatman Part #4420 222).
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