Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum

Abstract

A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC 50 values in the low nanomolar range.

Exploring the Contribution of Candidate Genes to Artemisinin Resistance in Plasmodium falciparum

“…Since mutations (and for pfmdr1 also amplification) in the candidate genes investigated here do not account for artesunate resistance, other approaches have to be followed. These include whole-genome sequencing of resistant parasite genes for comparison with the sequences of sensitive strains, analysis of gene expression profiles using microarrays, microsatellite mapping, and genomewide hybridization and single nucleotide polymorphism map- (2,13,15,16). These findings do not exclude the possibility that the gene products of the genes examined play a role in the mechanism of artemisinin's action, since resistance can be conferred through a variety of mechanisms, such as changes in influx and efflux mechanisms.…”

Quinolines and structurally related heterocycles as antimalarials

“…1) to target the propagation of prions, Guy et al reinvestigated this class of compounds for antimalarial activity, particularly against CQR strains [126]. Six compounds exhibited potent EC 50 values, best being 86a and 86b, displaying EC 50 values <1 nM against both CQR and CQS strains.…”

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

“…The synthetic route depicted in Scheme 1 led to low global synthesis yields (2-22%), but allowed fast production of compounds 6 for immediate screening as potential dual-stage antimalarials. Attempts to increase the yields by optimization of both S N Ar and condensation steps were carried out: (a) pre-activation of 9-chloroacridine 4 with phenol, followed by addition of an amine in anhydrous conditions, to avoid extensive formation of the respective acridones, according to Anderson and co-workers; 7 (b) use of condensation reagents of usually higher efficiency than TBTU, such as (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP).These procedures led to reaction mixtures apparently cleaner by thin layer chromatography (TLC), especially in the S N Ar step, but reaction yields were not significantly improved.…”