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.

Figure 1

Structures of common quinoline and acridine anti-malarial compounds.

Figure 2

A parallel synthetic strategy to generate libraries of 9-aminoacridines.

Scheme 1

Synthesis of 9-chloroacridines. Reagents and conditions: (a) MeI (1.05 eq.), Cs₂CO₃ (0.5 eq.) DMF (90-100% yield). (b) Tf₂O (1.1 eq.), Et₃N (2.0 eq.), CH₂Cl₂, −78 °C to rt (95-100% yield). (c) substituted anilines 6 (1.05 eq.), Pd(OAc)₂ (0.05 eq.), BINAP (0.08 eq.), Cs₂CO₃ (1.4 eq.), toluene. (d) Ba(OH)₂-8H₂O (2.5 eq.), CH₃OH, 80 °C overnight; (e) POCl₃ (neat) 120 °C, 1h (5-50% yield).

Scheme 2

Synthesis of diamines. Reagents and conditions: (a) 2-nitrobenzenesulfonyl chloride (0.1 eq.), CH₂Cl₂, °C to rt, overnight (70 g scale, 85% yield). (b) carboxylic anhydrides (14) (1.2 eq.), pyridine (1.1 eq.), THF (90-100% yields). (c) BH₃·dimethylsulfide complex (4.0 eq.), THF, 60 °C, 30 min. (67-77% yields) (d) aldehydes 16 (1.5 eq.), sodium triacetoxyborohydride (1.5 eq.), THF, sonicated, 35 °C, 1h. (e) benzenethiol (5 eq.), Cs₂CO₃ (2.5 eq.), degassed CH₃CN under argon.

Scheme 3

Coupling of 9-chloroacridines with diamines. Reagents and conditions: (a) phenol (15 eq.), Cs₂CO₃ (1 eq.), 3Å molecular sieves, DMSO, 100 °C, 2 h. (b) diamines (9) (4 eq.), DMSO, 100 °C, 4h; then methyl isocyanate polystyrene resin (NovaBiochem, 8 eq.), overnight, rt.

Figure 3

Composition of 9-chloroacridine (7) chemset.

Figure 4

Composition of disubstituted diamine (9) chemset.

Figure 3

Relative activity of the library defined in Table 3 against P. falciparum strains 3D7 and W2 cultured in human erythrocytes (measured at fixed concentration: 30 nM). Data is represented in blue scale, as percent parasite growth relative to un-treated controls, with darker squares indicating a higher activity against the parasites. Omitted entries are due to failure during synthesis.

Figure 5

Structures and EC₅₀ values of the most active compounds against P. falciparum strains 3D7 and W2 in cultured human erythrocytes, as well as for quinacrine (2) and chloroquine (3). Activity at a series of 12 concentrations was determined as percent parasite growth relative to un-treated controls, EC₅₀ values were determined with SigmaPlot.