Synthesis of a potent antimalarial agent through natural products conjugation

Abstract

Au naturel! (+)-Usnic acid (green) is a weak antimalarial agent, however, in conjugation with known antimalarial scaffolds and drugs, such as dihydroartemisinin (blue), potent activity against the blood-stage parasite can be seen both in vitro and in vivo. The compound shown exhibits an IC(50) value of 1.4 nM against Plasmodium falciparum in vitro and proved nearly as efficacious as artesunate in a mouse model of infection.

Figure 1

Chemical formulas of the synthesized compounds 2-15. Non IUPAC numbering for usnic usnic acid was used, which allowed comparison with spectroscopic assignments in the literature.

Scheme 1

Synthesis of compound 14. Reaction conditions: a: γ-aminobutyric acid, EtOH, reflux, N₂, 5 h, 73%; b: dihydroartemisinin, 2-chloro-4,6-dimethoxy-1,3,5-triazine/ N-methylmorpholine, rt, N₂, 24 h, 60%.

Scheme 2

Synthesis of compound 15. Reaction conditions: a: 4-amino-1-butanol, EtOH, reflux, N₂, 5 h, 66%; b: dihydroartemisinin, BF₃·Et₂O, CH₂Cl₂, 0°C to rt, N₂, 2 h, 75% (β/α 3:2).