Antiplasmodial activity of amides and amines from Withania aristata, an endemic species of the Canary islands

Abstract

Malaria continues to be a major health challenge in most tropical and subtropical regions. The most severe form of human malaria is caused by Plasmodium falciparum, responsible for more than one million deaths per year. Due to the emergence and spread of drug resistance to the available antiplasmodial drugs, its treatment has become a serious problem. Therefore, new molecules with novel mechanisms of action are required [1]. In this context, natural products can deliver new lead compounds for more effective drugs than those currently in clinical use [2]. As part of our research for bioactive metabolites from natural sources, Withania aristata (Aiton) Pauquy (Solanaceae), an endemic species of the Canary Islands used in folk medicine, was studied. The phytochemical analysis of the dichloromethane extract from the leaves of this plant led to the isolation of 3 amide and 6 amine type metabolites, two of them, 2-(4-hydroxy-3,5-dimethoxyphenyl)-3-oxetanamine and N-4-(3-furoylamine)-1-butanol, not previously reported. Their structures were determined by means of spectroscopic studies, including 1D and 2D NMR experiments. The antiplasmodial activity of the compounds was evaluated against a strain of Plasmodium falciparum (F-32 Tanzania). N-cis-feruloyltyramine and 4-O-methyldopamine showed moderate activity (IC50 4.2 and 3.0µg/mL, respectively), whereas the activity of the most potent compound, N-cis-p-coumaroyltyramine, was comparable to that of the control chloroquine (IC50 0.7 and 0.1µg/mL, respectively). A preliminary structure-activity relationship study indicated that the configuration of the double bond in the amides and the regiosubstitution of the aromatic ring in the amines play an important role in the activity.