Glycosyltriazoles from 1,4-naphthoquinones: a search for active compounds against P. falciparum

Malaria is a parasitic disease considered one of the most serious public health problems in the world and was responsible in the previou year for the deaths of 627,000 people and 241 million cases diagnosed according to the 2021 World Malaria Report. The 1,4-naphthoquinones present a mechanism of inhibition of hemozoin formation and their action on the cycle of glutathione reductase of Plasmodium is related to their redox behavior. Because of these activities, 1,4-naphthoquinones are a class of interest in the search for new compounds with antimalarial activity. An important representative of this class is the 1,4- naphtoquinone derivative atovaquone, one of the drugs used in the treatment of malaria, whose mechanism of action is related to the structural similarity of this drug with ubiquinone. In the present work we prepared 2-O-propargyllawsone and 3-C-propargyllawsone wich were converted into the corresponding glycosyltriazole derivatives, using peracetylated and deacetylated glycosyl azides derived from D-glucose, D-galactose, D-N-acetilglucosamine and L-fucose. All the 16 glycosyltriazoles obtained and the two starting compounds were characterized by spectroscopic techniques and evaluated against chloroquine resistant strains (W2) of Plasmodium falciparum. Only 2-O-propargyllawsone (IC₅₀= 1.74 μM) and its glycosyltriazole derivatives diplayed activity, among which the peracetylated D-galactosyltriazole was the most active (IC₅₀= 3.16 μM). The corresponding deacetylated galactosyltriazole displayed IC₅₀= 7.60 μM,, indicating that acetylation improves the activity. The same trend was observed among the other glycosyltriazoles of this series.