Bioorganic Chemistry (2019)
Update date:2022-08-16
Topics:
D'Alessandro, Sarah
Alfano, Gloria
Di Cerbo, Luisa
Brogi, Simone
Chemi, Giulia
Relitti, Nicola
Brindisi, Margherita
Lamponi, Stefania
Novellino, Ettore
Campiani, Giuseppe
Gemma, Sandra
Basilico, Nicoletta
Taramelli, Donatella
Baratto, Maria Camilla
Pogni, Rebecca
Butini, Stefania
Despite recent advancements in its control, malaria is still a deadly parasitic disease killing millions of people each year. Progresses in combating the infection have been made by using the so-called artemisinin combination therapies (ACTs). Natural and synthetic peroxides are an important class of antimalarials. Here we describe a new series of peroxides synthesized through a new elaboration of the scaffold of bicyclic-fused/bridged synthetic endoperoxides previously developed by us. These peroxides are produced by a straightforward synthetic protocol and are characterized by submicromolar potency when tested against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. To investigate their mode of action, the biomimetic reaction of the representative compound 6w with Fe(II) was studied by EPR and the reaction products were characterized by NMR. Rationalization of the observed structure-activity relationship studies was performed by molecular docking. Taken together, our data robustly support the hypothesized mode of activation of peroxides 6a-cc and led to the definition of the key structural requirements responsible for the antiplasmodial potency. These data will pave the way in future to the rational design of novel optimized antimalarials suitable for in vivo investigation.
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