Malaria still is one of the most threatening diseases in the world. In 2019, the WHO estimated 229 million of cases and 409,000 deaths mainly due to the most prevalent and lethal Plasmodium species: P. falciparum (Pf).

Fighting resistant Pf strains is henceforth one of the main challenges to eradicate malaria. Indeed, parasites have developed resistances against all the available therapeutic arsenal, including artemisinin-based combination therapies (ACT). Studies of resistance phenotypes identified efflux pumps involved in this phenomenom of which the multidrug resistance ABC transporter PfMDR1. Its overexpression is partly responsible of the carrying of two ACT partner drugs, mefloquine (MQ) and lumefantrine (LM), into the food vacuole away from their cytosolic targets, leading to the efficacy decline of these arylaminoalcohol drugs.

In order to limit this efflux, our laboratory has developed efflux pump inhibitor (EPI) patterns based on previous described resistance reversing agents such as penfluridol. A library of novel arylaminoalcohols is easily affordable into a previously optimized synthesis to obtain MQ, LM and enpiroline analogs. This stereoselective and convergent synthesis requires a key arylvinyl converted to the corresponding enantiopure aryloxirane thanks to a Sharpless asymmetric dihydroxylation followed by a one-pot cyclization. Finally, a regioselective ring-opening by EPI moieties led to efflux pump substrate compounds.

Both design and synthesis of these arylaminoalcohols will be herein presented. In vitro efficacy against two Pf strains, cytotoxicity and preliminary results of P-gp, BCRP and MRPs efflux modulation in Caco-2 cells model will be reported. First structure-activity relationships will be discussed.