To date, malaria still remains as one of the most threatening diseases in the world with 228 million of cases in 2018. The causative agents are Plasmodium parasites, among which P. falciparum (Pf) is the most virulent and common for human infection. The main challenge of the fight against malaria is the parasite resistance to antimalarial medicines. Despite the World Health Organization recommendations for preventing and reducing this risk with artemisinin-based combination therapy, more and more parasites are emerging with both decreased sensibility to artemisinin derivatives and resistance to the partner drug. Mefloquine (MQ) and lumefantrine (LM) are one of the most used partners with artesunate and artemether respectively. However, genic mutations or overexpression of efflux pumps in Pf are responsible of their decreased antimalarial efficacy. Thus, covalent conjugation of their respective structure with efflux pump inhibitors (EPI) or reversal agents can allow to struggle resistant parasites.

Our laboratory has previously developed an asymmetric synthesis to prepare 4-aminoalcohol-quinoline and -fluorene as enantiopure MQ and LM analogs. Some of them were active on nanomolar range against Pf3D7 (chloroquine-sensitive) and PfW2 (chloroquine-resistant) with a good selectivity index. Interestingly, eudysmic ratio was often observed between the enantiomers. Follow this previous work, we are focus on conjugation of EPI patterns to develop new classes of 4-aminoalcohol-quinolines and -fluorenes as enantiopure hybrid compounds able to limit the resistance with efflux transporters. The design of these hybrids will be discussed and described. First results concerning their biological activity against Pf3D7 and PfW2 and their cytotoxicity will be debated.