Enantiopure aminoaryl-alcohols with fluorene core to antimalarial activity

Malaria is a neglected tropical disease that remains a leading cause of morbidity and mortality among the world’s poorest populations. In 2015, 91 tropical and sub-tropical countries are endemic for this infectious disease. Pregnant women and children are the most sensitive to this infection and, in 2015, 429 000 people died. Among the five species of Plasmodium responsible for human malaria, P. falciparum is the parasite which causes the most serious form of the disease. More recent efforts focused on the development of antimalarial vaccines and since 2006, World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs). In drugs resistance areas, several antimalarial drugs, such as aminoaryl-alcohol (mefloquine (MQ), lumefantrine (LM)), are currently used in combination with artemisinin derivatives. However, the emergence of multi-drug-resistant parasites decreases efficacy of ACTs. Thus, the design of new active compounds on Plasmodium-resistant strains is urgently. We have previously developed an asymmetric synthesis to prepare 4-aminoquinoline-methanol enantiomers (AQM) as MQ analogs. They were active on nanomolar range against Pf3D7 (chloroquine-sensitive) and PfW2 (chloroquine-resistant) P. falciparum strains. Interestingly, (S)-enantiomers displayed an activity increased by 2 to 15-fold as compared to their (R)-counterparts. Currently their mechanisms of actions are not totally clear and remain to be explored. In continuation of our work, we are interested now to study the change of heterocycle (fluorene vs quinoline) on the antimalarial activity. We focus on the design and the preparation of novel asymmetric 2,4,7-trisusbtituted fluorenes, new aminofluorene-methanol derivatives (AFM) as LM analogs. The evaluation of their antiplasmodial activities against P. falciparum and their corresponding cytotoxicities proved the interest of this pharmacophore with activities on nanomolar range against Pf3D7 and PfW2. We will present here the access and the biological results on these AFMs.