Novel Racemic and Enantiopure Amino-Fluorene-Methanol Coumponds with Antimalarial Activities

Malaria is a neglected tropical disease that remains a leading cause of morbidity and mortality among the world’s poorest populations. More than 100 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 2001, World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs). In drugs resistance areas, several antimalarial drugs, such as aminoalcohol-aryl (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 urgent. We have previously developed an asymmetric synthesis to prepare 4-aminoalcohol-quinoline enantiomers (AQ) as MQ analogs. They were active on nanomolar range against 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. Interestingly, (S)-enantiomers displayed an activity increased by 2 to 15-fold as compared to their (R)-counterparts. During the Plasmodium intra-erythrocytic asexual stages, hemozoin formation and the oxidative and glutathione-dependent degradation of heme are inhibited by these aminoalcohol-aryls (MQ, LM). Currently, their mechanisms of actions are not totally clear and remain to be explored. In continuation of our work, we are interested to study the change of heterocycle (fluorene vs quinoline) on the antimalarial activity. We focus on the design and the preparation of novel racemic and enantiopure aminoalcohol-fluorene derivatives (AFM) as LM analogs. The evaluation of their antiplasmodial activity against P. falciparum and their corresponding cytotoxicity is under progress.