Synthesis and antiplasmodial activity of novel Fosmidomycin derivatives and conjugates with Artemisinin and Aminochloroquinoline

Despina Palla (1) , Antonia Antoniou (1) , Michel Baltas (2, 3) , Christophe Menendez (2, 3) , Philippe Grellier (4) , Mouray Elisabeth (4) , Constantinos Athanassopoulos (1)

1 University of Patras
2 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
3 LCC - Laboratoire de chimie de coordination
4 MCAM - Molécules de Communication et Adaptation des Micro-organismes

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

Mots clés: fosmidomycin; chloroquine; artemisinin; hybrid; conjugates; antimalarial activity

Domaines: Chimie thérapeutique; Maladies infectieuses

Despina Palla, Antonia Antoniou, Michel Baltas, Christophe Menendez, Philippe Grellier, et al.. Synthesis and antiplasmodial activity of novel Fosmidomycin derivatives and conjugates with Artemisinin and Aminochloroquinoline. Molecules, 2020, 25 (20), pp.4858. ⟨10.3390/molecules25204858⟩. ⟨hal-02967532⟩