Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

Abstract

Malaria is still considered as the major parasitic disease and the development of artemisinin resistance does not improve this alarming situation. Based on the recent identification of relevant malaria targets in the artemisinin resistance context, novel drug combinations were evaluated against artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites. Corresponding hybrid molecules were also synthesized and evaluated for comparison with combinations and individual pharmacophores (e.g. atovaquone, mefloquine or triclosan).Combinations and hybrids showed remarkable antimalarial activity (IC50 = 0.6 to 1.1 nM for the best compounds), strong selectivity, and didn't present any cross-resistance with artemisinin. Moreover, the combination triclosan + atovaquone showed high activity against artemisinin-resistant parasites at the quiescent stage but the corresponding hybrid lost this pharmacological property. This result is essential since only few molecules active against quiescent artemisinin-resistant parasites are reported. Our promising results highlight the potential of these combinations and paves the way for pharmacomodulation work on the best hybrids.

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

“…The esterification process of homologous MQ-36 resulted only in the deprotected product MQ-39 . Both the derivatives MQ-38 and MQ-39 turned out to be more active (IC 50 : 0.6–1.1 nM) against P. falciparum F32-TEM than the unmodified drugs MQ and atovaquone (IC 50 : 87 and 2 nM) [ 49 ].…”

“…Under these conditions, some transfer of acyl group from oxygen 11 to nitrogen 13 atom occurred, resulting in amidoester by-product MQ-42 [ 34 ]. This reaction did not occur in the synthesis of MQ-38 and MQ-39 [ 49 ].…”

Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs

“…Therefore, we designed prodrugs, combining in a single molecule an alkoxyamine and a peptide selective of parasite PLMs [ 16 ]. This strategy of hybrid molecules was previously found valuable [ 17 , 18 ]. In the present case, the approach was based on the release of a reactive and non-selective alkyl radical resulting from the homolysis of an alkoxyamine R 1 R 2 NOR 3 , itself triggered by specific enzymatic activities of parasite plasmepsins ( Scheme 1 ).…”

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis

“…The initial concept was that hybrid-based drugs could combine the antiplasmodial effects of its components (i.e., additivity or synergism) in a single molecule, facilitating the evaluation of pharmacokinetics, pharmaceutical formulation, and other aspects [7,8]. Among the concepts for designing hybrid-based drugs, there are three main possibilities: using non-cleavable chemical linkers [9,10], cleavable linkers (triggered by proteases or pH) [11,12] and transition metals that all play dual roles as cleavable chemical linkers and as antimalarials [13] (Figure 1). While all these possibilities have been investigated and have yielded promising results, the use of metals as chemical linkers offers the advantage of being pharmacologically active against parasites, while typically, organic chemical linkers are devoid of such effects.…”