New endoperoxides highly active in vivo and in vitro against artemisinin-resistant Plasmodium falciparum

Abstract

BackgroundThe emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs.MethodsA chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay.ResultsThe synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti-malarial activity (IC50 0.3–71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration.ConclusionThe investigated, trioxolane–tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra-erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2281-x) contains supplementary material, which is available to authorized users.

Synthesis and Antileishmanial Activity of 1,2,4,5-Tetraoxanes against Leishmania donovani

“…The structures of the 15 tetraoxanes assayed against intramacrophage amastigote forms of L. donovani differ only in the chemical nature of the cyclohexyl substituent (Table 1). From this library, only compounds L137 [40], LC140 [14], L153 [41], and LC163 [19] were previously reported in the context of antiparasitic chemotherapy (compound LC163 was disclosed by our group). For comparative purposes, we have also evaluated the activity of a small library of 1,2,4-trioxolanes and that of the known peroxide-based antiplasmodial drugs dihydroartemisinin (DHA) and artesunate (ATS) ( Table 1).…”

“…Among these, trioxolanes and tetraoxanes have shown activity against different parasites, such as the protozoans Plasmodium spp. [10][11][12][13][14][15][16][17][18][19], Perkinsus spp. [20], and the parasitic flatworms Schistosoma spp [21].…”

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

“…Artemisinin (structure (a), Figure 3), a sesquiterpene lactone that contains a peroxide bridge essential for its activity, is one of a very limited number of naturally occurring endoperoxides and was shown to inhibit chloroquine-resistant strains of Plasmodium falciparum parasites at low nanomolar concentrations [60], with efficacies comparable to those exhibited by chloroquine and mefloquine when tested against the corresponding sensitive strains. Artemisinin was initially used to treat malaria but limitations, such as low solubility in both water and oil, a short half-life, and its fast metabolization to dihydroartemisinin, DHA, (structure (b), Figure 3), which is neurotoxic, demanded for more soluble and less toxic semi-synthetic derivatives, commonly known as artemisinins [61][62][63]. Additionally, low yields, high production costs, and inefficacy against all strains of Plasmodium prompted the development of synthetic endoperoxides [62][63][64][65].…”

“…Artemisinin was initially used to treat malaria but limitations, such as low solubility in both water and oil, a short half-life, and its fast metabolization to dihydroartemisinin, DHA, (structure (b), Figure 3), which is neurotoxic, demanded for more soluble and less toxic semi-synthetic derivatives, commonly known as artemisinins [61][62][63]. Additionally, low yields, high production costs, and inefficacy against all strains of Plasmodium prompted the development of synthetic endoperoxides [62][63][64][65]. Nevertheless, artemisinin and some of its semi-synthetic derivatives, namely DHA, artemether, artesunate, and artelinate (represented as structures b, c, d, and e in Figure 3, respectively), when used in combination with other longer-lived antimalarials, provide the artemisinin-based combination therapy (ACT), which is used as frontline treatment for malaria [6].…”

“…as artemisinins [61][62][63]. Additionally, low yields, high production costs, and inefficacy against all strains of Plasmodium prompted the development of synthetic endoperoxides [62][63][64][65].…”