Studies of Potency and Efficacy of an Optimized Artemisinin-Quinoline Hybrid against Multiple Stages of the Plasmodium Life Cycle

Abstract

A recently developed artemisinin-quinoline hybrid, named 163A, has been shown to display potent activity against the asexual blood stage of Plasmodium, the malaria parasite. In this study, we determined its in vitro cytotoxicity to mammalian cells, its potency to suppress P. berghei hepatic infection and to decrease the viability of P. falciparum gametocytes, in addition to determining whether the drug exhibits efficacy of a P. berghei infection in mice. This hybrid compound has a low level of cytotoxicity to mammalian cells and, conversely, a high level of selectivity. It is potent in the prevention of hepatic stage development as well as in killing gametocytes, denoting a potential blockage of malaria transmission. The hybrid presents a potent inhibitory activity for beta-hematin crystal formation, in which subsequent assays revealed that its endoperoxide component undergoes bioactivation by reductive reaction with ferrous heme towards the formation of heme-drug adducts; in parallel, the 7-chloroquinoline component has binding affinity for ferric hemin. Both structural components of the hybrid co-operate to enhance the inhibition of beta-hematin, and this bitopic ligand property is essential for arresting the growth of asexual blood parasites. We demonstrated the in vivo efficacy of the hybrid as an erythrocytic schizonticide agent in comparison to a chloroquine/artemisinin combination therapy. Collectively, the findings suggest that the bitopic property of the hybrid is highly operative on heme detoxification suppression, and this provides compelling evidence for explaining the action of the hybrid on the asexual blood stage. For sporozoite and gametocyte stages, the hybrid conserves the potency typically observed for endoperoxide drugs, and this is possibly achieved due to the redox chemistry of endoperoxide components with ferrous heme.

The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs

“…Bioavailability of heme in these parasite stages has been less studied [55,56], and susceptibility of these parasites to artemisinin treatment can vary [68,86]. For instance, the asexual blood stages and the young gametocytes are quite susceptible to dihydroartemisinin by typically displaying IC 50 values in a low nanomolar range; this contrasts with mature gametocytes, which are approximately two hundred times less susceptible to dihydroartemisinin treatment [87]. This is intriguing, especially considering that the mature gametocytes are quite susceptible to methylene blue, a drug whose mechanism of action is attributed to oxidative stress and a redox imbalance [88], resembling the mechanisms of artemisinins.…”

The antimalarial activity of 1,2,4‐trioxolane/trioxane hybrids and dimers: A review

“…Among them, hybrid 25a (IC 50 : 0.56 mM) inhibited β-hematin formation with potency as high as that of chloroquine (IC 50 : 0.89 mM) and 1,2,4-trioxane fragment induced bioactivation by reductive reaction with ferrous heme during the formation of heme-drug adducts. [44,45] Moreover, hybrid 25a was potent in the prevention of hepatic stage development as well as in killing gametocytes, indicating a potential blockage of malaria transmission. [45] In the P. berghei-infected mice model, hybrid 25a (65 mg/kg, subcutaneous administration) could cure all mice with >41 median survival days and confer 100% animal survival.…”

“…[44,45] Moreover, hybrid 25a was potent in the prevention of hepatic stage development as well as in killing gametocytes, indicating a potential blockage of malaria transmission. [45] In the P. berghei-infected mice model, hybrid 25a (65 mg/kg, subcutaneous administration) could cure all mice with >41 median survival days and confer 100% animal survival. Moreover, hybrid 25a had reduced parasitemia by 56.1% and impaired hemozoin formation by 71.9%, while artesunic acid was only half as effective as hybrid 25a in reducing parasitemia (25.9%).…”

“…Additionally, hybrid 25a possessed in vivo synergistic effect with artesunic acid. [ 45 ] Collectively, hybrid 25a was considered as a forward‐looking and promising candidate for further preclinical evaluations in the treatment of malaria.…”

PfMDR1 Transport Rates Assessed in Intact Isolated Plasmodium falciparum Digestive Vacuoles Reflect Functional Drug Resistance Relationship with pfmdr1 Mutations

“…Treatment options have become difficult, and new drug development is essential and requires testing in appropriate preclinical assays. An example for potential new generation compounds would be the formation of drug-hybrids to prevent fast resistance development [2,3]. Most common assays currently employ in vitro parasite growth assays and focus on the global readout of parasitic proliferation in infected red blood cells (iRBC) by detection of DNA [4] or metabolic activity [5].…”