The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Abstract

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.M alaria remains one of the most severe infectious diseases that disproportionately affects the public health and economic welfare of the world's poorest communities. The causative agents of malaria are protozoan parasites of the genus Plasmodium. Among the five Plasmodium species that can cause malaria in humans (Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi), P. falciparum is the most virulent and is responsible for severe clinical outcomes and most of the deaths associated with malaria. Until the development of an effective vaccine, chemotherapy remains a major frontline strategy for the control and possible future elimination of malaria. The emergence and rapid spread of drug-resistant parasites undermine efforts at reducing the global disease burden and emphasize the need for drugs with novel chemical entities that exploit new molecular targets while overcoming established drug resistance mechanisms. Ideally, such drugs should quickly kill the pathogenic asexual blood stages of P. falciparum and, in addition, be effective against other developmental stages, in particular the sexual stages that transmit the infection from the human to the mosquito host (1, 2).Previously, we presented the chemical design and synthesis of a novel class of compounds, the 3-[substituted-benzyl]-menadiones, that exhibit potent activities against P. falciparum blood stages in vitro and moderate activities in v...

Cognitive Reflection, Decision Biases, and Response Times

“…Evidence from neuroscience points out that conflict detection and resolution occurs extremely early in decision making (see, e.g., Achtziger et al, 2014 ) and hence should have a moderate effect in response times of large magnitude. In Achtziger and Alós-Ferrer ( 2014 ), decisions where a reinforcement heuristic had been shut down were observed to be significantly slower (and error rates significantly lower) than decisions where the heuristic was active. On the basis of this evidence, we formulate the following hypothesis.…”

“…For instance, Achtziger and Alós-Ferrer ( 2014 ) study a paradigm where a reinforcement-based heuristic can conflict or be aligned with more rational decision making (optimization based on Bayesian updating of beliefs). The main predictions of the study (following the Dual-Process Diffusion Model, Alós-Ferrer, 2016 ) concern the relative speed of errors and correct responses for a given individual , i.e., a within-participant comparison.…”

Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes

“…Artemisinin or one of its synthetic derivatives constitutes the other major component of most anti-malaria therapies [7,8]. Although the mechanisms of action of ACTs (artemisinin combination therapies) are still debated [9,10], most hypotheses invoke involvement of redox reactions in their cytotoxicity, since (i) the essential moiety in all therapeutically active forms of artemisinin is its endoperoxide ring [11], (ii) other components of common ACTs promote the accumulation of oxidative heme [12], (iii) erythrocyte mutations that increase oxidative stress within the parasitized RBC confer partial protection against malaria [13][14][15][16][17][18][19] (e.g., sickle cell, β-thalassemia, G6PDH (Glucose-6-phosphate dehydrogenase) deficiency, etc., and (iv) many other oxidizing drugs were found to exhibit antimalarial activity [20,21]. Taken together, these observations suggest that oxidative stress can be detrimental to the parasite, probably by creating an environment that is harmful to parasite maturation, proliferation, or egress.…”

Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties

“…Recently, we synthesized a series of 3-benzylmenadione derivatives [ 3 , 4 ], which were identified as potent antimalarial redox-active agents. Among these, the 3-[4-(trifluoromethyl)benzyl]-menadione (called plasmodione, Figure 1 ) showed the most promising ‘early lead’ features for drug optimization [ 5 , 6 ]. Mechanistic studies revealed that plasmodione may enter a cascade of redox reactions for drug bioactivation: in its oxidized state, the menadione derivative was proposed to be reduced by the NADPH-dependent glutathione reductases of the Plasmodium -parasitized erythrocytes; in its reduced state, the hydronaphthoquinone was shown to transfer 1e − to methemoglobin (Fe III ) (metHb), the major nutrient of the parasite [ 3 , 4 , 7 ].…”