Synthesis and biological evaluation of 1,4-naphthoquinones and quinoline-5,8-diones as antimalarial and schistosomicidal agents

Lanfranchi, Don Antoine; Rodo, Elena Cesar; Bertrand, Benoît; Huang, Hsin‐Hung; Day, L. A.; Johann, Laure; Elhabiri, Mourad; Becker, Katja; Williams, David L.; Davioud‐Charvet, Elisabeth

doi:10.1039/c2ob25812a

Cited by 53 publications

(40 citation statements)

References 94 publications

(105 reference statements)

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“…The generation of analogues needs to be approached by total synthesis of 1,4-naphthoquinones substituted at the phenyl ring of the menadione core, thus requiring complete regiocontrol of the chemical reactions. Efficient synthetic methodologies have been established (4,5) and will allow preparation of a large array of diverse benzylmenadiones for further structureactivity relationship investigations. Already developed chemoinformatic tools are available for predicting the redox potentials of polysubstituted menadiones (6,7).…”

Section: Discussionmentioning

confidence: 99%

“…The synthesis of plasmodione is achieved in only one step from cheap commercially available starting materials, and its low-molecular-weight structure provides a large chemical space for optimization by derivatization (3). Its structure served as a starting point for development of chemical optimization strategies aimed at generating benzylmenadione derivatives with superior pharmacokinetic or pharmacodynamic properties (4)(5)(6)(7).…”

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confidence: 99%

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

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Antimicrob Agents Chemother

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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...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Ehrhardt

Deregnaucourt

Goetz

et al. 2016

Antimicrob Agents Chemother

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“…The flavoprotein-catalyzed redox cycling of quinones in cells would, therefore, quickly lead to conditions of oxidative stress due to excess of the superoxide radical. These oxygen intermediates or reactive oxygen species (ROS) may react directly with DNA or other biomolecules such as proteins and lipids, which leads to cell damage [21][22][23][24]. In in vivo, the flavoprotein NAD(P)H which is a quinone-acceptor oxidoreductase, catalyzes the two-electron reduction of quinones to hydroquinones without the formation of semiquinone radical intermediates, whereas NADPH-cytochrome P-450 reductase and NADH-ubiquinone oxidoreductase catalyze the one-electron reduction of quinones to semiquinone radicals.…”

Section: Mechanism Of Biological Activitymentioning

confidence: 99%

Synthesis and characterization of n-alkylamino derivatives of vitamin K3: Molecular structure of 2-propylamino-3-methyl-1,4-naphthoquinone and antibacterial activities

Chadar

Camilles

Patil

et al. 2015

Journal of Molecular Structure

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“…The cycloaddition step is followed by aromatization of the originally formed tetrahydroquinolinedione 35 to give the corresponding quinoline quinone 36 via elimination of HBr and dimethylamine molecules (Scheme 16). 79 …”

Section: Scheme 12mentioning

confidence: 99%

Hydrazones as substrates for cycloaddition reactions

Belskaya¹,

Eliseeva²,

Бакулев³

2015

Russ. Chem. Rev.

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Synthesis and biological evaluation of 1,4-naphthoquinones and quinoline-5,8-diones as antimalarial and schistosomicidal agents

Cited by 53 publications

References 94 publications

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

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

Synthesis and characterization of n-alkylamino derivatives of vitamin K3: Molecular structure of 2-propylamino-3-methyl-1,4-naphthoquinone and antibacterial activities

Hydrazones as substrates for cycloaddition reactions

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