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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
- Source :
- Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2016, 60 (9), pp.5146-5158. ⟨10.1128/AAC.02975-15⟩, Antimicrobial Agents and Chemotherapy, 2016, 60 (9), pp.5146-5158. ⟨10.1128/AAC.02975-15⟩
- Publication Year :
- 2016
- Publisher :
- American Society for Microbiology, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Drug
Erythrocytes
media_common.quotation_subject
030106 microbiology
Plasmodium falciparum
Drug Resistance
Drug resistance
Pharmacology
Gametogenesis
03 medical and health sciences
chemistry.chemical_compound
Antimalarials
Inhibitory Concentration 50
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Gametocyte
medicine
Humans
Pharmacology (medical)
Drug Interactions
Antimalarial Agent
Atovaquone
media_common
Life Cycle Stages
biology
Chemistry
medicine.disease
biology.organism_classification
Artemisinins
3. Good health
Methylene Blue
Infectious Diseases
Susceptibility
Lead compound
Malaria
medicine.drug
Naphthoquinones
Subjects
Details
- Language :
- English
- ISSN :
- 00664804 and 10986596
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2016, 60 (9), pp.5146-5158. ⟨10.1128/AAC.02975-15⟩, Antimicrobial Agents and Chemotherapy, 2016, 60 (9), pp.5146-5158. ⟨10.1128/AAC.02975-15⟩
- Accession number :
- edsair.doi.dedup.....bcec4db27ad577dcbb3fadd95081caaa