ArticleThe Journal of antimicrobial chemotherapy2020
The relative rate of kill of the MMV Malaria Box compounds provides links to the mode of antimalarial action and highlights scaffolds of medicinal chemistry interest.
Article in The Journal of antimicrobial chemotherapy, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Cellular and molecular basis of PfCoronin function in artemisinin resistance in Plasmodium falciparum.Nature communications · 2026Article
- Novel Antiplasmodial Natural Products Identified Through a Modified Bioluminescence-Based Rate-of-Kill Assay.Biomedicines · 2026Article
- Identification of α-Azacyclic Acetamide-Based Inhibitors ofACS infectious diseases · 2025Article
- Accelerating Antimalarial Drug Discovery with a New High-Throughput Screen for Fast-Killing Compounds.ACS infectious diseases · 2024Article
- An adaptable, fit-for-purpose screening approach with high-throughput capability to determine speed of action and stage specificity of anti-malarial compounds.Antimicrobial agents and chemotherapy · 2024Article
- Fast-Killing Tyrosine Amide ((ACS infectious diseases · 2023Article
- Down the membrane hole: Ion channels in protozoan parasites.PLoS pathogens · 2022Review
- The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites.Traffic (Copenhagen, Denmark) · 2022Article
- Biotransformation of artemisinin to a novel derivative via ring rearrangement by Aspergillus niger.Applied microbiology and biotechnology · 2022Article
- Temperate Zone Plant Natural Products-A Novel Resource for Activity against Tropical Parasitic Diseases.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Rapid and quantitative antimalarial drug efficacy testing via the magneto-optical detection of hemozoin.Scientific reports · 2020Article
- An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box PromotesACS infectious diseases · 2020Article
- In Vitro Activities of MMV Malaria Box Compounds against the Apicomplexan ParasiteMolecules (Basel, Switzerland) · 2020Article
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Authors and funding
6 authors.
Funding
Abstract
objectivesRapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds is linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest.
methodsWe used a bioluminescence relative RoK (BRRoK) assay over 6 and 48 h, with exposure to equipotent IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds with those of benchmark antimalarials.
resultsBRRoK assay data demonstrate the following relative RoKs, from fast to slow: inhibitors of PfATP4>parasite haemoglobin catabolism>dihydrofolate reductase-thymidylate synthase (DHFR-TS)>dihydroorotate dehydrogenase (DHODH)>bc1 complex. Core-scaffold clustering analyses revealed intrinsic rapid cytocidal action for diamino-glycerols and 2-(aminomethyl)phenol, but slow action for 2-phenylbenz-imidazoles, 8-hydroxyquinolines and triazolopyrimidines.
conclusionsThis study provides proof of principle that a compound's RoK is related to its MoA and that the target's intrinsic RoK is also modified by factors affecting a drug's access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development campaigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates.
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