ArticleAntimicrobial agents and chemotherapy2016
Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 74 citations in OpenAlex.
- The ZN domain acts as a dynamic switch coordinating multiple-step aminoacylation in bacterial leucyl-tRNA synthetase.Nucleic acids research · 2026Article
- Structure-Guided Optimization of Novel Inhibitors ofJournal of medicinal chemistry · 2026Article
- A Novel Class of Orally Bioavailable Phenylglycine-Benzoxaborole Conjugates with Antimalarial Activity and Potentially Novel Mechanism of Action.ACS medicinal chemistry letters · 2026Article
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- Quinoline conjugates for enhanced antimalarial activity: a review on synthesis by molecular hybridization and structure-activity relationship (SAR) investigation.American journal of translational research · 2025Review
- New antibacterial candidates against Acinetobacter baumannii discovered by in silico-driven chemogenomics repurposing.PloS one · 2024Article
- Antimalarial drug discovery: progress and approaches.Nature reviews. Drug discovery · 2023Review
- Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline.Microbiology spectrum · 2023Article
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- Aminoacyl tRNA Synthetases: Implications of Structural Biology in Drug Development against Trypanosomatid Parasites.ACS omega · 2023Review
- Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target.Science translational medicine · 2023Article
- Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis.PLoS pathogens · 2023Article
- Adenosine-Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase.Journal of the American Chemical Society · 2023Article
- Access to Unexplored 3D Chemical Space: cis-Selective Arene Hydrogenation for the Synthesis of Saturated Cyclic Boronic Acids.Angewandte Chemie (International ed. in English) · 2022Article
- The Boron Advantage: The Evolution and Diversification of Boron's Applications in Medicinal Chemistry.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Recent developments in the medicinal chemistry of single boron atom-containing compounds.Acta pharmaceutica Sinica. B · 2021Review
- Structural analyses of the malaria parasite aminoacyl-tRNA synthetases provide new avenues for antimalarial drug discovery.Protein science : a publication of the Protein Society · 2021Review
- Organoboron Compounds: Effective Antibacterial and Antiparasitic Agents.Molecules (Basel, Switzerland) · 2021Review
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.
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