FR-900098, an antimalarial development candidate that inhibits the non-mevalonate isoprenoid biosynthesis pathway, shows no evidence of acute toxicity and genotoxicity
| Autor: | Hassan Jomaa, Armin Reichenberg, Martin Schlitzer, Martin Hintz, Andreas Vilcinskas, Jochen Wiesner, Christina Ziemann, Regina Ortmann, Nina Timmesfeld, Rainer Fuhst |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Male Salmonella typhimurium Erythrocytes plasmodium falciparum 030106 microbiology Immunology malaria Pharmacology Biology Gene mutation acute toxicity medicine.disease_cause Microbiology Ames test 03 medical and health sciences Antimalarials Mice Fosfomycin Drug Discovery medicine Animals chemistry.chemical_classification ames test Mutagenicity Tests genotoxicity Fosmidomycin drug development In vitro Acute toxicity Rats FR-900098 micronucleus test 030104 developmental biology Infectious Diseases Enzyme chemistry Toxicity Parasitology Administration Intravenous Genotoxicity Mouse lymphoma assay medicine.drug Research Paper DNA Damage |
| Zdroj: | Virulence |
| Popis: | FR-900098 is an inhibitor of 1-deoxy-d-xylulose-5-phosphate (DXP) reductoisomerase, the second enzyme in the non-mevalonate isoprenoid biosynthesis pathway. In previous studies, FR-900098 was shown to possess potent antimalarial activity in vitro and in a murine malaria model. In order to provide a basis for further preclinical and clinical development, we studied the acute toxicity and genotoxicity of FR-900098. We observed no acute toxicity in rats, i.e. there were no clinical signs of toxicity and no substance-related deaths after the administration of a single dose of 3000 mg/kg body weight orally or 400 mg/kg body weight intravenously. No mutagenic potential was detected in the Salmonella typhimurium reverse mutation assay (Ames test) or an in vitro mammalian cell gene mutation test using mouse lymphoma L5178Y/TK+/− cells (clone 3.7.2C), both with and without metabolic activation. In addition, FR-900098 demonstrated no clastogenic or aneugenic capability or significant adverse effects on blood formation in an in vivo micronucleus test with bone marrow erythrocytes from NMRI mice. We conclude that FR-900098 lacks acute toxicity and genotoxicity, supporting its further development as an antimalarial drug. |
| Databáze: | OpenAIRE |
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