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Imidazolopiperazines: hit to lead optimization of new antimalarial agents
- Source :
- Journal of medicinal chemistry. 54(14)
- Publication Year :
- 2011
-
Abstract
- [Image: see text] Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.
- Subjects :
- Plasmodium berghei
Plasmodium falciparum
Drug Resistance
Parasitemia
Pharmacology
Piperazines
Cell Line
chemistry.chemical_compound
Antimalarials
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
In vivo
Drug Discovery
parasitic diseases
medicine
Benzene Derivatives
Potency
Animals
Humans
Amino Acids
Mice, Inbred BALB C
Aniline Compounds
biology
Chemistry
Imidazoles
Hit to lead
medicine.disease
biology.organism_classification
Malaria
Rats
Drug development
Molecular Medicine
Female
Lead compound
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 54
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....38d868962b7620c4673d34cdecd094cd