Endochin Optimization: Structure−Activity and Structure−Property Relationship Studies of 3-Substituted 2-Methyl-4(1H)-quinolones with Antimalarial Activity
| Autor: | Dennis E. Kyle, Roman Manetsch, Andrii Monastyrskyi, Jeremy N. Burrows, R. Matthew Cross, Tina S. Mutka |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Erythrocytes
medicine.drug_class Stereochemistry Plasmodium falciparum Drug Resistance Stereoisomerism In Vitro Techniques Quinolones Permeability Antimalarials Structure-Activity Relationship Drug Stability Parasitic Sensitivity Tests Drug Discovery medicine Humans Structure–activity relationship Atovaquone biology Chemistry Biological activity biology.organism_classification Quinolone In vitro Multiple drug resistance Solubility Hydroxyquinolines Microsomes Liver Molecular Medicine medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 53:7076-7094 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of multidrug resistant W2 and TM90-C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy-4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|