Structure–Activity Relationship Studies of Pyrrolone Antimalarial Agents
| Autor: | Karen L. White, Paul G. Wyatt, Suzanne Norval, Marcel Kaiser, Ian H. Gilbert, Clive Yeates, Dinakaran Murugesan, Jennifer Riley, Susan A. Charman, Kevin D. Read |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Plasmodium falciparum
malaria Drug Resistance Drug resistance Biology Pharmacology 010402 general chemistry 01 natural sciences Biochemistry chemistry.chemical_compound Antimalarials Mice Structure-Activity Relationship Chloroquine Drug Discovery medicine Structure–activity relationship Animals Pyrroles Antimalarial Agent General Pharmacology Toxicology and Pharmaceutics 010405 organic chemistry Organic Chemistry Full Papers biology.organism_classification pyrrolones In vitro 0104 chemical sciences 3. Good health Pyrimethamine chemistry Microsomes Liver Molecular Medicine structure–activity relationships Piperidine antiprotozoal agents medicine.drug Half-Life |
| Zdroj: | Chemmedchem |
| ISSN: | 1860-7187 1860-7179 |
| Popis: | Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival. |
| Databáze: | OpenAIRE |
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