Synthesis, Antimalarial Activity, and Preclinical Pharmacology of a Novel Series of 4′-Fluoro and 4′-Chloro Analogues of Amodiaquine. Identification of a Suitable 'Back-Up' Compound for N-tert-Butyl Isoquine
| Autor: | Stephen Hindley, Paul M. O'Neill, Eghbaleh Asadollahy, Karen Rimmer, Alison E. Shone, Gemma L. Nixon, James L. Maggs, Stephen A. Ward, Richard A. Brigandi, Martin Bates, Patrick G. Bray, P. A. Winstanley, Paul A. Stocks, Jill Davies, Silvia Parapini, Livia Vivas, Domingo Gargallo, Stephanie L. Gresham, Hollie Lander, Giancarlo A. Biagini, B. Kevin Park, Donatella Taramelli, Ramesh Bambal, Federico M. Gomez-de-las-Heras, Charles B. Davis, Charlotte Hall, Neil G. Berry, Phil Roberts, Deborah Stanford |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cell Survival Plasmodium berghei Stereochemistry Plasmodium falciparum Drug Resistance Amodiaquine In Vitro Techniques Chemical synthesis Antimalarials Mice Structure-Activity Relationship Dogs Parasitic Sensitivity Tests In vivo Drug Discovery medicine Animals Humans Structure–activity relationship Rats Wistar ADME Chemistry Chloroquine Biological activity Haplorhini Plasmodium yoelii In vitro Malaria Rats Bioavailability Aminoquinolines Hepatocytes Molecular Medicine Female medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 52:1828-1844 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm8012757 |
| Popis: | On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile. |
| Databáze: | OpenAIRE |
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