|
|||||
|
|
Substituted Aminoacetamides as Novel Leads for Malaria Treatment |
|
| Authors: | Neil R Norcross Caroline Wilson Beatriz Baragaña Irene Hallyburton Maria Osuna-Cabello Suzanne Norval Jennifer Riley Daniel Fletcher Robert Sinden Michael Delves Andrea Ruecker Sandra Duffy Stephan Meister Yevgeniya Antonova-Koch Benigno Crespo Cristina de?Cózar Laura M Sanz Francisco Javier Gamo Vicky M Avery Julie A Frearson David W Gray Alan H Fairlamb Elizabeth A Winzeler David Waterson Simon F Campbell Paul A Willis Kevin D Read Ian H Gilbert |
| Affiliation: | 1. Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1?5EH UK;2. Imperial College, South Kensington, London, SW7?2AZ UK;3. Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, 4111 Australia;4. Department of Pediatrics, University of California San Diego School of Medicine, 9500 Gilman Drive 0741, La?Jolla, CA, 92093 USA;5. GlaxoSmithKline, Diseases of the Developing World – Tres Cantos Medicines Development Campus, c/ Severo Ochoa 2, Tres Cantos, 28760 Madrid, Spain;6. Medicines for Malaria Venture, International Centre, Cointrin, Entrance G, 3rd Floor, Route de Pré-Bois 20, PO Box 1826, Geneva, 1215 Switzerland |
| Abstract: | Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28 ) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm . Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification. |
| Keywords: | aminoacetamides antimalarial agents hit optimization malaria Plasmodium falciparum |