Synthesis, Antimalarial Activity, and Preclinical Pharmacology of a Novel Series of 4′-Fluoro and 4′-Chloro Analogues of Amodiaquine
1828 J. Med. Chem. 2009, 52, 1828–1844 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 Paul M. O’Neill,*,†,‡ Alison E. Shone,‡ Deborah Stanford,† Gemma Nixon,† Eghbaleh Asadollahy,† B. Kevin Park,‡ James L. Maggs,‡ Phil Roberts,‡ Paul A. Stocks,† Giancarlo Biagini,§ Patrick G. Bray,§ Jill Davies,§ Neil Berry,† Charlotte Hall,§ Karen Rimmer,§ Peter A. Winstanley,‡ Stephen Hindley,† Ramesh B. Bambal,| Charles B. Davis,| Martin Bates,⊥ Stephanie L. Gresham,# Richard A. Brigandi,∇ Federico M. Gomez-de-las-Heras,O Domingo V. Gargallo,O Silvia Parapini,¶ Livia Vivas,[ Hollie Lander,[ Donatella Taramelli,¶ and Stephen A. Ward§ Department of Chemistry, UniVersity of LiVerpool, LiVerpool L69 7ZD, U.K., MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, School of Biomedical Sciences, UniVersity of LiVerpool, LiVerpool L69 3GE, U.K., LiVerpool School of Tropical Medicine, Pembroke Place, LiVerpool L3 5QA, U.K., Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Drug DiscoVery, 1250 South CollegeVille Road, CollegeVille, PennsylVania 19426, Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, SteVenage, Hertfordshire SG1 2NY, U.K., Safety Assessment, GlaxoSmithKline, The Frythe, Welwyn, Hertfordshire AL6 9AR, U.K., DiscoVery Medicine Infectious Diseases CEDD, DDW DPU, GlaxoSmithKline, Upper ProVidence, PennsylVania, GlaxoSmithKline, S.A., Parque Tecnolo´gico de Madrid, SeVero Ochoa, 2, 28760 Tres Cantos, Madrid, Spain, Dipartimento di Sanita` Pubblica, Microbiologia, Virologia, UniVersita` degli Studi di Milano, Via Pascal, 36, 20133 Milan, Italy, and Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K.
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