title: Structure-Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines.
abstract: Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Diego
authors: D
authors: Gonzàlez Cabrera
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Frederic
authors: F
authors: Douelle
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Claire
authors: C
authors: Le Manach
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Ze
authors: Z
authors: Han
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Tanya
authors: T
authors: Paquet
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
authors: Dale
authors: D
authors: Taylor
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
authors: Mathew
authors: M
authors: Njoroge
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.
authors: Nina
authors: N
authors: Lawrence
authors: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory, Cape Town 7925, South Africa.|Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Lubbe
authors: L
authors: Wiesner
authors: Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors: David
authors: D
authors: Waterson
authors: Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.
authors: Michael J
authors: MJ
authors: Witty
authors: Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , 4002 Basel, Switzerland.
authors: Sergio
authors: S
authors: Wittlin
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Leslie J
authors: LJ
authors: Street
authors: Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.|Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.|South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town , Rondebosch, Cape Town 7701, South Africa.
authors: Kelly
authors: K
authors: Chibale
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004351:Drug Resistance; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D051638:Ether-A-Go-Go Potassium Channels; D011743:Pyrimidines