Mayoka, GodfreyNjoroge, MathewOkombo, JohnGibhard, LiezlSanches-Vaz, MargaridaFontinha, DianaBirkholtz, Lyn-MarieReader, JanetteVan der Watt, Mariette ElizabethCoetzer, Theresa L.Lauterbach, Sonja B.Churchyard, AlisjeBezuidenhout, Belinda C.Egan, Timothy J.Yeates, Clive LeonardWittlin, SergioPrudêncio, MiguelChibale, Kelly2019-01-222019Mayoka, G., Njoroge, M., Okombo, J. et al. 2019, 'Structure-activity relationship studies and Plasmodium life cycle profiling identifies pan-active N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles which are efficacious in an in vivo mouse model of malaria', Journal of Medicinal Chemistry, NYP.0022-2623 (print)1520-4804 (online)10.1021/acs.jmedchem.8b01769http://hdl.handle.net/2263/68202Supplement 1 : Additional details of the characterization of selected compounds and the procedures used for the in vitro and in vivo antimalarial and ADME studies as well as PK studies.Supplement 2 : Molecular formula stringsStructure–activity relationship studies involving N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles (PBI) identified several compounds possessing potent in vitro activities against the asexual blood, liver, and gametocyte stages of the Plasmodium parasite with no cross-resistance to chloroquine. Frontrunner lead compounds with good in vitro absorption, distribution, metabolism, and excretion (ADME) profiles were subjected to in vivo proof-of-concept studies in NMRI mice harboring the rodent P. berghei infection. This led to the identification of compounds 10 and 49, effecting 98% and 99.93% reduction in parasitemia with mean survival days of 12 and 14, respectively, at an oral dose of 4 × 50 mg/kg. In vivo pharmacokinetics studies on 10 revealed slow absorption, low volume of distribution, and low clearance profiles. Furthermore, this series displayed a low propensity to inhibit the human ether-a-go-go-related gene (hERG) potassium ion channel whose inhibition is associated with cardiotoxicity.enThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, © 2018 American Chemical Society after peer review and technical editing by the publisher.Structure–activity relationshipPlasmodium life cycleProfilingN-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazolesIn vivoMalariaPostprint Article