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

Structure–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.Supplement 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 stringsThe University of Cape Town (UCT), South African Medical Research Council, and South African Research Chairs Initiative of the Department of Science and Technology, administered through the South African National Research Foundation are gratefully acknowledged for support (K.C. and L.B. UID84627). At Swiss TPH, we thank Christoph Fischli, Sibylle Sax, Christian Scheurer and Ursula Lehmann for assistance in performing the antimalarial assays. At UCT, we thank Dr. Dale Taylor for running cytotoxicity assays and Trevor Finch for assistance with the animal work. At UP, we thank Sindisiwe Nondaba for assistance in performing the gametocyte assays.http://pubs.acs.org/loi/jmcmar2019-12-18hj2019BiochemistryGeneticsMicrobiology and Plant Patholog