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

dc.contributor.authorMayoka, Godfrey
dc.contributor.authorNjoroge, Mathew
dc.contributor.authorOkombo, John
dc.contributor.authorGibhard, Liezl
dc.contributor.authorSanches-Vaz, Margarida
dc.contributor.authorFontinha, Diana
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.authorReader, Janette
dc.contributor.authorVan der Watt, Mariette Elizabeth
dc.contributor.authorCoetzer, Theresa L.
dc.contributor.authorLauterbach, Sonja B.
dc.contributor.authorChurchyard, Alisje
dc.contributor.authorBezuidenhout, Belinda C.
dc.contributor.authorEgan, Timothy J.
dc.contributor.authorYeates, Clive Leonard
dc.contributor.authorWittlin, Sergio
dc.contributor.authorPrudêncio, Miguel
dc.contributor.authorChibale, Kelly
dc.date.accessioned2019-01-22T10:16:02Z
dc.date.issued2019
dc.descriptionSupplement 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.en_ZA
dc.descriptionSupplement 2 : Molecular formula stringsen_ZA
dc.description.abstractStructure–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.en_ZA
dc.description.departmentBiochemistryen_ZA
dc.description.departmentGeneticsen_ZA
dc.description.departmentMicrobiology and Plant Pathologyen_ZA
dc.description.embargo2019-12-18
dc.description.librarianhj2019en_ZA
dc.description.sponsorshipThe 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.en_ZA
dc.description.urihttp://pubs.acs.org/loi/jmcmaren_ZA
dc.identifier.citationMayoka, 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.en_ZA
dc.identifier.issn0022-2623 (print)
dc.identifier.issn1520-4804 (online)
dc.identifier.other10.1021/acs.jmedchem.8b01769
dc.identifier.urihttp://hdl.handle.net/2263/68202
dc.language.isoenen_ZA
dc.publisherAmerican Chemical Societyen_ZA
dc.rightsThis 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.en_ZA
dc.subjectStructure–activity relationshipen_ZA
dc.subjectPlasmodium life cycleen_ZA
dc.subjectProfilingen_ZA
dc.subjectN-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazolesen_ZA
dc.subjectIn vivoen_ZA
dc.subjectMalariaen_ZA
dc.titleStructure-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 malariaen_ZA
dc.typePostprint Articleen_ZA

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