Antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains inhibit microtubule and hemozoin formation : structure–activity relationship and in vivo oral efficacy studies

dc.contributor.authorDziwornu, Godwin Akpeko
dc.contributor.authorCoertzen, Dina
dc.contributor.authorLeshabane, Meta Kgaogelo
dc.contributor.authorKorkor, Constance M.
dc.contributor.authorCloete, Cleavon K.
dc.contributor.authorNjoroge, Mathew
dc.contributor.authorGibhard, Liezl
dc.contributor.authorLawrence, Nina
dc.contributor.authorReader, Janette
dc.contributor.authorVan der Watt, Mariette Elizabeth
dc.contributor.authorWittlin, Sergio
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.authorChibale, Kelly
dc.date.accessioned2021-07-21T13:40:25Z
dc.date.issued2021-04
dc.description.abstractA novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure–activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.en_ZA
dc.description.departmentBiochemistryen_ZA
dc.description.departmentGeneticsen_ZA
dc.description.departmentMicrobiology and Plant Pathologyen_ZA
dc.description.departmentUP Centre for Sustainable Malaria Control (UP CSMC)en_ZA
dc.description.embargo2022-04-12
dc.description.librarianhj2021en_ZA
dc.description.sponsorshipThe University of Cape Town, South African Medical Research Council and South African Research Chairs Initiative of the Department of Science and Innovation, administered through the South African National Research Foundation (NRF) and a NRF Community of Practice on ‘Evaluating Malaria Control Interventions’.en_ZA
dc.description.urihttp://pubs.acs.org/loi/jmcmaren_ZA
dc.identifier.citationDziwornu G.A., Coertzen D., Leshabane M. et al. 2021, 'Antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains inhibit microtubule and hemozoin formation : structure–activity relationship and in vivo oral efficacy studies', Journal of Medicinal Chemistry, vol. 64, no. 8, pp. 5198-5215.en_ZA
dc.identifier.issn0022-2623 (print)
dc.identifier.issn1520-4804 (online)
dc.identifier.other10.1021/acs.jmedchem.1c00354
dc.identifier.urihttp://hdl.handle.net/2263/80929
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, © 2020 American Chemical Society after peer review and technical editing by the publisher.en_ZA
dc.subjectAntiplasmodiumen_ZA
dc.subjectAntimalarialsen_ZA
dc.subjectGametocytesen_ZA
dc.subjectBenzimidazoleen_ZA
dc.subjectPhenolic Mannich basesen_ZA
dc.subjectHemozoinen_ZA
dc.subjectMicrotubulesen_ZA
dc.titleAntimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains inhibit microtubule and hemozoin formation : structure–activity relationship and in vivo oral efficacy studiesen_ZA
dc.typePostprint Articleen_ZA

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