Multistage antiplasmodium activity of astemizole analogues and inhibition of hemozoin formation as a contributor to their mode of action

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dc.contributor.author Kumar, Malkeet
dc.contributor.author Okombo, John
dc.contributor.author Mambwe, Dickson
dc.contributor.author Taylor, Dale
dc.contributor.author Lawrence, Nina
dc.contributor.author Reader, Janette
dc.contributor.author Van der Watt, M.E. (Mariette)
dc.contributor.author Fontinha, Diana
dc.contributor.author Sanches-Vaz, Margarida
dc.contributor.author Bezuidenhout, Belinda C.
dc.contributor.author Lauterbach, Sonja B.
dc.contributor.author Liebenberg, Dale
dc.contributor.author Birkholtz, Lyn-Marie
dc.contributor.author Coetzer, Theresa L.
dc.contributor.author Prudêncio, Miguel
dc.contributor.author Egan, Timothy J.
dc.contributor.author Wittlin, Sergio
dc.contributor.author Chibale, Kelly
dc.date.accessioned 2019-01-22T09:29:02Z
dc.date.issued 2019-02
dc.description Supplement 1 : Additional details of the structures of all derivatives assessed. en_ZA
dc.description Supplement 2 : Excel file with the compounds SMILES format en_ZA
dc.description.abstract A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver and gametocyte stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the seventeen derivatives showed IC50s < 0.1 µM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 (PfNF54) strain while maintaining submicromolar potency against the multidrug resistant strain, PfK1, with most showing low likelihood of cross-resistance with CQ. Selected analogues (PfNF54- IC50 < 0.1 µM) were tested for cytotoxicity on CHO cells and found to be highly selective (selectivity index > 100). The first ever gametocytes screening of AST and its analogues revealed their moderate activity (IC50: 1 - 5 µM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with three-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-haematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery. en_ZA
dc.description.department Music en_ZA
dc.description.embargo 2020-02-08
dc.description.librarian hj2019 en_ZA
dc.description.sponsorship The University of Cape Town (KC), South African Medical Research Council (KC, TJE, LMB and TLC), and South African Research Chairs Initiative of the Department of Science and Technology (KC: UID 64767 and LMB: UID84627), administered through the South African National Research Foundation. en_ZA
dc.description.uri https://pubs.acs.org/journal/aidcbc en_ZA
dc.identifier.citation Kumar, M., Okombo, J., Mambwe, D. et al. 2019, 'Multistage antiplasmodium activity of astemizole analogues and inhibition of hemozoin formation as a contributor to their mode of action', ACS Infectious Diseases, vol. 5, no. 2, pp. 303-315. en_ZA
dc.identifier.issn 2373-8227 (print)
dc.identifier.issn 2373-8227 (online)
dc.identifier.other 10.1021/acsinfecdis.8b00272
dc.identifier.uri http://hdl.handle.net/2263/68201
dc.language.iso en en_ZA
dc.publisher American Chemical Society en_ZA
dc.rights © 2018 American Chemical Society en_ZA
dc.subject Astemizole en_ZA
dc.subject Gametocytes en_ZA
dc.subject Plasmodium falciparum (Pf) en_ZA
dc.subject Repositioning en_ZA
dc.subject β-hematin en_ZA
dc.title Multistage antiplasmodium activity of astemizole analogues and inhibition of hemozoin formation as a contributor to their mode of action en_ZA
dc.type Postprint Article en_ZA


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