Antimalarial benzoheterocyclic 4-aminoquinolines : structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3247108
Author(s) Ongarora, Dennis S. B.; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J.; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M.; Chibale, Kelly
Author(s) at UniBasel Wittlin, Sergio
Year 2015
Title Antimalarial benzoheterocyclic 4-aminoquinolines : structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies
Journal Bioorganic & medicinal chemistry
Volume 23
Number 17
Pages / Article-Number 5419-32
Keywords Amodiaquine, Benzoxazole, Antiplasmodial activity, Antimalarial activity, Malaria, Reactive metabolite, 4-Aminoquinolines, Bioactivation, Structure-activity relationship, beta-Haematin, Quinone imine
Abstract A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.
Publisher Elsevier
ISSN/ISBN 0968-0896
edoc-URL http://edoc.unibas.ch/dok/A6438875
Full Text on edoc Available
Digital Object Identifier DOI 10.1016/j.bmc.2015.07.051
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/26264839
ISI-Number WOS:000360349900019
Document type (ISI) Journal Article
 
   

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