Antimalarial pyrido[1,2-a]benzimidazole derivatives with mannich base side chains: synthesis, pharmacological evaluation and reactive metabolite trapping studies
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4500098
Author(s) Okombo, John; Brunschwig, Christel; Singh, Kawaljit; Dziwornu, Godwin Akpeko; Barnard, Linley; Njoroge, Mathew; Wittlin, Sergio; Chibale, Kelly
Author(s) at UniBasel Wittlin, Sergio
Year 2019
Title Antimalarial pyrido[1,2-a]benzimidazole derivatives with mannich base side chains: synthesis, pharmacological evaluation and reactive metabolite trapping studies
Journal ACS infectious diseases
Volume 5
Number 3
Pages / Article-Number 372-384
Abstract A novel series of pyrido[1,2- a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum ( P. falciparum) strains. Rapid metabolism was observed for all the analogues with <40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered.
Publisher ACS Publications
ISSN/ISBN 2373-8227
edoc-URL https://edoc.unibas.ch/69818/
Full Text on edoc No
Digital Object Identifier DOI 10.1021/acsinfecdis.8b00279
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/30608648
 
   

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