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Antimalarial pyrido[1,2-a]benzimidazole derivatives with mannich base side chains: synthesis, pharmacological evaluation and reactive metabolite trapping studies

Okombo, John and Brunschwig, Christel and Singh, Kawaljit and Dziwornu, Godwin Akpeko and Barnard, Linley and Njoroge, Mathew and Wittlin, Sergio and Chibale, Kelly. (2019) Antimalarial pyrido[1,2-a]benzimidazole derivatives with mannich base side chains: synthesis, pharmacological evaluation and reactive metabolite trapping studies. ACS infectious diseases, 5 (3). pp. 372-384.

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Official URL: https://edoc.unibas.ch/69818/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:ACS Publications
ISSN:2373-8227
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:18 Mar 2019 13:00
Deposited On:18 Mar 2019 13:00

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