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Structure-activity relationship and in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of N-aryl 3-trifluoromethyl pyrido[1,2-a]benzimidazoles that are efficacious in a mouse model of Schistosomiasis

Mayoka, Godfrey and Keiser, Jennifer and Häberli, Cécile and Chibale, Kelly. (2019) Structure-activity relationship and in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of N-aryl 3-trifluoromethyl pyrido[1,2-a]benzimidazoles that are efficacious in a mouse model of Schistosomiasis. ACS infectious diseases, 5 (3). pp. 418-429.

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Official URL: https://edoc.unibas.ch/69813/

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Abstract

We have previously reported on the antischistosomal activity of pyrido[1,2- a]benzimidazole (PBI) derivatives. As a follow-up, we designed and prosecuted further structure-activity relationship (SAR) studies that incorporate N-aryl substitutions on the PBI scaffold. Investigations into the in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms revealed several leads with promising potency. Active compounds with a good cytotoxicity profile were tested in vivo whereby 6 and 44 induced noteworthy reduction (62-69%) in the worm load in the Schistosoma mansoni mouse model. Pharmacokinetic analysis on 44 pointed to slow absorption, low volume of distribution, and low plasma clearance indicating the potential of these compounds to achieve a long duration of action. Overall, our work demonstrates that PBI chemotype is a promising scaffold in the discovery of new antischistosomal leads.
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 > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer and Häberli, Cécile
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 12:58
Deposited On:18 Mar 2019 12:58

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