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Antimalarial benzoheterocyclic 4-aminoquinolines : structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies

Ongarora, Dennis S. B. and Strydom, Natasha and Wicht, Kathryn and Njoroge, Mathew and Wiesner, Lubbe and Egan, Timothy J. and Wittlin, Sergio and Jurva, Ulrik and Masimirembwa, Collen M. and Chibale, Kelly. (2015) Antimalarial benzoheterocyclic 4-aminoquinolines : structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies. Bioorganic & medicinal chemistry, 23 (17). pp. 5419-5432.

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Official URL: http://edoc.unibas.ch/dok/A6438875

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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.
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 > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0968-0896
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:03 Jan 2018 08:20
Deposited On:06 Nov 2015 10:21

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