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Structure-activity relationship studies and Plasmodium life cycle profiling identifies pan-active N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles which are efficacious in an in vivo mouse model of malaria

Mayoka, Godfrey and Njoroge, Mathew and Okombo, John and Gibhard, Liezl and Sanches-Vaz, Margarida and Fontinha, Diana and Birkholtz, Lyn-Marie and Reader, Janette and van der Watt, Mariëtte and Coetzer, Theresa L. and Lauterbach, Sonja and Churchyard, Alisje and Bezuidenhout, Belinda and Egan, Timothy J. and Yeates, Clive Leonard and Wittlin, Sergio and Prudêncio, Miguel and Chibale, Kelly. (2019) Structure-activity relationship studies and Plasmodium life cycle profiling identifies pan-active N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles which are efficacious in an in vivo mouse model of malaria. Journal of medicinal chemistry, 62 (2). pp. 1022-1035.

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Official URL: https://edoc.unibas.ch/69812/

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Abstract

Structure-activity relationship studies involving N-aryl-3-trifluoromethyl pyrido[1,2-a] benzimidazoles (PBI) identified several compounds possessing potent in vitro activities against the asexual blood, liver and gametocyte stages of the Plasmodium parasite with no cross-resistance to chloroquine. Frontrunner lead compounds with good in vitro absorption, distribution, metabolism and excretion (ADME) profiles were subjected to in vivo proof-of-concept studies in NMRI mice harboring the rodent P. berghei infection. This led to the identification of compounds 10 and 49, effecting 98% and 99.93% reduction in parasitemia with mean survival days of 12 and 14, respectively, at an oral dose of 4x50 mg/kg. In vivo pharmacokinetics studies on 10 revealed slow absorption, low volume of distribution and low clearance profiles. Furthermore, this series displayed low propensity to inhibit the human ether-a-go-go-related gene (hERG) potassium ion channel whose inhibition is associated with cardiotoxicity.
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:American Chemical Society
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:18 Mar 2019 12:57
Deposited On:18 Mar 2019 12:57

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