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
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Date
Authors
Mayoka, Godfrey
Njoroge, Mathew
Okombo, John
Gibhard, Liezl
Sanches-Vaz, Margarida
Fontinha, Diana
Birkholtz, Lyn-Marie
Reader, Janette
Van der Watt, Mariette Elizabeth
Coetzer, Theresa L.
Journal Title
Journal ISSN
Volume Title
Publisher
American Chemical Society
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 4 × 50 mg/kg. In vivo pharmacokinetics studies on 10 revealed slow absorption, low volume of distribution, and low clearance profiles. Furthermore, this series displayed a low propensity to inhibit the human ether-a-go-go-related gene (hERG) potassium ion channel whose inhibition is associated with cardiotoxicity.
Description
Supplement 1 : Additional details of the characterization of selected compounds and the procedures used for the in vitro and in vivo antimalarial and ADME studies as well as PK studies.
Supplement 2 : Molecular formula strings
Supplement 2 : Molecular formula strings
Keywords
Structure–activity relationship, Plasmodium life cycle, Profiling, N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles, In vivo, Malaria
Sustainable Development Goals
Citation
Mayoka, G., Njoroge, M., Okombo, J. et al. 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, NYP.