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

  • J Med Chem. 2019 Jan 24;62(2):1022-1035. doi: 10.1021/acs.jmedchem.8b01769.
Godfrey Mayoka  1 ,  Mathew Njoroge  2 ,  John Okombo  1 ,  Liezl Gibhard  2 ,  Margarida Sanches-Vaz  3 ,  Diana Fontinha  3 ,  Lyn-Marie Birkholtz  4 ,  Janette Reader  4 ,  Mariëtte van der Watt  4 ,  Theresa L Coetzer  5 ,  Sonja Lauterbach  5 ,  Alisje Churchyard  5 ,  Belinda Bezuidenhout  5 ,  Timothy J Egan  1  6 ,  Clive Yeates  7 ,  Sergio Wittlin  8  9 ,  Miguel Prudêncio  3 ,  Kelly Chibale  1  10  6
Affiliations
  • 1. Department of Chemistry , University of Cape Town , Rondebosch 7701 , South Africa.
  • 2. Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine , University of Cape Town , Observatory , Cape Town 7925 , South Africa.
  • 3. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina , Universidade de Lisboa , Av. Prof. Egas Moniz , 1649-028 Lisbon , Portugal.
  • 4. Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control , University of Pretoria , Private Bag X20 , Hatfield 0028 , South Africa.
  • 5. Wits Research Institute for Malaria, Faculty of Health Sciences , University of the Witwatersrand and National Health Laboratory Service , Johannesburg 2193 , South Africa.
  • 6. Institute of Infectious Disease and Molecular Medicine , University of Cape Town , Rondebosch 7701 , South Africa.
  • 7. Inpharma Consultancy, 6 Dudley Hill Close , Welwyn , Hertfordshire AL60QQ , U.K.
  • 8. Department of Medical Parasitology and Infection Biology , Swiss Tropical and Public Health Institute , Basel , Switzerland.
  • 9. University of Basel , Basel , Switzerland.
  • 10. South African Medical Research Council, Drug Discovery and Development Research Unit , University of Cape Town , Rondebosch 7701 , South Africa.
PMID: 30562027 DOI: 10.1021/acs.jmedchem.8b01769
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.