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

Dennis S B Ongarora; Natasha Strydom; Kathryn Wicht; Mathew Njoroge; Lubbe Wiesner; Timothy J Egan; Sergio Wittlin; Ulrik Jurva; Collen M Masimirembwa; Kelly Chibale

doi:10.1016/j.bmc.2015.07.051

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

Bioorg Med Chem. 2015 Sep 1;23(17):5419-32. doi: 10.1016/j.bmc.2015.07.051. Epub 2015 Jul 30.

Authors

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Department of Pharmaceutical Chemistry, University of Nairobi, Nairobi, Kenya.
² Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
³ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
⁴ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
⁵ Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland; University of Basel, Socinstrasse 57, 4002 Basel, Switzerland.
⁶ AstraZeneca R&D, Mölndal, Sweden.
⁷ African Institute of Biomedical Science and Technology, Zimbabwe.
⁸ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: [email protected].

PMID: 26264839
DOI: 10.1016/j.bmc.2015.07.051

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.

Keywords: 4-Aminoquinolines; Amodiaquine; Antimalarial activity; Antiplasmodial activity; Benzoxazole; Bioactivation; Malaria; Quinone imine; Reactive metabolite; Structure–activity relationship; β-Haematin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminoquinolines / chemistry*
Aminoquinolines / pharmacokinetics
Aminoquinolines / pharmacology
Aminoquinolines / therapeutic use*
Animals
Antimalarials / chemistry*
Antimalarials / pharmacokinetics
Antimalarials / pharmacology
Antimalarials / therapeutic use*
Benzene Derivatives / chemistry
Benzene Derivatives / pharmacokinetics
Benzene Derivatives / pharmacology
Benzene Derivatives / therapeutic use
Humans
Malaria / drug therapy*
Malaria, Falciparum / drug therapy
Mice
Mice, Inbred C57BL
Plasmodium berghei / drug effects*
Plasmodium falciparum / drug effects*
Structure-Activity Relationship

Substances

Aminoquinolines
Antimalarials
Benzene Derivatives
4-aminoquinoline