2. Academic Validation
  3. Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents

Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents

  • Eur J Med Chem. 2016 Aug 25:119:231-49. doi: 10.1016/j.ejmech.2016.04.058.
Aicha Boudhar 1,  Xiao Wei Ng 2,  Chiew Yee Loh 2,  Wan Ni Chia 2,  Zhi Ming Tan 2,  Francois Nosten 3,  Brian W Dymock 4,  Kevin S W Tan 5
Affiliations

Affiliations

  • 1 Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore; Department of Pharmacy, National University of Singapore, Singapore.
  • 2 Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore.
  • 3 Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Headington, Oxford, United Kingdom.
  • 4 Department of Pharmacy, National University of Singapore, Singapore. Electronic address: phadbw@nus.edu.sg.
  • 5 Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore. Electronic address: mictank@nus.edu.sg.
PMID: 27173385 DOI: 10.1016/j.ejmech.2016.04.058
Abstract

Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies.

Keywords

Antimalarial; Artemisinin-resistant; Chemoreversal; Chemosensitiser; Chloroquine; Chloroquine-resistant.

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