title: Overcoming chloroquine resistance in malaria: Design, synthesis and structure-activity relationships of novel chemoreversal agents.
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.
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore; Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Aicha
authors.initials: A
authors.lastname: Boudhar
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore.
authors.forename: Xiao Wei
authors.initials: XW
authors.lastname: Ng
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore.
authors.forename: Chiew Yee
authors.initials: CY
authors.lastname: Loh
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore.
authors.forename: Wan Ni
authors.initials: WN
authors.lastname: Chia
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore.
authors.forename: Zhi Ming
authors.initials: ZM
authors.lastname: Tan
authors.affiliation: Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand; Center for Clinical Vaccinology and Tropical Medicine, Headington, Oxford, United Kingdom.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore. Electronic address: phadbw@nus.edu.sg.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore. Electronic address: mictank@nus.edu.sg.
authors.forename: Kevin S W
authors.initials: KS
authors.lastname: Tan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D002738:Chloroquine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004351:Drug Resistance / Q000187:drug effects*; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D002738:Chloroquine
keywords: Antimalarial; Artemisinin-resistant; Chemoreversal; Chemosensitiser; Chloroquine; Chloroquine-resistant