title: Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds.
abstract: Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.
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 phadbw@nus.edu.sg mictank@nus.edu.sg.
authors.forename: Brian W
authors.identifier: 0000-0002-2374-5756
authors.initials: BW
authors.lastname: Dymock
authors.affiliation: Laboratory of Molecular and Cellular Parasitology, Department of Microbiology and Immunology, National University of Singapore, Singapore phadbw@nus.edu.sg mictank@nus.edu.sg.
authors.forename: Kevin S W
authors.initials: KS
authors.lastname: Tan
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000737:chemistry* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D002738:Chloroquine; C031327:artemisinin