title: The antimalarial potential of 4-quinolinecarbinolamines may be limited due to neurotoxicity and cross-resistance in mefloquine-resistant Plasmodium falciparum strains.
abstract: The clinical potential of mefloquine has been compromised by reports of adverse neurological effects. A series of 4-quinolinecarbinolamines were compared in terms of neurotoxicity and antimalarial activity in an attempt to identify replacement drugs. Neurotoxicity (MTT [thiazolyl blue reduction] assay) was assessed by exposure of cultured embryonic rat neurons to graded concentrations of the drugs for 20 min. The 50% inhibitory concentration (IC(50)) of mefloquine was 25 microM, while those of the analogs were 19 to 200 microM. The relative (to mefloquine) therapeutic indices of the analogs were determined after using the tritiated hypoxanthine assay for assessment of the antimalarial activity of the analogs against mefloquine-sensitive (W2) and -resistant (D6 and TM91C235) Plasmodium falciparum strains. Five analogs, WR157801, WR073892, WR007930, WR007333, and WR226253, were less neurotoxic than mefloquine and exhibited higher relative therapeutic indices (RTIs) against TM91C235 (2.9 to 12.2). Conventional quinoline antimalarials were generally less neurotoxic (IC(50)s of 400, 600, and 900 for amodiaquine, chloroquine, and quinine) or had higher RTIs (e.g., 30 for halofantrine against TM91C235). The neurotoxicity data for the 4-quinolinecarbinolamines were used to develop a three-dimensional (3D), function-based pharmacophore. The crucial molecular features correlated with neurotoxicity were a hydrogen bond acceptor (lipid) function, an aliphatic hydrophobic function, and a ring aromatic function specifically distributed in the 3D surface of the molecule. Mapping of the 3D structures of a series of structurally diverse quinolines to the pharmacophore allowed accurate qualitative predictions of neurotoxicity (or not) to be made. Extension of this in silico screening approach may aid in the identification of less-neurotoxic quinoline analogs.
authors.affiliation: Parasitology Department, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. geoffrey.dow@na.amedd.army.mil
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Dow
authors.forename: Michael L
authors.initials: ML
authors.lastname: Koenig
authors.forename: Lesley
authors.initials: L
authors.lastname: Wolf
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Miriam
authors.initials: M
authors.lastname: Lopez-Sanchez
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hudson
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Bhattacharjee
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004351:Drug Resistance; D006706:Homeostasis / Q000187:drug effects; D015767:Mefloquine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000648:ultrastructure; D011237:Predictive Value of Tests; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: D000962:Antimalarials; D010616:Phenanthrenes; C023768:halofantrine; D002118:Calcium; D015767:Mefloquine