title: In vitro evaluation of imidazo[4,5-c]quinolin-2-ones as gametocytocidal antimalarial agents.
abstract: Novel imidazo[4,5-c]quinolin-2-ones were synthesized and evaluated in asexual blood stage and late stage gametocyte assays of Plasmodium falciparum, a major causative agent of malaria. The design of these compounds is based on a recently identified lead compound from a high throughput screen. A concise synthesis was developed that allowed for generation of analogues with substitution around both the quinoline and imidazolidinone rings. Through structure-activity relationship studies, a number of potent compounds were identified that possessed excellent antimalarial activity against both the asexual and sexual stages with minimal cytotoxicity in mammalian cells. This is the first Letter describing SAR and gametocytocidal activity of imidazo[4,5-c]quinolin-2-ones, a new lead series for malaria treatment and prevention.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Paresma R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Myunghoon
authors.initials: M
authors.lastname: Kim
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Huang
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Sanderson
authors.affiliation: Department of Biology, Loyola University Chicago, Chicago, IL 60660, United States.
authors.forename: Takeshi Q
authors.initials: TQ
authors.lastname: Tanaka
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: Department of Biology, Loyola University Chicago, Chicago, IL 60660, United States.
authors.forename: Kim C
authors.initials: KC
authors.lastname: Williamson
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: huangwe@mail.nih.gov.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Huang
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D007093:Imidazoles; D015363:Quinolones; C000621341:imidazo(4,5-c)quinolin-2-one
keywords: Antimalarial; Gametocytes; Gametocytocidal; Imidazo[4,5-c]quinolin-2-one; Plasmodium falciparum