title: Synthesis of functionalized 3-, 5-, 6- and 8-aminoquinolines via intermediate (3-pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines and evaluation of their antiplasmodial and antifungal activity.
abstract: (3-Pyrrolin-1-yl)- and (2-oxopyrrolidin-1-yl)quinolines were prepared via cyclization of diallylaminoquinolines and 4-chloro-N-quinolinylbutanamides, respectively, as novel synthetic intermediates en route to N-functionalized 3-, 5-, 6- and 8-aminoquinolines with potential biological activity. (3-Pyrrolin-1-yl)quinolines were subjected to bromination reactions, and the reactivity of (2-oxopyrrolidin-1-yl)quinolines toward lithium aluminum hydride and methyllithium was assessed, providing an entry into a broad range of novel functionalized (pyrrolidin-1-yl)- and (hydroxyalkylamino)quinolines. Antiplasmodial evaluation of these novel quinolines and their functionalized derivatives revealed moderate micromolar potency against a chloroquine-sensitive strain of the malaria parasite Plasmodium falciparum, and the two most potent compounds also showed micromolar activity against a chloroquine-resistant strain of P. falciparum. Antifungal assessment of (hydroxyalkylamino)quinolines revealed three compounds with promising MIC values against Rhodotorula bogoriensis and one compound with potent activity against Aspergillus flavus.
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Vandekerckhove
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Van Herreweghe
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Willems
authors.affiliation: Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Danneels
authors.affiliation: Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Desmet
authors.affiliation: Division of Pharmacology, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.affiliation: Division of Pharmacology, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch, 7701, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium. Electronic address: Matthias.Dhooghe@UGent.be.
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001231:Aspergillus flavus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D012248:Rhodotorula / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000935:Antifungal Agents; D000962:Antimalarials
keywords: Antimalarial agents; Antimicrobial agents; Pyrrolidine derivatives; Quinolines