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

Stéphanie Vandekerckhove; Sofie Van Herreweghe; Jasmine Willems; Barbara Danneels; Tom Desmet; Carmen de Kock; Peter J Smith; Kelly Chibale; Matthias D'hooghe

doi:10.1016/j.ejmech.2014.12.020

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

Eur J Med Chem. 2015 Mar 6:92:91-102. doi: 10.1016/j.ejmech.2014.12.020. Epub 2014 Dec 12.

Authors

Stéphanie Vandekerckhove¹, Sofie Van Herreweghe¹, Jasmine Willems¹, Barbara Danneels², Tom Desmet², Carmen de Kock³, Peter J Smith³, Kelly Chibale⁴, Matthias D'hooghe⁵

Affiliations

¹ SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
² Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium.
³ Division of Pharmacology, University of Cape Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South Africa.
⁴ 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.
⁵ 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: [email protected].

PMID: 25544689
DOI: 10.1016/j.ejmech.2014.12.020

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.

Keywords: Antimalarial agents; Antimicrobial agents; Pyrrolidine derivatives; Quinolines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aminoquinolines / chemical synthesis
Aminoquinolines / chemistry
Aminoquinolines / pharmacology*
Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Aspergillus flavus / drug effects*
Dose-Response Relationship, Drug
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Rhodotorula / drug effects*
Structure-Activity Relationship

Substances

Aminoquinolines
Antifungal Agents
Antimalarials