Synthesis of halogenated 4-quinolones and evaluation of their antiplasmodial activity.
Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K2CO3 resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2-methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C-N coupling of the latter 3-bromo-4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4-quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 4 and 70 μM.
SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
Stéphanie
S
Vandekerckhove
Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
Tom
T
Desmet
Centre for Industrial Biotechnology and Biocatalysis, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
Hai Giang
HG
Tran
Division of Pharmacology, Department of Medicine, University of Cape Town, K45, OMB Groote Schuur Hospital, Observatory 7925, South Africa.
Carmen
C
de Kock
Division of Pharmacology, Department of Medicine, University of Cape Town, K45, OMB Groote Schuur Hospital, Observatory 7925, South Africa.
Peter J
PJ
Smith
Department of Chemistry and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
Kelly
K
Chibale
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.
Matthias
M
D'hooghe
D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D000962:Antimalarials
4-Quinolones; Antimalarial agents; Halogenated substrates; Quinolines