title: Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities.
abstract: As part of a programme aimed at identifying rational new triple drug combinations for treatment of malaria, tuberculosis and toxoplasmosis, we have selected quinolones as one component, given that selected examples exhibit exceptionally good activities against the causative pathogens of the foregoing diseases. The quinolone decoquinate (DQ), an old and inexpensive coccidiostat, displays anti-malarial activity in vitro against Plasmodium falciparum (Pf). However, because of its exceedingly poor solubility in water or organic solvents, development of DQ as a drug is problematical. We have therefore converted DQ in straightforward fashion into tractable new derivatives that display good activities in vitro against chloroquine-sensitive NF54 and multidrug-resistant K1 and W2 Pf, and relatively low toxicities against human fibroblast cells. The most active compound, the N-acetyl derivative 30, is 5-fold more active than DQ against NF54 and K1 and equipotent with DQ against W2. It possesses an activity profile against all strains comparable with that of the artemisinin derivative artesunate. Overall, this compound and the other accessible and active derivatives serve as an attractive template for development of new and economic lead quinolones.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Beteck
authors.affiliation: Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Pretoria 0002, South Africa.
authors.forename: Dina
authors.initials: D
authors.lastname: Coertzen
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Smit
authors.affiliation: Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria, Pretoria 0002, South Africa.
authors.forename: Lyn-Marie
authors.initials: LM
authors.lastname: Birkholtz
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. Electronic address: richard.haynes@nwu.ac.za.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Haynes
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa. Electronic address: david.nda@nwu.ac.za.
authors.forename: David D
authors.initials: DD
authors.lastname: N'Da
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D003667:Decoquinate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D018432:Drug Resistance, Multiple; D004640:Emetine / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D015363:Quinolones; C000621100:ethyl 1-acetyl-6-decoxy-7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate; D003667:Decoquinate; D000077332:Artesunate; D000077549:Artemether; D004640:Emetine
keywords: Antimalarial activity; Decoquinate; Derivatives; Malaria; Quinolone