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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Beteck RM,Coertzen D,Smit FJ,Birkholtz LM,Haynes RK,N'Da DD

doi

10.1016/j.bmcl.2016.05.024

subject

Has Abstract

pub_date

2016-07-01 00:00:00

pages

3006-3009

issue

13

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(16)30509-1

journal_volume

26

pub_type

杂志文章

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