Selective anti-malarial minor groove binders

Scott, Fraser J., Khalaf, Abedawn I., Duffy, Sandra , Avery, Vicky M. and Suckling, Colin J. (2016) Selective anti-malarial minor groove binders. Bioorganic & Medicinal Chemistry Letters, 26 (14). pp. 3326-3329. ISSN 0960-894X

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A set of 31 DNA minor groove binders (MGBs) with diverse structural features relating to both physical chemical properties and DNA binding sequence preference has been evaluated as potential drugs to treat Plasmodium falciparum infections using a chloroquine sensitive strain (3D7) and a chloroquine resistant strain (Dd2) in comparison with human embryonic kidney (HEK) cells as an indicator of mammalian cell toxicity. MGBs with an alkene link between the two N-terminal building blocks were demonstrated to be most active with IC50 values in the range 30 – 500 nM and therapeutic ratios in the range 10 - > 500. Many active compounds contained a C-alkylthiazole building block. Active compounds with logD7.4 values of approximately 3 or 7 were identified. Importantly the MGBs tested were essentially equally effective against both chloroquine sensitive and resistant strains. The results show that suitably designed MGBs have the potential for development into clinical candidates for antimalarial drugs effective against resistant strains of Plasmodia.

Keywords:DNA minor groove binder, Plasmodium falciparum, Antimalarial drug, JCNotOpen
Subjects:F Physical Sciences > F150 Medicinal Chemistry
Divisions:College of Science > School of Chemistry
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ID Code:25565
Deposited On:11 Jan 2017 15:00

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