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Parallel synthesis of a series of non-functional ATP/NAD analogs with activity against trypanosomatid parasites

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Abstract

Non-functional analogs of the cofactors ATP and NAD are putative inhibitors of ATP- or NAD-dependant enzymes. Since pathogenic protozoa rely heavily on the salvage of purine nucleosides from the bloodstream of their host, such compounds are of interest as antiplasmodial and antitrypanosomal agents with a multitude of molecular targets. By replacing the negatively charged phosphate residues with a constrained unsaturated amide spacer and the nicotinamide moiety of NAD with various lipophilic substituents, 15 new ATP/NAD analogs were obtained in screening quantities. In these compounds, a 5′-desoxyadenosine moiety was conserved as key molecular recognition motif. The inhibition of P. falciparum and T. brucei ssp. in a whole parasite in vitro assay is reported.

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Abbreviations

BAD:

Benzamide adenine dinucleotide

CDK:

Cyclin-dependent kinase

COMT:

Catechol O-methyltransferase

DIC:

N,N′-Diisopropyl-carbodiimide

DMAP:

4-Dimethylamino-pyridine

DMF:

N,N-Dimethyl formamide

GAPDH:

Glyceraldehyde phosphate dehydrogenase

HOBt:

N-Hydroxy benzotriazole

MPLC:

Medium pressure liquid chromatography

NEK:

(Never-in-mitosis-A)-related protein kinase

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Authors and Affiliations

  1. Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Straße 17, 17487, Greifswald, Germany

    Andreas Link

  2. Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032, Marburg, Germany

    Philipp Heidler

  3. Swiss Tropical Institute, Socinstraße 57, 4002, Basel, Switzerland

    Marcel Kaiser & Reto Brun

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  1. Philipp Heidler
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  2. Marcel Kaiser
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  3. Reto Brun
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Correspondence to Andreas Link.

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Dedicated to Prof. Dr. Hans-Hartwig Otto on the occasion of his 70th birthday.

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Link, A., Heidler, P., Kaiser, M. et al. Parallel synthesis of a series of non-functional ATP/NAD analogs with activity against trypanosomatid parasites. Mol Divers 14, 215–224 (2010). https://doi.org/10.1007/s11030-009-9160-x

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