Parallel synthesis of a series of non-functional ATP/NAD analogs with activity against trypanosomatid parasites.
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.
Link
Andreas
A
Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Strasse 17, 17487, Greifswald, Germany. link@uni-greifswald.de
Heidler
Philipp
P
Kaiser
Marcel
M
Brun
Reto
R
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry; D065098:Catechol O-Methyltransferase Inhibitors; D006801:Humans; D008958:Models, Molecular; D009243:NAD / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000201:enzymology
D000962:Antimalarials; D001565:Benzoates; D065098:Catechol O-Methyltransferase Inhibitors; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D009243:NAD; D000255:Adenosine Triphosphate