Inhibitors of adenosine consuming parasites through polymer-assisted N-acylation of N6-substituted 5'-amino-5'-deoxyadenosines.
A series of 30 adenosine derivatives with three different substituents at the N(6)-position were prepared in order to evaluate their potential to inhibit the pathogenic protozoa Plasmodium falciparum and Trypanosoma brucei in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that N(6)-substitutents should increase stability against adenosine deaminases and allow the molecules to diffuse across parasite membranes. Starting from inosine, the new compounds were prepared as single isomers using a polymer-assisted acylation protocol enabling the straightforward isolation of the target compounds in pure form. Three of the compounds displayed anti-plasmodial and one anti-trypanosomal activity in the single digit micromolar concentration range.
Zohrabi-Kalantari
Vida
V
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032, Marburg, Germany.
Heidler
Philipp
P
Kaiser
Marcel
M
Brun
Reto
R
Kamper
Christoph
C
Link
Andreas
A
D000215:Acylation; D000241:Adenosine / Q000378:metabolism; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects*; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D000962:Antimalarials; D003839:Deoxyadenosines; D014344:Trypanocidal Agents; C057928:5'-amino-5'-deoxyadenosine; D000241:Adenosine