Inhibitors of adenosine consuming parasites through polymer-assisted solution phase synthesis of lipophilic 5'-amido-5'-deoxyadenosine derivatives.
Given the more or less global spread of multidrug-resistant plasmodia, structurally diverse starting points for the development of chemotherapeutic agents for the treatment of malaria are urgently needed. Thus, a series of 20 adenosine derivatives with a large lipophilic substituent in N(6)-position were prepared in order to evaluate their potential to inhibit the chloroquine resistant Plasmodium falciparum strain K1 in vitro. The rationale for synthesis of these structures was the high probability of interactions with multiple adenosine associated targets and the assumption that a large hydrophobic N(6)-(4-phenoxy)benzyl substitution should allow the molecules to diffuse across parasite membranes. Starting from readily available 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. Heterocyclic ring systems were synthesized on-bead on Kenner's safety-catch linker prior to acylation of the scaffold in solution. Most of the highly pure compounds displayed anti-plasmodial activity in the low micromolar or even submicromolar concentration range.
Heidler
Philipp
P
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany.
Zohrabi-Kalantari
Vida
V
Kaiser
Marcel
M
Brun
Reto
R
Emmrich
Thomas
T
Link
Andreas
A
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011108:Polymers / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D003839:Deoxyadenosines; D011108:Polymers; D000241:Adenosine