Synthesis and biological evaluation of s-triazine substituted polyamines as potential new anti-trypanosomal drugs.
The P2 transporter is a nucleoside transporter which is unique to the protozoan parasite Trypanosoma brucei, the causative organism of Human African Trypanosomasis. The transporter has been shown to bind some structural motifs not recognized by other transporters. In this paper we describe the use of the melamine motif, a substrate of the P2 transporter, as a potential tool to selectively deliver polyamine analogues to the parasites. The synthesis of a number of polyamine analogues attached to a variety of melamine analogues is described. Many of the compounds were shown to competitively inhibit uptake of adenosine, indicating that they are recognized by the transporter. Some of the compounds showed good in vitro activity against the parasites.
Klenke
B
B
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, U.K.
Stewart
M
M
Barrett
M P
MP
Brun
R
R
Gilbert
I H
IH
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015800:Protozoan Proteins / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000187:drug effects
D002352:Carrier Proteins; D011073:Polyamines; D015800:Protozoan Proteins; D014227:Triazines; D014344:Trypanocidal Agents; D000241:Adenosine