6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities.
Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents.
Rais
Reem H
RH
Department of Pharmacology and Toxicology, Center for AIDS Research, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Al Safarjalani
Omar N
ON
Yadav
Vikas
V
Guarcello
Vincenzo
V
Kirk
Marion
M
Chu
Chung K
CK
Naguib
Fardos N M
FN
el Kouni
Mahmoud H
MH
D000248:Adenosine Kinase / Q000378:metabolism*; D000818:Animals; D000981:Antiprotozoal Agents; D005260:Female; D051379:Mice; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology
C485108:6-benzylthioinosine; D000981:Antiprotozoal Agents; D013868:Thioinosine; D000248:Adenosine Kinase