Structure-activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase.
Carbocyclic 6-benzylthioinosine analogues were synthesized and evaluated for their binding affinity against Toxoplasma gondii adenosine kinase [EC.2.7.1.20]. Various substituents on the aromatic ring of the 6-benzylthio group resulted in increased binding affinity to the enzyme as compared to the unsubstituted compound. Carbocyclic 6-(p-methylbenzylthio)inosine 9n exhibited the most potent binding affinity. Docking simulations were performed to position compound 9n into the T. gondii adenosine kinase active site to determine the probable binding mode. Experimental investigations and theoretical calculations further support that an oxygen atom of the sugar is not critical for the ligand-binding. In agreement with its binding affinity, carbocyclic 6-(p-methylbenzylthio)inosine 9n demonstrated significant anti-toxoplasma activity (IC(50)=11.9microM) in cell culture without any apparent host-toxicity.
Kim
Young Ah
YA
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA.
Rawal
Ravindra K
RK
Yoo
Jakyung
J
Sharon
Ashoke
A
Jha
Ashok K
AK
Chu
Chung K
CK
Rais
Reem H
RH
Al Safarjalani
Omar N
ON
Naguib
Fardos N M
FN
El Kouni
Mahmoud H
MH
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D007288:Inosine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014122:Toxoplasma / Q000201:enzymology*
C485108:6-benzylthioinosine; D013868:Thioinosine; D007288:Inosine; D000248:Adenosine Kinase