Structure–activity relationships of carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 10; pp. 3403 - 3412
• Main Authors: Kim, Young Ah, Rawal, Ravindra K., Yoo, Jakyung, Sharon, Ashoke, Jha, Ashok K., Chu, Chung K., Rais, Reem H., Al Safarjalani, Omar N., Naguib, Fardos N.M., el Kouni, Mahmoud H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-05-2010
• Subjects: Adenosine Kinase - antagonists & inhibitors; Animals; Carbocyclic nucleoside; Drug Design; Inosine - pharmacology; Molecular modeling; Structure-Activity Relationship; Substrate Specificity; Thioinosine - analogs & derivatives; Thioinosine - chemical synthesis; Thioinosine - chemistry; Thioinosine - pharmacology; Toxoplasma - enzymology; Toxoplasma gondii adenosine kinase; Toxoplasmosis; Toxoplasma gondii adenosine kinase; Carbocyclic nucleoside; Toxoplasmosis; Molecular modeling
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.003

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
=
11.9
μM) in cell culture without any apparent host-toxicity.