Structure−Activity Relationships of 7-Deaza-6-benzylthioinosine Analogues as Ligands of Toxoplasma gondii Adenosine Kinase

• Published in: Journal of medicinal chemistry Vol. 51; no. 13; pp. 3934 - 3945
• Main Authors: Kim, Young Ah, Sharon, Ashoke, Chu, Chung K, Rais, Reem H, Al Safarjalani, Omar N, Naguib, Fardos N. M, el Kouni, Mahmoud H
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.07.2008; Amer Chemical Soc
• Subjects: Adenosine Kinase - antagonists & inhibitors; Adenosine Kinase - metabolism; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Kinase Inhibitors - analogs & derivatives; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Thioinosine - analogs & derivatives; Thioinosine - chemical synthesis; Thioinosine - chemistry; Thioinosine - pharmacology; Toxoplasma - drug effects; Toxoplasma - enzymology; POTENT; THERAPY; METABOLISM; NUCLEOSIDES; ENCEPHALITIS; SUBSTRATE; TARGETS; GLYCOSYLATION; INHIBITORS; 6-BENZYLTHIOINOSINE ANALOGS; Protozoa; Apicomplexa; Nitrile; Enzyme; Nitrogen heterocycle; Transferases; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Modeling; Antiprotozoal agent; Toxoplasma gondii; Structure activity relation; Adenosine kinase; Molecular model; Bicyclic compound; Binding mode; Parasiticide; Benzonitrile derivatives; Nucleoside; Ribonucleoside; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800201s

Several 7-deaza-6-benzylthioinosine analogues with varied substituents on aromatic ring were synthesized and evaluated against Toxoplasma gondii adenosine kinase (EC.2.7.1.20). Structure−activity relationships indicated that the nitrogen atom at the 7-position does not appear to be a critical structural requirement. Molecular modeling reveals that the 7-deazapurine motif provided flexibility to the 6-benzylthio group as a result of the absence of H-bonding between N7 and Thr140. This flexibility allowed better fitting of the 6-benzylthio group into the hydrophobic pocket of the enzyme at the 6-position. In general, single substitutions at the para or meta position enhanced binding. On the other hand, single substitutions at the ortho position led to the loss of binding affinity. The most potent compounds, 7-deaza-p-cyano-6-benzylthioinosine (IC50 = 5.3 μM) and 7-deaza-p-methoxy-6-benzylthioinosine (IC50 = 4.6 μM), were evaluated in cell culture to delineate their selective toxicity.