Adenosine kinase inhibitors. 2. Synthesis, enzyme inhibition, and antiseizure activity of diaryltubercidin analogues

In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reporte d that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Desp ite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-a mino-5'-deoxy-5-iodotubercidin (1c) (IC50 = 0.0006 mu M), no compounds were identified that exhibited a safety, efficacy, and side effect profile suit able for further development. In this article, we demonstrate that substitu tion of the tubercidin molecule with aromatic rings at the N4- and the C5-p ositions not only retains AKI potency but also improves in vivo activity. S ynthesis of such compounds entailed transformation of 4-arylanlino-5-iodotu bercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-suylamino-5-arylpyrrolo[2,3-d]pyrimdine bases were constructed and then glycosylated with appropriately protected alpha- ribofuranosyl chlorides using a phase-transfer catalyst. Several compounds exhibited potent activity in the rat MES seizure assay with ED(50)s less th an or equal to 2.0 mg/kg, ip, and showed relatively mild side effects.