Adenosine Kinase Inhibitors. 2. Synthesis, Enzyme Inhibition, and Antiseizure Activity of Diaryltubercidin Analogues
Citations Over TimeTop 16% of 2000 papers
Abstract
In the preceding article (Ugarkar et al. J. Med. Chem. 2000, 43) we reported that analogues of tubercidin are potent adenosine kinase (AK) inhibitors with antiseizure activity in the rat maximum electroshock (MES) model. Despite the discovery of several highly potent AK inhibitors (AKIs), e.g., 5'-amino-5'-deoxy- 5-iodotubercidin (1c) (IC50 = 0.0006 microM), no compounds were identified that exhibited a safety, efficacy, and side effect profile suitable for further development. In this article, we demonstrate that substitution of the tubercidin molecule with aromatic rings at the N4- and the C5-positions not only retains AKI potency but also improves in vivo activity. Synthesis of such compounds entailed transformation of 4-arylamino-5-iodotubercidin analogues to their corresponding 5-aryl derivatives via the Suzuki reaction. Alternatively, 4-N-arylamino-5-arylpyrrolo[2,3-d]pyrimidine 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 ED50s < or = 2.0 mg/kg, ip, and showed relatively mild side effects.
Related Papers
- → Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure–Activity Relationship, and X-ray Structural Studies(2021)89 cited
- → Evaluation of 6,7-Aziridinyl Steroids and Related Compounds as Inhibitors of Aromatase (P-450arom)(1995)9 cited
- → Synthesis and biological evaluation of pyrazolo[4,3-d]pyrimidine analogues(2013)8 cited
- → A Novel Synthetic Inhibitor of Endopeptidase(1996)8 cited
- → Synthesis and in vitro activity of a non-epimerizable analog of the angiotensin-converting enzyme inhibitor A58365A(2001)3 cited