Mohan Kasula, Masaaki Toyama, Ramakrishnamraju Samunuri, Ashok Kumar Jha, Mika Okamoto, Masanori Baba and Ashoke Sharon
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引用次数: 0
Abstract
The discovery of selective and potent inhibitors through de novo pathways is essential to combat drug resistance in chronic hepatitis B (CHB) infections. Recent studies have highlighted that neplanocin A (NepA) derivatives are biologically selective inhibitors of the hepatitis B virus (HBV). In this study, we designed, synthesized, and evaluated various pyrazolo[3,4-d]pyrimidine-based NepA analogues (4a–h) for their anti-HBV activity. Notably, analogue 4g demonstrated significant activity against HBV replication, with EC50 (HBV DNA) = 0.96 μM, CC50 > 100 μM and EC50 (HBsAg) = 0.82 μM, showing selective inhibition of HBsAg secretion. The SAR analysis concluded that replacing the polar 4-NH2 group with –CH3 also acted as a weak H-bonding donor, and the presence of 3-iodo was found to be desirable for the activity/toxicity profile. The nucleoside analogues exhibited a distinct mechanism of action compared to existing nucleoside analogues for the selective inhibition of HBsAg secretion. Based on these findings, compound 4g represents a promising lead molecule for the development of new anti-HBV agents with unique mechanisms of action.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.