Organic & biomolecular chemistry · 2026
4-Diketopyrrole-2-carboxamide derivatives affecting HBV capsid assembly: structure-activity relationship around the GLP-26 scaffold.
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Chen Zhe, Zhou Shaoman, Liu Peng, Wiseman John, Zhou Longhu, Fan Chia-Han Vanessa, Bowers Heather B, Salman Mohammad, Verma Kiran, Monroe Danielle R, Downs-Bowen Jessica, Patel Dharmeshkumar, Bassit Leda, Schinazi Raymond F, Amblard Franck
Аннотация
Chronic hepatitis B virus (HBV) infection remains a major global health burden with limited curative options. Capsid assembly modulators (CAMs) have emerged as a promising antiviral strategy by disrupting nucleocapsid formation and suppressing cccDNA amplification. In this study, we discuss the structure-activity relationship (SAR) around the 4-diketopyrrole-2-carboxamide scaffold of GLP-26, focusing on modifying the aniline moiety and the oxoacetamide region, and introducing alternative acetamide groups. Compounds were synthesized through efficient coupling strategies, including microwave-assisted amidation, and several analogs exhibited potent inhibition of HBV DNA replication in HepAD38 cells, with EC50 values in the low nanomolar range and minimal cytotoxicity. This work broadens the chemical space surrounding GLP-26 and provides a valuable roadmap for designing new scaffolds for next-generation HBV CAMs.