1-Hydroxy-1,8-napthyridinone (DHN) Analogs Potently Inhibit Monkeypox Virus Resolvase (Mpr)

This is the authors' abstract. We don't add key points for this paper.

The virally encoded Holliday junction resolvase is required for poxvirus genome replication and viral maturation. Previously, a 1-hydroxy-1,8-napthyridinone (DHN) analog ( 3 ) was discovered as an inhibitor hit of mpox resolvase (Mpr). Herein, we have conducted Mpr-based comprehensive structure–activity relationship (SAR) studies of compound 3 via the synthesis of 70 analogs of four distinct subtypes. The SAR identified a phenyl ring and a biphenyl moiety as the optimal substituent for C-3 and C-6/C-5, respectively, and that C-5 analogs are generally better than their C-6 regio-isomers. Against vaccinia virus (VACV), the tested new analogs demonstrated antiviral activity in the low μM to nM range. In the end, the best compound 5-1 conferred drastically improved inhibitory profiles against Mpr (IC 50 = 36 nM, 10-fold improvement) and VACV (EC 50 = 3.2 nM, 400-fold improvement) over compound 3, with significantly lower binding free energy as predicted from free energy perturbation, and highly favorable ADME properties.