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

Area of Science:

• Biochemistry
• Virology
• Medicinal Chemistry

Background:

• Poxvirus genome replication and maturation depend on virally encoded Holliday junction resolvase.
• A 1-hydroxy-1,8-napthyridinone (DHN) analog, compound 3, was identified as an initial inhibitor of mpox resolvase (Mpr).

Purpose of the Study:

• To conduct comprehensive structure-activity relationship (SAR) studies on compound 3 to optimize Mpr inhibitors.
• To synthesize and evaluate novel Mpr inhibitors for antiviral activity against vaccinia virus (VACV).

Main Methods:

• Synthesis of 70 analogs of compound 3 with variations at C-3, C-5, and C-6 positions.
• Evaluation of Mpr inhibitory activity and antiviral efficacy against VACV.
• Computational prediction of binding free energy and assessment of ADME properties.

Main Results:

• SAR studies identified optimal substituents at C-3 (phenyl) and C-5/C-6 (biphenyl moiety) for Mpr inhibition, with C-5 analogs showing superiority.
• Novel analogs demonstrated antiviral activity against VACV in the low μM to nM range.
• The lead compound, 5-1, exhibited a 10-fold improvement in Mpr inhibition (IC50 = 36 nM) and a 400-fold improvement in VACV efficacy (EC50 = 3.2 nM) compared to compound 3.

Conclusions:

• Optimized DHN analogs exhibit significantly enhanced Mpr inhibitory profiles and potent VACV antiviral activity.
• Compound 5-1 represents a promising candidate for further development as an antiviral therapeutic, showing improved potency and favorable ADME characteristics.