Design, synthesis and antiviral activity of ciclopirox (CPX) analogs against orthopoxvirus

In search for structurally novel antiviral leads against orthopoxvirus, we have previously identified and characterized ciclopirox (CPX) as a strong antiviral hit inhibiting vaccinia virus (VACV) replication. We report herein the antiviral activity-guided structure-activity relationship (SAR) of CPX, probing three structural zones (R¹–R³) with the synthesis of 29 analogs. Major findings include that the hydroxyl group as R¹ is required for activity, that most R² modifications confer cytotoxicity, and that R³ changes are largely tolerated. In the end, the SAR identified one analog (5h, EC₅₀ = 0.12 μM) showing substantially improved antiviral activity over CPX (EC₅₀ = 0.51 μM), and numerous analogs exhibiting strong antiviral activities (EC₅₀ = 0.71–1.2 μM) comparable to CPX without significant cytotoxicity. These SAR trends and additional potent analogs identified provide a strong foundation for future optimization efforts.