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.