SAR study culminates in a series of HDAC6 selective inhibitors featuring Schisandrin C-analogous Cap as potential immunomodulatory agents for cancer therapy

•29 HDAC6 inhibitors featuring Schisandrin C-analogous Cap were designed and synthesized.•SAR study identified compound 24h as the most attractive one throughout this series.•24h exhibited single-digit nanomolar IC50 against HDAC6, along with favorable selectivity over HDAC1, 8 and 11.•In A549 cells, 24h was capable of reversing IL-6-mediated PD-L1 upregulation.•24h displayed acceptable oral bioavailability, high oral exposure, and long elimination half-life in SD rats.