Discovery of Thiazolamide-based PI4KIIIβ/HDAC Dual Inhibitors with Potent Activity against Hepatitis C Virus

Chronic hepatitis C virus (HCV) infection remains a critical global public health burden affecting hundreds of millions of people worldwide. The emergence of antiviral resistance persistently undermines the long-term clinical efficacy of current direct-acting antiviral (DAA) regimens, creating an urgent need for therapeutics with different mechanisms of action. Host-directed multi-target therapy offers a promising avenue to overcome DAA resistance, yet dual inhibitors targeting HCV-essential host kinase phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) and epigenetic regulator histone deacetylases (HDACs) have not been reported for HCV treatment to date. Herein, we describe the rational design, chemical synthesis, and comprehensive biological evaluation of a series of novel thiazolamide-based dual PI4KIIIβ/HDAC inhibitors. Lead compounds displayed potent dual-target enzymatic inhibition, robust in vitro anti-HCV activity and excellent in vivo tolerability. This work establishes a novel host-directed dual-target therapeutic paradigm for HCV, providing a viable strategy to address the unmet clinical challenge of DAA resistance.