2-amido-3-aryl-4-methyl-thiazole derivatives as broad-spectrum anti-rhinoviral agents

Human rhinoviruses (RVs) are major pathogens responsible for respiratory tract infections, yet no approved antiviral therapy is available to combat these diseases. In this investigation, we designed and synthesized members of a group of 2-amido-3-aryl-4-methyl-thiazole derivatives and evaluated their inhibitory activities against phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), which is a host-directed target co-opted by a broad range of positive-sense RNA viruses, including RVs. In this series, 2e and 2f were found to exhibit strong activities against Group A and B RVs (EC₅₀ = 0.06-0.843 μM), low cytotoxicities (CC₅₀ ≥ 100 μM), high selectivity indices and additional submicromolar potencies against multiple coxsackieviruses. In addition, 2e and 2f retain high potencies (EC₅₀ = 0.118 and 0.059 μM, respectively) against RV-C15. Both 2e and 2f selectively inhibit PI4KIIIβ more potently than they do PI4KIIIα, and they significantly reduce infectious virion production in plaque assays. Molecular dynamics simulations suggest that stable binding of these agents to PI4KIIIβ takes place through hydrogen bonding interactions with Lys549 and Ile595, and hydrophobic contacts with Ile547, Val598 and related residues. Results of in vitro liver microsomal assays indicate that 2e and 2f have moderate metabolic stability, and those arising from pharmacokinetic studies in rats demonstrate that they display favorable half-lives, oral bioavailabilities (52.4 % for 2e) and sustained plasma exposures. Collectively, these findings indicate that 2e (KR-27452) is a promising lead for the development of next-generation, broad-spectrum anti-RV agents targeting PI4KIIIβ.