Design and synthesis of imidazo[2,1-b]thiazole derivatives as potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors for antiviral activity

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130346. doi: 10.1016/j.bmcl.2025.130346.
Koji Ochiai  1 ,  Masahiko Kinebuchi  2 ,  Takekazu Kondo  2 ,  Takahiro Suezawa  2 ,  Morio Higuchi  2 ,  Motomichi Fujita  2 ,  Akinobu Yokoyama  2 ,  Hitomi Matsui  2 ,  Makoto Rembutsu  2 ,  Yuji Ishibashi  2 ,  Yuta Tanaka  2 ,  Aki Yonezawa  2 ,  Hirotaka Ando  2 ,  Yoshiaki Kitamura  2 ,  Michiaki Nagasawa  2 ,  Masahiro Ueno  2
Affiliations
  • 1. Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: [email protected].
  • 2. Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
PMID: 40701196 DOI: 10.1016/j.bmcl.2025.130346
Abstract

The type III phosphatidylinositol 4-kinase beta (PI4KB, PI4KIIIβ) is a lipid kinase that catalyzes the phosphorylation of phosphatidylinositol at the 4-position. PI4KB is widely understood to play a critical role in supporting viral replication, and PI4KB inhibitors are under investigation as potential host-targeting antivirals. In this study, we report potent and selective imidazo[2,1-b]thiazole inhibitors of PI4KB with Antiviral activity. Guided by ligand efficiency, optimization efforts yielded potent PI4KB inhibitors, and reducing proton donor count enhanced cellular potency (anti HRV: EC50 0.027 μM for compound 29, 0.007 μM for compound 30). Furthermore, compound 30 selectively inhibited PI4KB, with minimal off-target kinase activity, as confirmed by profiling.

Keywords
HRV; Host-targeting antiviral; Imidazo[2,1-b]thiazole; Lipid kinase; PI4KB.
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