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

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI:10.1016/j.bmcl.2025.130346

Koji Ochiai, Masahiko Kinebuchi, Takekazu Kondo, Takahiro Suezawa, Morio Higuchi, Motomichi Fujita, Akinobu Yokoyama, Hitomi Matsui, Makoto Rembutsu, Yuji Ishibashi, Yuta Tanaka, Aki Yonezawa, Hirotaka Ando, Yoshiaki Kitamura, Michiaki Nagasawa, Masahiro Ueno

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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.

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咪唑[2,1-b]噻唑衍生物作为有效的选择性磷脂酰肌醇4-激酶IIIβ抑制剂的设计和合成

III型磷脂酰肌醇4-激酶β (PI4KB, pi4kii β)是一种能催化磷脂酰肌醇4位磷酸化的脂质激酶。人们普遍认为PI4KB在支持病毒复制中起着关键作用，PI4KB抑制剂作为潜在的宿主靶向抗病毒药物正在研究中。在这项研究中，我们报道了具有抗病毒活性的有效和选择性咪唑[2,1-b]噻唑抑制剂PI4KB。在配体效率的指导下，优化工作产生了有效的PI4KB抑制剂，减少质子供体计数增强了细胞效力（抗HRV：化合物29的EC50为0.027 μM，化合物30的EC50为0.007 μM）。此外，化合物30选择性地抑制PI4KB，具有最小的脱靶激酶活性，如分析所证实的那样。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.