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

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

  • Eur J Med Chem. 2026 Jan 15;302(Pt 3):118318. doi: 10.1016/j.ejmech.2025.118318.
Sileshi Abera Ayele 1,  Hye Lim Lee 2,  Céline Sablon 3,  Alba Reneesh 1,  Kyeongdeok Seo 2,  Eunju Jeong 1,  Dasom Hwang 2,  Mi Jin Kim 2,  Jae Hak Kim 2,  Eunhye Jung 2,  Joo-Youn Lee 1,  Yejin Ju 1,  Johan Neyts 4,  Hendrik Jan Thibaut 5,  Sunjoo Ahn 6,  Heyrhyoung Lyoo 3,  Jin Soo Shin 7,  Young-Sik Jung 8
Affiliations

Affiliations

  • 1 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Republic of Korea.
  • 2 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 3 Department of Microbiology, Immunology and Transplantation, Rega Institute, Translational Platform for Virus, Vaccine and Cancer Research (TPVC), KU Leuven, Leuven, Belgium.
  • 4 Department of Microbiology, Immunology and Transplantation, Rega Institute, Virology, Antiviral Drug & Vaccine Research Group, KU Leuven, Leuven, Belgium; Department of Microbiology, Immunology and Transplantation, VirusBank Platform, KU Leuven, Leuven, Belgium.
  • 5 Department of Microbiology, Immunology and Transplantation, Rega Institute, Translational Platform for Virus, Vaccine and Cancer Research (TPVC), KU Leuven, Leuven, Belgium. Electronic address: hendrikjan.thibaut@kuleuven.be.
  • 6 Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Republic of Korea.
  • 7 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Republic of Korea. Electronic address: jsshin@krict.re.kr.
  • 8 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Republic of Korea. Electronic address: ysjung@krict.re.kr.
PMID: 41240474 DOI: 10.1016/j.ejmech.2025.118318
Abstract

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.

Keywords

Broad-spectrum antiviral; Human rhinovirus; PI4KIIIβ inhibitor; RV-C15; Thiazole derivatives.

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