Discovery and evaluation of a 4-(benzothiazol-2-yl)-N-substituted aniline scaffold as MERS-CoV inhibitors

  • Eur J Med Chem. 2026 Oct 15:316:119055. doi: 10.1016/j.ejmech.2026.119055.
Kaili Dai  1 ,  Xiaomeng Zhang  2 ,  Jun Dai  3 ,  Minqi Hu  1 ,  Jinjin Ren  4 ,  Dandan Hu  5 ,  Jie Tang  1 ,  Chunlan Feng  2 ,  Fan Wang  5 ,  Yi Liu  6 ,  Suxiang Li  5 ,  Ting Liu  1 ,  Ye Hong  5 ,  Lifang Yu  1 ,  Fan Yang  7 ,  Wei Tang  8
Affiliations
  • 1. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3. State Key Laboratory of Respiratory Disease, Guangzhou Customs Technology Center, Guangzhou, 510623, China.
  • 4. The Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China.
  • 5. Guangzhou Customs Technology Center, Guangzhou, 510623, China.
  • 6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 7. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: [email protected].
  • 8. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; The Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: [email protected].
PMID: 42308606 DOI: 10.1016/j.ejmech.2026.119055
Abstract

Highly pathogenic coronaviruses pose a serious health threat. However, currently available small-molecule inhibitors (SMIs) targeting the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) spike (S) protein generally lack potency. Here, we design and synthesize a novel class of 4-(benzothiazol-2-yl)-N-substituted aniline derivatives. Distinct from most SMIs targeting viral Enzymes, compound 22 potently inhibited both MERS-CoV pseudotyped and live viruses in vitro, with surface plasmon resonance (SPR) providing evidence for a direct interaction with the S protein. Alongside good solubility and metabolic stability, compound 22 exhibited in vivo proof-of-concept efficacy in hDPP4-transgenic mice by significantly reducing pulmonary viral loads. Overall, this study validates the 4-(benzothiazol-2-yl)-N-substituted aniline scaffold as an early anti-MERS-CoV pre-lead series, with compound 22 as a solid starting point for further optimization.

Keywords
Antiviral; MERS-CoV; Small-molecule inhibitors; Spike protein.
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