2. Academic Validation
  3. Design, synthesis and pharmacological evaluation of phenylthiophene-2-carboxamide-based RSV fusion protein inhibitors

Design, synthesis and pharmacological evaluation of phenylthiophene-2-carboxamide-based RSV fusion protein inhibitors

  • Bioorg Chem. 2026 Jun 15:174:109690. doi: 10.1016/j.bioorg.2026.109690.
Muhammad Kashif Zaman 1,  Chunguang Yang 1,  Fengming He 1,  Chuang He 1,  Qiubao Wu 2,  Hongxia Zhou 2,  Zifeng Yang 3,  Yingjun Li 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Joint International Research Laboratory of Respiratory Health, Guangdong Basic Research Center of Excellence for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China.; China - Portugal Artificial Intelligence and Public Health Technologies Joint Laboratory, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangdong Provincial Key Laboratory of Respiratory Disease Research Guangzhou Medical University, Guangzhou 510180, China.
  • 2 Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
  • 3 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Joint International Research Laboratory of Respiratory Health, Guangdong Basic Research Center of Excellence for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China.; China - Portugal Artificial Intelligence and Public Health Technologies Joint Laboratory, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangdong Provincial Key Laboratory of Respiratory Disease Research Guangzhou Medical University, Guangzhou 510180, China.; Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.. Electronic address: [email protected].
  • 4 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Joint International Research Laboratory of Respiratory Health, Guangdong Basic Research Center of Excellence for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510180, China.; China - Portugal Artificial Intelligence and Public Health Technologies Joint Laboratory, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangdong Provincial Key Laboratory of Respiratory Disease Research Guangzhou Medical University, Guangzhou 510180, China.. Electronic address: [email protected].
PMID: 41795339 DOI: 10.1016/j.bioorg.2026.109690
Abstract

Respiratory syncytial virus (RSV) remains a significant cause of serious lower respiratory tract Infection, highlighting the urgent need for new antivirals. A series of amide bond containing fluorinated benzimidazole derivatives was synthesized, and substitution of the N-phenylcarboxamide moiety with five-membered heteroaryl groups led to enhanced potency, with 2- and 3-halogenated thiophene rings significantly improved anti-RSV activity. Structural optimization afforded compound 21, bearing a 3-bromo-N-phenylthiophene-2-carboxamide moiety, which exhibited subnanomolar potency against RSV (IC50 = 0.10 nM). Molecular docking studies suggest compound 21 forms stable hydrogen bonds and π-π stacking interactions with the pre-fusion F protein, providing a mechanistic basis for its activity. Compound 21 dose-dependently suppressed RSV F protein expression in HEp-2 cells and significantly reduced viral burden in the lungs in an RSV-infected murine model. These results identify compound 21 as a highly potent RSV fusion inhibitor and a promising lead for further Antiviral development.

Keywords

Amide bond; Antiviral; Fusion inhibitors; Respiratory syncytial virus; Thiophene.

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