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

Authors

Muhammad Kashif Zaman, Chunguang Yang, Fengming He, Chuang He, Qiubao Wu, Hongxia Zhou, Zifeng Yang, Yingjun Li

Published in

Bioorganic chemistry. Volume 174. Pages 109690. Feb 26, 2026. Epub Feb 26, 2026.

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.

PMID:
41795339
Bibliographic data and abstract were imported from PubMed on 08 Mar 2026.

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