Roberta Bivacqua
| Chemical Exploration of N-(2-phenyl-1,3-thiazol-5-yl)benzamides as Inhibitors of Influenza A/H1N1 Hemagglutinin-Mediated Viral Fusion |
| Raso Miriam1, Bivacqua Roberta1,2, Romeo Isabella2, Barreca Marilia1, Raimondi Maria Valeria1, Spanò Virginia1, Alcaro Stefano2, Barraja Paola1, Cagno Valeria3 and Montalbano Alessandra1 1 Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, 90123, Palermo, Italy 2 Dipartimento di Scienze della Salute, Università “Magna Græcia”, 88100, Catanzaro, Italy 3 Institute of Microbiology, University Hospital of Lausanne, University of Lausanne, 1011, Lausanne, Switzerland |
| Abstract The rapid evolution of influenza A virus (IAV) and the emergence of drug-resistant strains with reduced susceptibility to currently available antivirals emphasize the need for innovative therapeutic approaches [1]. The viral hemagglutinin (HA) glycoprotein plays a crucial role in the early stages of the viral life cycle by mediating host cell attachment and membrane fusion, making it an attractive target for the development of novel entry inhibitors [2]. In our previous studies, we identified a series of N-(2-phenyl-1,3-thiazol-5-yl)benzamide derivatives (1) displaying promising antiviral activity against influenza viruses, with potent inhibition of A/H1N1 replication in MDCK cells and EC₅₀ values in the submicromolar range (unpublished results). The A/H1N1 pseudovirus entry assay further supported a mechanism of action consistent with inhibition of the HA-mediated viral entry process. Based on these encouraging results, we started an exploration of the chemical space around the 1,3-thiazole scaffold through the design and synthesis of novel chemotypes (2), focusing on the key positions of chemical variability within the molecule (Figure 1). This chemical diversification is expected to provide further insight into the structural features related to the antiviral activity and the structure–activity relationships within this promising class of HA-targeting inhibitors. |
| References [1] Beigel J.H. and Hayden F.G. Influenza Therapeutics in Clinical Practice – Challenges and Recent Advances. Cold Spring Harb. Perspect. Med. 2021, 11, a038463. DOI: https://doi.org/10.1101/cshperspect.a038463 [2] Hermoso-Pinilla, F.J., Valdivia, A., Camarasa, M.J., Ginex, T., Luque, F.J. Influenza A virus hemagglutinin: from classical fusion inhibitors to proteolysis targeting chimera-based strategies in antiviral drug discovery. Explor. Drug Sci. 2024, 2, 85-116. DOI: https://doi.org/10.37349/eds.2024.00037 |