Synthesis and evaluation of bicyclo[3.1.0]hexane carboxylic acids as candidate inhibitors of influenza A neuraminidase

Influenza A virus is a RNA virus enclosed within a lipoprotein envelope, which contains two types of integral membrane glycoproteins, the hemagglutinin (HA) and the neuraminidase (NA). NA is the hydrolytic enzyme that cleaves sialic acid residues from membrane oligosaccharides on host cells and is responsible for the release and spreading of the newly assembled virus. [1] The most successful drugs derived from targeting NA function are Oseltamivir, Zanamivir, and Peramivir.[2] These molecules consist of an unsaturated six- or five-membered ring that mimics the sialic acid natural substrate. The emergence of resistant NA strains [2] highlights the demand for new antiviral drugs, with novel structural motifs and/or substitution patterns. The communication presents the design, synthesis and evaluation of constrained sialic acid analogues based on a bicyclo[3.1.0]hexane scaffold (Figure 1). These structures were designed to mimic the boat conformation of sialic acid in the Michaelis complex with neuraminidase. They were synthesized through two different approaches, exploiting either 1) the photochemical cyclization of a pyridinium cation, followed by a Johnson-Corey-Chaykovsky cyclopropanation; or 2) the cyclopropanation of cyclopentenone, followed by an aziridination and further functionalization of the five-member ring. Functionalization with the aim of reaching an additional binding site, the 150-cavity,[3] was also exploited.[4] The inhibitory activity was studied by enzyme inhibition assays against neuraminidases H5N1, the H274Y mutant and H9N2. The results will be presented. [1] Gamblin S. J.; Skehel J. J.; Influenza Hemagglutinin and Neuraminidase Membrane Glycoproteins. J. Biol. Chem. 2010; 285, 28403-28409. [2] McKimm-Breschkin, J. L; Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza. Other. Respir. Viruses 2013, 7, 25-36. [3] Russell, R.J., et al., The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature, 2006, 443, 45-49. [4] Colombo, C.; Pinto, B. M.; Bernardi A.; Bennet, A. J.; Synthesis and evaluation of influenza A viral neuraminidase candidate inhibitors based on a bicyclo[3.1.0]hexane scaffold. Org Biomol Chem, 2016, 14, 6539-6553.