Synthesis and evaluation of influenza neuraminidases inhibitors based on a bicyclo[3.1.0]hexane scaffold

Influenza neuraminidase (NA) is the enzyme that releases influenza virions from infected cells, cleaving the sialic acid receptor on host cells. To date, the most successful drugs derived from targeting NA function are Oseltamivir,1 Zanamivir,2 and Peramivir.3 Structurally, these drugs consist of an unsaturated six- or five-membered ring and distinctive structural features incorporated from the sialic acid-based natural substrates. Ultimately, these structural differences have led to resistant viral strains, especially in the case of oseltamivir.4 The emergence of resistant seasonal and pandemic influenza strains5 underscores the growing demand for the development of new antiviral drugs with novel structural motifs and/or substitution patterns. This communication describes a novel class of derivatives based on a fused cyclopropane-cyclopentane scaffold, proposed as mimics of the sialic acid distorted boat conformation that occurs during catalysis by influenza neuraminidases (sialidases). A general synthetic route for these constrained-ring molecules was developed utilizing a photochemical reaction, followed by a Johnson-Corey-Chaykovsky cyclopropanation. Functionalization with the aim of additionally reaching the neuraminidase 150-cavity6 was also exploited. Inhibition assays demonstrated low micromolar inhibition against both group-1 (H5N1) and group-2 (H9N2) influenza neuraminidase subtypes, indicating good affinity for the alpha and beta sialic acid mimics and 150-cavity-targeted derivatives. These results provide validation of the design of a rigid bicyclo [3.1.0] analogue as a close mimic of sialic acid in the neuraminidase active site during catalysis. 1. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H. T.; Zhang, L. J.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Amer. Chem. Soc. 1997, 119 (4), 681-690. 2. Vonitzstein, M.; Wu, W. Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.; Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R. C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Nature 1993, 363 (6428), 418-423. 3. Babu, Y. S.; Chand, P.; Bantia, S.; Kotian, P.; Dehghani, A.; El-Kattan, Y.; Lin, T. H.; Hutchison, T. L.; Elliott, A. J.; Parker, C. D.; Ananth, S. L.; Horn, L. L.; Laver, G. W.; Montgomery, J. A. J. Med. Chem. 2000, 43 (19), 3482-3486. 4. Nguyen, H. T.; Nguyen, T.; Mishin, V. P.; Sleeman, K.; Balish, A.; Jones, J.; Creanga, A.; Marjuki, H.; Uyeki, T. M.; Nguyen, D. H.; Nguyen, D. T.; Do, H. T.; Klimov, A. I.; Davis, C. T.; Gubareva, L. V. Emerging Infect. Dis. 2013, 19 (12), 1963-1971. 5. McKimm-Breschkin, J. L. Influenza Other. Respir. Viruses 2013, 7, 25-36. 6. Russell, R. J.; Haire, L. F.; Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.; Hay, A. J.; Gamblin, S. J.; Skehel, J. J. J. Amer. Chem. Soc. 2009, 131 (13), 4702-4709.