Design and synthesis of constrained bicyclic molecules as candidate inhibitors of influenza A neuraminidase

Abstract

The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.

Inhibition of sialidase activity as a therapeutic approach

“…Despite the achieved advances, none of these new compounds was efficient against influenza A neuraminidase at concentrations <2 mM. 10 …”

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

“…From the study, it was concluded that NEU1 may represent a promising target for managing atherosclerosis. Colombo and co-workers 106 have reported a mini library of new bicyclic compounds ( Fig. 24 ) and characterized them by enzyme inhibition assays.…”

Design and synthesis of glycomimetics: Recent advances

“…With a similar approach, a bicyclo[3.1.0]hexane scaffold, with general structure 55 (Figure A) was designed as a carbocyclic analogue of sialic acid (NeuAc) with the aim of mimicking the conformation adopted during its enzymatic cleavage within the active site of influenza A neuraminidase . Desialylation of host membrane oligosaccharides is a key step for the spread of viral infection after budding of new flu virus particle from host cells.…”