Potent Inhibitors against Newcastle Disease Virus Hemagglutinin‐Neuraminidase

Abstract

Neuraminidase activity is essential for the infection and propagation of paramyxoviruses, including human parainfluenza viruses (hPIVs) and the Newcastle disease virus (NDV). Thus, many inhibitors have been developed based on the 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid inhibitor (DANA) backbone. Along this line, herein we report a series of neuraminidase inhibitors, having C4 (p-toluenesulfonamido and azido substituents) and C5 (N-perfluorinated chains) modifications to the DANA backbone, resulting in compounds with 5- to 15-fold greater potency than the currently most active compound, the N-trifluoroacetyl derivative of DANA (FANA), toward the NDV hemagglutinin-neuraminidase (NDV-HN). Remarkably, these inhibitors were found to be essentially inactive against the human sialidase NEU3, which is present on the outer layer of the cell membrane and is highly affected by the current NDV inhibitor FANA.

The acidic hydrolysis ofN-acetylneuraminic 4,5-oxazoline allows a direct functionalization of the C5 position of Neu5Ac2en (DANA)

“…Indeed, differently to the well-established oxazoline chemistry, 18 it was reported that the acidic treatment of the oxazoline 3a afforded the 4-epi hydroxyl derivative 4b, as a single product, in variable yields (42-88%), calling for further studies. 6,[9][10][11][12][13] As a result of our continuing interest in the sialic acid chemistry/ biochemistry, 2,3,7,[14][15][16][19][20][21][22][23] in this work we solved this mechanistic puzzle, as we unveil that, the acidic hydrolysis of the 4,5-oxazoline 3a affords the amino ester 5, which could be isolated in good yields and fully characterized under appropriate work-up conditions. Furthermore, we detailed the shortened synthesis of the precursor of BCX 2798 (2c) and other sialidase inhibitors (such as BCX 2755 and various C4 triazole derivatives) further highlighting the synthetic utility of 5.…”

“…As a result of our continuing interest in the sialic acid chemistry/biochemistry, 2,3,7,14–16,19–23 in this work we solved this mechanistic puzzle, as we unveil that, the acidic hydrolysis of the 4,5-oxazoline 3a affords the amino ester 5, which could be isolated in good yields and fully characterized under appropriate work-up conditions. Furthermore, we detailed the shortened synthesis of the precursor of BCX 2798 (2c) and other sialidase inhibitors (such as BCX 2755 and various C4 triazole derivatives) further highlighting the synthetic utility of 5.…”

“…Several 2,3-unsaturated derivatives of the N-acetylneuraminic acid (Neu5Ac, 1) have been developed as potent inhibitors of sialidases, the glycolytic enzymes critical for bacteria and virus spread. [1][2][3][4][5][6] This class of inhibitors includes the 5-acetamido-2,6anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enoic acid 2a (Neu5Ac2en, DANA), the N-triuoroacetylated congener 2b (FANA), the N-isobutyrylated one 2c (BCX 2798), and the 4-guanidino derivative 2d (Zanamivir), which has been widely used in the clinic against the inuenza virus ( Fig. 1).…”

“…1). [1][2][3][4][5][6] Interestingly, the 4,5-oxazoline of Neu5Ac 3a has been shown [1][2][3][4][5][6][7][8][9][10][11][12] to be a key intermediate for the synthesis of various C4or C4-and C5-modied DANA derivatives (e.g. BCX 2798 2c and Zanamivir 2d), 1,5,6 of the 4-epi DANA 4a 3 (or its protected 4-epi hydroxyl derivative 4b 6,[9][10][11][12][13] ), as well as of several 3,4-unsaturated DANA-homologs, which were obtained through a Ferrier reaction.…”

“…8,14 In this context, our group has revealed the conditions to perform a critical intermolecular nucleophilic attack on 3a at its C4 position, while avoiding its intramolecular formation, and reported the synthesis of several C5-peruorinated 4-epi DANA derivatives. 2,3,7,15,16 Overall, the synthetic strategies involving the synthon 3a could be summarized with three distinctive reactions (Scheme 1): (a) a nucleophilic attackvia S N 2on the carbon at C4, which eventually opens up the oxazoline ring, thus restoring the acetyl group at C5 (analogously to the reaction used for the insertion of the azido group at C4), 17 (b) a hydrolytic ring-opening caused by the direct attack of a water molecule on the sp 2 -carbon of the oxazoline ring, which affords the 4b-hydroxy derivative 4b, 6,[9][10][11][12][13] and (c) a nucleophilic attack on the anomeric carbon (C2), followed by a shi of the double bond and the restoration of the N-acetyl group through a Ferrier reaction. 8,14 To date, the formation of the amino ester 5, an isomer of 4b and derived from the C]N bond cleavage of the oxazoline ring, has never been described.…”