Syntheses of 2-Deoxy-2,3-didehydro-<i>N</i>-acetylneuraminic Acid Analogues Modified by α-Acylaminoamido Groups at the C-4 Position Using Isocyanide-Based Four-Component Coupling and Biological Evaluation as Inhibitors of Human Parainfluenza Virus Type 1

Abstract

Novel sialidase inhibitors 11 having an α-acylaminoamido group at the C-4 position of Neu5Ac2en 1 against human parainfluenza virus type 1 (hPIV-1) were synthesized using one-pot isocyanide-based fourcomponent condensation, and their inhibitory activities against hPIV-1 sialidase were studied. Compound 11b showed inhibitory activity (IC 50 =5.1 mm) against hPIV-1 sialidase. The degree of inhibition of 11b was much weaker than that of 1 (IC 50 =0.3 mm).Key words human parainfluenza virus type 1; sialidase inhibitor; sialic acid; 4-isocyano Neu5Ac2en derivative; isocyanide-based four-component coupling Human parainfluenza viruses (hPIVs), members of the human parainfluenza viruses (hPIVs), which are part of the Paramyxoviridae family, are important respiratory tract pathogens in infants and children. Four different types of hPIV have been identified, all of which cause a spectrum of illnesses of the upper and lower respiratory tracts of children.

The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin‐Neuraminidase Revealed

“…[10] This multifunctional role makes HN an ideal target for antiparainfluenza drug design. Despite the large number of Neu5Ac2en (1)-based inhibitors designed to target this essential protein, [11][12][13][14] such as BCX2798 (2), [15][16][17] none of these inhibitors has progressed to the clinic. Elucidation of the, as yet undescribed, catalytic mechanism of this critical protein is an important step towards the design of more specific and potent inhibitors of hPIV-3 infection.…”

Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin–neuraminidase inhibitors

“…A limited number of unsaturated neuraminic acid-based HN inhibitors (2-6, Fig. 1a) have been reported [18][19][20][21][22][23] , although none of these inhibitors have advanced as clinical candidates presumably due to the lack of sufficient antiviral effect. One of the most potent and widely investigated hPIV type 3 haemagglutinin-neuraminidase (hPIV-3 HN) inhibitors 18,20,21 to date, 6, has a neuraminidase IC 50 value of B20 mM.…”

The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin‐Neuraminidase Revealed

“…This multifunctional role makes HN an ideal target for anti‐parainfluenza drug design. Despite the large number of Neu5Ac2en ( 1 )‐based inhibitors designed to target this essential protein,11–14 such as BCX2798 ( 2 ),15–17 none of these inhibitors has progressed to the clinic. Elucidation of the, as yet undescribed, catalytic mechanism of this critical protein is an important step towards the design of more specific and potent inhibitors of hPIV‐3 infection.…”