Antiviral activities of phenylalanine derivatives carrying carboxylic acid bioisosteres against chikungunya and parainfluenza virus type 3

Pathogenic RNA viruses from various virus families represent substantial public health hazards. Specific antiviral drugs effective against most RNA virus infections have not yet been developed. In this study, it was aimed to investigate the broad-spectrum antiviral activities of phenylalanine derivatives designed by replacing the carboxylic acid moiety with various bioisosteres such as nitrile, hydroxamidine and 5-oxo/thioxo-1,2,4-oxadiazole. Novel synthesized N-(1-substituted 2-phenylethyl)-N-(3-chlorobenzyl)-2,4-dichlorobenzamides (6e, 7e, 8e and 9d), together with phenylalanine derivatives previously prepared by our group, were evaluated antiviral activities against chikungunya (CHIKV), Zika (ZIKV), parainfluenza virus type 3 (PIV3), and enterovirus 71 (EV71). All phenylalanine derivatives showed antiviral activities against PIV3, with the 3-fluorobenzyl substituted analogue 6d emerging as the most potent compound (IC50 = 3.74 mu M, CC50 > 100 mu M), whereas the 3-chlorobenzyl analogue 6e (IC50 = 5.72 mu M, CC50 > 100 mu M) possessed the best non-toxic antiviral activity against CHIKV. Combined molecular docking and molecular dynamics (MD) simulation studies were conducted to predict the interactions of compounds 6d and 6e with the possible viral proteins of PIV3 and CHIKV, respectively.