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Three series of thiazolylhydrazone derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activity against influenza virus H1N1 in vitro. Compounds 1 and 2 were synthesized via the one-pot reaction and compound 3 was synthesized in two steps. Pharmacological results showed that the majority of the target compounds 1, 2, and 3 exhibited moderate-to-good influenza NA inhibitory activity. The NA inhibitory activity of the most active compound 2g (IC50 = 7.12 μg/ml) is better than that of the lead compound A. Molecular docking was performed to study the possible interactions between compound 2g and the active site of NA. On the basis of biological results, a preliminary structure–activity relationship (SAR) was derived and discussed. Moreover, density functional theory (DFT) calculation was also performed to explain why the thiazolylhydrazone skeleton has NA inhibitory activity, especially compound 2g with the most potent inhibitory activity.

A series of 4-thiazolinone derivatives (D1-D58) were designed and synthesized. All of the derivatives were evaluated in vitro for neuraminidase (NA) inhibitory activities against influenza virus A (H1N1), and the inhibitory activities of the five most potent compounds were further evaluated on NA from two different influenza viral subtypes (H3N2 and B), and then their in vitro anti-viral activities were evaluated using the cytopathic effect (CPE) reduction assay. The results showed that the majority of the target compounds exhibited moderate to good NA inhibitory activity. Compound D18 presented the most potent inhibitory activity with IC50 values of 13.06 μM against influenza H1N1 subtype. Among the selected compounds, D18 and D41 turned out to be the most potent inhibitors against influenza virus H3N2 subtype (IC50 = 15.00 μM and IC50 = 14.97 μM, respectively). D25 was the most potent compound against influenza B subtype (IC50 = 16.09 μM). In addition, D41 showed low toxicity and greater potency than reference compounds Oseltamivir and Amantadine against N1–H275Y variant in cellular assays. The structure-activity relationship (SAR) analysis showed that introducing 4-CO2H, 4-OH, 3-OCH3-4-OH substituted benzyl methylene can greatly improve the activity of 4-thiazolinones. Further SAR analysis indicated that 4-thiazolinone and ferulic acid fragments are necessary fragments of target compounds for inhibiting NA. Molecular docking was performed to study the interaction between compound D41 and the active site of NA. This study may providing important information for new drug development for anti-influenza virus including mutant influenza virus.

Four series of ferulic acid derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activities against influenza virus H1N1 in vitro. The pharmacological results showed that the majority of the target compounds exhibited moderate influenza NA inhibitory activity, which was also better than that of ferulic acid. The two most potent compounds were 1m and 4a with IC50 values of 12.77 ± 0.47 and 12.96 ± 1.34 μg/ml, respectively. On the basis of the biological results, a preliminary structure-activity relationship (SAR) was derived and discussed. Besides, molecular docking was performed to study the possible interactions of compounds 1p, 2d, 3b, and 4a with the active site of NA. It was found that the 4-OH-3-OMe group and the amide group (CON) of ferulic acid amide derivatives were two key pharmacophores for NA inhibitory activity. It is meaningful to further modify the natural product ferulic acid to improve its influenza NA inhibitory activity.