Design, Synthesis, and Biological Evaluation of Novel Acylhydrazone Derivatives as Potent Neuraminidase Inhibitors

Abstract

Neuraminidase (NA) is an important target for current research on anti-influenza drugs. The acylhydrazone derivatives containing the −CONHNCH− framework have been shown to have good NA inhibitory activity. In this paper, a series of novel acylhydrazone NA inhibitors (9a−9n) were designed and synthesized, and the inhibitory activities against NA were evaluated in vitro. The NA inhibition results showed that compound 9j has the most potent inhibitory activity (IC 50 = 0.6 μM) against NA, which is significantly lower than that of the positive control oseltamivir carboxylic acid (OSC) (IC 50 = 17.00 μM). Molecular docking analysis indicates that the acylhydrazone group plays an important role in compound 9j, which can bind well to the residues Arg371 and Arg292 in the S1 subsite of NA. The good potency of 9j may be also ascribed to the extending of morpholinyl ring into the 430-cavity. The results of this work may contribute to the development of more potent NA inhibitors to against mutant influenza viruses.

Recent Efforts in Identification of Privileged Scaffolds as Antiviral Agents

“…The essential residues Arg371 and Arg292 in the S1 subsite of NA can bind to the acyl hydrazone group, which can play a significant role, according to a molecular docking study. The extension of the morpholinyl ring into the 430‐cavity may also be responsible for the high potency of 67 [49] …”

“…The extension of the morpholinyl ring into the 430-cavity may also be responsible for the high potency of 67. [49] Wang et al described the identification of (�)-(2S,3R,4R)-2 (trifluoroacetamido)methyl-3-amino-1-(N'-ethyl-N'isopropylcarbamyl)pyrrolidine-4-carboxylic acid (A-192558, 71) (Figure 29) as a strong NA inhibitor (IC 50 = 0.2 μM against NA(A) ) of the enzyme active site were seen in the X-ray crystallographic structure of A-192558 coupled to NA. [50] Lee et al Identified novel Caryophyllaceae-type cyclopeptides from the leaves of Melicopep teleifolia in the hunt for antiviral cyclopeptides against the influenza A virus.…”

Influenza Viruses: Harnessing the Crucial Role of the M2 Ion-Channel and Neuraminidase toward Inhibitor Design

“…Furthermore, Yu et al [ 210 ] also designed and synthesized benzoylhydrazone NA inhibitors with higher NA inhibitory activity to the positive control oseltamivir carboxylic acid. Li et al [ 211 ] likewise designed and synthesized novel acylhydrazone NA inhibitors, with most of them exhibiting good inhibition activity with a significantly lower activity than that of the positive control oseltamivir carboxylic acid.…”

N-Glycan Profiles of Neuraminidase from Avian Influenza Viruses

“…After the formation of an oxocarbonium ion at the C2 atom of SA, strong ionic interactions occur between the carboxylate group of SA and the peripheral alkaline residues, leading to the subsequent cleavage of the glycosidic bond. Numerous basic and acid residues comprise the enzymatic center in NA from Type A and Type B IVs (e.g., Arg118, Asp151, Arg152, Arg224, Glu276, Arg292, and Arg371 in the N1 numbering system) [ 6 , 7 ]. Conserved Tyr406 is also a key catalytic residue that serves as a nucleophile [ 8 ].…”