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Abstract
The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, 1H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20–30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.
Highlights
Influenza is one of the most common and dangerous viral respiratory diseases; it affects three to five million cases of severe illness and leads to approximately 250,000 to 500,000 deaths every year worldwide [1,2]
C-9 positions were accomplished, our attention was directed to the biological activities of the antiSince the synthesis of sialic acid derivatives having a pentacyclic triterpene substituent at the C-5 or influenza
The results showed that they displayed no inhibition activity on VSV entry, indicating that they are specific anti-influenza entry inhibitors
Summary
Influenza is one of the most common and dangerous viral respiratory diseases; it affects three to five million cases of severe illness and leads to approximately 250,000 to 500,000 deaths every year worldwide [1,2]. Virus to be inhibiting unable to and zanamivir (Relenza),activity on the other hand, target neuraminidase protein, escape from its host cells. Emergence of drug-resistant influenza viruses hasitslimited the its enzymatic activity and causing thethe tethered progeny virus to be unable to escape from host cells. N-acetylneuraminic acid—Neu5Ac), a negatively acharged nine-carbon nine-carbon monosaccharide, present at the non-reducing terminal positions of carboxylated carboxylated monosaccharide, is present at theisnon-reducing terminal positions of carbohydrate chains carbohydrate chains of glycoproteins and glycolipids on the cell surface [12]. Many efforts have been made to develop made to develop an anti-influenza drug based on a sialic acid scaffold [14,15,16]. The analogs an anti-influenza drug based on a sialic acid scaffold [14,15,16].
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