9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases

Wanqing Li, Abhishek Santra, Hai Yu, Teri J. Slack, Musleh M. Muthana, Dashuang Shi, Yang Liu, Xi Chen

Research output: Contribution to journalArticle

Abstract

A library of 2(a),3(a/e)-difluorosialic acids and their C-5 and/or C-9 derivatives were chemoenzymatically synthesized. Pasteurella multocida sialic acid aldolase (PmAldolase), but not its Escherichia coli homologue (EcAldolase), was found to catalyze the formation of C5-azido analogue of 3-fluoro(a)-sialic acid. In comparison, both PmAldolase and EcAldolase could catalyze the synthesis of 3-fluoro(a/e)-sialic acids and their C-9 analogues although PmAldolase was generally more efficient. The chemoenzymatically synthesized 3-fluoro(a/e)-sialic acid analogues were purified and chemically derivatized to form the desired difluorosialic acids and derivatives. Inhibition studies against several bacterial sialidases and a recombinant human cytosolic sialidase hNEU2 indicated that sialidase inhibition was affected by the C-3 fluorine stereochemistry and derivatization at C-5 and/or C-9 of the inhibitor. Opposite to that observed for influenza A virus sialidases and hNEU2, compounds with axial fluorine at C-3 were better inhibitors (up to 100-fold) against bacterial sialidases compared to their 3F-equatorial counterparts. While C-5-modified compounds were less-efficient antibacterial sialidase inhibitors, 9-N3-modified 2,3-difluoro-Neu5Ac showed increased inhibitory activity against bacterial sialidases. 9-Azido-9-deoxy-2-(e)-3-(a)-difluoro-N-acetylneuraminic acid [2(e)3(a)DFNeu5Ac9N3] was identified as an effective inhibitor with a long effective duration selectively against pathogenic bacterial sialidases from Clostridium perfringens (CpNanI) and Vibrio cholerae.

Original languageEnglish (US)
Pages (from-to)6697-6708
Number of pages12
JournalJournal of Organic Chemistry
Volume84
Issue number11
DOIs
StatePublished - Jun 7 2019

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N-acetylneuraminate lyase
Neuraminidase
N-Acetylneuraminic Acid
Fluorine
Sialic Acids
Derivatives
Clostridium
Stereochemistry
Acids
Viruses
Escherichia coli
2,3-difluorosialic acid

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases. / Li, Wanqing; Santra, Abhishek; Yu, Hai; Slack, Teri J.; Muthana, Musleh M.; Shi, Dashuang; Liu, Yang; Chen, Xi.

In: Journal of Organic Chemistry, Vol. 84, No. 11, 07.06.2019, p. 6697-6708.

Research output: Contribution to journalArticle

Li, Wanqing ; Santra, Abhishek ; Yu, Hai ; Slack, Teri J. ; Muthana, Musleh M. ; Shi, Dashuang ; Liu, Yang ; Chen, Xi. / 9-Azido-9-deoxy-2,3-difluorosialic Acid as a Subnanomolar Inhibitor against Bacterial Sialidases. In: Journal of Organic Chemistry. 2019 ; Vol. 84, No. 11. pp. 6697-6708.
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