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

• Published in: Journal of organic chemistry Vol. 84; no. 11; pp. 6697 - 6708
• Main Authors: Li, Wanqing, Santra, Abhishek, Yu, Hai, Slack, Teri J, Muthana, Musleh M, Shi, Dashuang, Liu, Yang, Chen, Xi
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07-06-2019
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.9b00385

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.