Sulfonamide-based non-alkyne LpxC inhibitors as Gram-negative antibacterial agents

Tetsuya Kawai; Iwase Kazuhiko; Noriko Takaya; Yuko Yamaguchi; Ryuta Kishii; Yasushi Kohno; Haruaki Kurasaki

doi:10.1016/j.bmcl.2016.12.059

Sulfonamide-based non-alkyne LpxC inhibitors as Gram-negative antibacterial agents

Bioorg Med Chem Lett. 2017 Feb 15;27(4):1045-1049. doi: 10.1016/j.bmcl.2016.12.059. Epub 2016 Dec 24.

Authors

Tetsuya Kawai¹, Iwase Kazuhiko¹, Noriko Takaya¹, Yuko Yamaguchi¹, Ryuta Kishii¹, Yasushi Kohno¹, Haruaki Kurasaki²

Affiliations

¹ Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
² Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: haruaki.kurasaki@mb.kyorin-pharm.co.jp.

PMID: 28082037
DOI: 10.1016/j.bmcl.2016.12.059

Abstract

We attempted to optimize sulfonamide-based non-alkyne LpxC inhibitors by focusing on improvements in enzyme inhibitory and antibacterial activity. It was discovered that inhibitors possessing 2-aryl benzofuran as a hydrophobe exhibited good activity. In particular, compound 21 displayed impressive antibacterial activity (E. coli MIC=0.063μg/mL, K. pneumoniae MIC=0.5μg/mL, and P. aeruginosa MIC=0.5μg/mL), and is a promising lead for further exploration as an antibacterial agent.

Keywords: Antibacterial; Benzofuran; Gram-negative; LpxC; Sulfonamide.

MeSH terms

Amidohydrolases / antagonists & inhibitors*
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Drug Resistance, Bacterial
Gram-Negative Bacteria / drug effects*
Microbial Sensitivity Tests
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

Anti-Bacterial Agents
Sulfonamides
Amidohydrolases
UDP-3-O-acyl-N-acetylglucosamine deacetylase