Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5'-O-aminoribosyluridine as MraY inhibitors

Shintaro Kusaka; Kazuki Yamamoto; Motoko Shinohara; Yusuke Minato; Satoshi Ichikawa

doi:10.1016/j.bmc.2022.116744

Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5'-O-aminoribosyluridine as MraY inhibitors

Bioorg Med Chem. 2022 Jul 1:65:116744. doi: 10.1016/j.bmc.2022.116744. Epub 2022 Apr 20.

Authors

Shintaro Kusaka¹, Kazuki Yamamoto¹, Motoko Shinohara², Yusuke Minato², Satoshi Ichikawa³

Affiliations

¹ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
² Department of Microbiology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
³ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: ichikawa@pharm.hokudai.ac.jp.

PMID: 35500521
DOI: 10.1016/j.bmc.2022.116744

Abstract

It is important to understand and control the biologically active conformation in medicinal chemistry. Muraymycins and caprazamycins, which are strong inhibitors of MraY, are promising antibacterial agents with a novel mode of action. Focusing on a sugar puckering and a dihedral angle ϕ of the uridine moiety of these natural products, LNA/BNA-type 5'-O-aminoribosyluridine analogues, whose puckering of the ribose moiety are completely restricted to the N-type, were designed and synthesized as simplified MraY inhibitors. Their conformation-activity relationship was further investigated in details. The conformation-activity relationship analysis investigated in this study could be a general guideline for simplification and rational drug design of MraY inhibitory nucleoside natural products.

Keywords: Antibacterial; MraY; Natural product; Nucleoside; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemistry
Bacterial Proteins
Biological Products* / chemistry
Structure-Activity Relationship
Transferases (Other Substituted Phosphate Groups)
Transferases*

Substances

Anti-Bacterial Agents
Bacterial Proteins
Biological Products
Transferases
Transferases (Other Substituted Phosphate Groups)