Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold

Kazuhiro Okamoto; Aoi Ishikawa; Ryotaro Okawa; Kazuki Yamamoto; Toyotaka Sato; Shin-Ichi Yokota; Kazuhiro Chiba; Satoshi Ichikawa

doi:10.1016/j.bmc.2021.116556

Design, synthesis and biological evaluation of simplified analogues of MraY inhibitory natural product with rigid scaffold

Bioorg Med Chem. 2022 Feb 1:55:116556. doi: 10.1016/j.bmc.2021.116556. Epub 2021 Dec 25.

Authors

Kazuhiro Okamoto¹, Aoi Ishikawa², Ryotaro Okawa², Kazuki Yamamoto², Toyotaka Sato³, Shin-Ichi Yokota⁴, Kazuhiro Chiba¹, Satoshi Ichikawa⁵

Affiliations

¹ Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
² Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
³ Department of Microbiology, Sapporo Medical University, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan; Laboratory of Veterinary Hygiene, School/Faculty of Veterinary Medicine, Hokkaido University, Kita-18, Nishi-9, Kita-ku, Sapporo 060-0818, Japan.
⁴ Department of Microbiology, Sapporo Medical University, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan.
⁵ 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.

PMID: 35016115
DOI: 10.1016/j.bmc.2021.116556

Abstract

Muraymycins and caprazamycins are strong inhibitors of MraY, which is responsible for peptidoglycan biosynthesis. Although they are promising antibacterial agents with a novel mode of action, their chemical structures are rather complex. This study investigated the simplification of these natural products by structure-based drug design, synthesis, and biological evaluation. We developed a simplified rigid scaffold with an arylalkyne moiety, which shows sub-micromolar MraY inhibitory activity. The scaffold is suitable for further investigating the structure-activity relationship by virtue of our synthetic strategy, where the substituent of interest is installed in the last stage of synthesis. This scaffold shows the potential for further use in optimizing MraY inhibitory and antibacterial activities.

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