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

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.
Shintaro Kusaka 1,  Kazuki Yamamoto 1,  Motoko Shinohara 2,  Yusuke Minato 2,  Satoshi Ichikawa 3
Affiliations

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: [email protected].
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.

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