Synthesis and antimicrobial activities of N6-hydroxyagelasine analogs and revision of the structure of ageloximes

Britt Paulsen; Kim Alex Fredriksen; Dirk Petersen; Louis Maes; An Matheeussen; Ali-Oddin Naemi; Anne Aamdal Scheie; Roger Simm; Rui Ma; Baojie Wan; Scott Franzblau; Lise-Lotte Gundersen

doi:10.1016/j.bmc.2019.01.002

Synthesis and antimicrobial activities of N⁶-hydroxyagelasine analogs and revision of the structure of ageloximes

Bioorg Med Chem. 2019 Feb 15;27(4):620-629. doi: 10.1016/j.bmc.2019.01.002. Epub 2019 Jan 4.

Authors

Affiliations

¹ Department of Chemistry, University of Oslo, P.O.Box 1033, Blindern, 0315 Oslo, Norway.
² Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Wilrijk, Belgium.
³ Institute of Oral Biology, University of Oslo, P.O. Box 1052, Blindern, 0316 Oslo, Norway.
⁴ Institute for Tuberculosis Research, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL, USA.
⁵ Department of Chemistry, University of Oslo, P.O.Box 1033, Blindern, 0315 Oslo, Norway. Electronic address: [email protected].

PMID: 30638761
DOI: 10.1016/j.bmc.2019.01.002

Abstract

(+)-N⁶-Hydroxyagelasine D, the enantiomer of the proposed structure of (-)-ageloxime D, as well as N⁶-hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N⁶-[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N⁶-Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation. However these compounds were also toxic towards mammalian fibroblast cells (MRC-5). The spectral data of N⁶-hydroxyagelasine D did not match those reported for ageloxime D before. Hence, a revised structure of ageloxime D was proposed. Basic hydrolysis of agelasine D gave (+)-N-[4-amino-6-(methylamino)pyrimidin-5-yl]-N-copalylformamide, a compound with spectral data in full agreement with those reported for (-)-ageloxime D.

Keywords: Agelasine; Ageloxime; Antimicrobial activity; Structure elucidation.

Publication types

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / pharmacology*
Anti-Bacterial Agents / toxicity
Biofilms / drug effects
Candida albicans / drug effects
Cell Line
Diterpenes / chemical synthesis
Diterpenes / pharmacology*
Diterpenes / toxicity
Escherichia coli / drug effects
Humans
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Pyrimidines / toxicity
Staphylococcus aureus / drug effects
Trypanosomatina / drug effects

Substances

Anti-Bacterial Agents
Diterpenes
Pyrimidines