Synthesis and Antibacterial Analysis of Analogues of the Marine Alkaloid Pseudoceratidine

• Main Authors: David Barker, Stephanie Lee, Kyriakos G. Varnava, Kevin Sparrow, Michelle van Rensburg, Rebecca C. Deed, Melissa M. Cadelis, Steven A. Li, Brent R. Copp, Vijayalekshmi Sarojini, Lisa I. Pilkington
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Molecules
• Subjects: marine natural product; analogue synthesis; SAR; pseudoceratidine; antibacterial activity
• Online Access: https://www.mdpi.com/1420-3049/25/11/2713

In an effort to gain more understanding on the structure activity relationship of pseudoceratidine <b>1</b>, a di-bromo pyrrole spermidine alkaloid derived from the marine sponge <i>Pseudoceratina purpurea</i> that has been shown to exhibit potent biofouling, anti-fungal, antibacterial, and anti-malarial activities, a large series of 65 compounds that incorporated several aspects of structural variation has been synthesised through an efficient, divergent method that allowed for a number of analogues to be generated from common precursors. Subsequently, all analogues were assessed for their antibacterial activity against both Gram-positive (<i>Staphylococcus aureus</i>) and Gram-negative (<i>Escherichia coli</i>) bacteria. Overall, several compounds exhibited comparable or better activity than that of pseudoceratidine <b>1</b>, and it was found that this class of compounds is generally more effective against Gram-positive than Gram-negative bacteria. Furthermore, altering several structural features allowed for the establishment of a comprehensive structure activity relationship (SAR), where it was concluded that several structural features are critical for potent anti-bacterial activity, including di-halogenation (preferable bromine, but chlorine is also effective) on the pyrrole ring, two pyrrolic units in the structure and with one or more secondary amines in the chain adjoining these units, with longer chains giving rise to better activities.