A new selective inhibitor for IMP-1 metallo-β-lactamase, 3Z,5E-octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride

Abstract

3Z,5E-Octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride (ODTAA, 1) was isolated from Paecilomyces sp. FKI-6801 for its selective IMP-1 MBL inhibitory activity. The first total synthesis of 1 from the commercially available compound was achieved in 9 steps with 28% overall yield. Introduction of catechol to the maleic anhydride of 1 improved the IC₅₀ toward IMP-1 MBL and the inhibitory activity against IMP-1 MBL-producing P. aeruginosa. Treatment of the maleic anhydride scaffold with amine showed that the β-carbonyl-α,β-unsaturated carboxylic acid moiety is required as a pharmacophore for IMP-1 MBL inhibition.

Keywords: 3Z,5E-Octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride; Metallo-β-lactamase; Pseudomonas aeruginosa; Selective inhibition for IMP-1 MBL; β-carbonyl-α,β-unsaturated carboxylic acid.