A new selective inhibitor for IMP-1 metallo-β-lactamase, 3Z, 5E-octa-3, 5-diene-1, 3, 4-tricarboxylic acid-3, 4-anhydride. (15th January 2023)

• Record Type: Journal Article
• Authors: Ikeda, Akari; Ikegaya, Yoshiki; Honsho, Masako; Matsui, Hidehito; Nonaka, Kenichi; Ishii, Takahiro; Asami, Yukihiro; Hanaki, Hideaki; Hirose, Tomoyasu; Sunazuka, Toshiaki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 78(2023)
• Publication Date: 2023-01-15
• Subjects: Metallo-β-lactamase -- Selective inhibition for IMP-1 MBL -- 3Z, 5E-Octa-3, 5-diene-1, 3, 4-tricarboxylic acid-3, 4-anhydride -- Pseudomonas aeruginosa -- β-carbonyl-α, β-unsaturated carboxylic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.117109
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstracts: Highlights: 3 Z, 5 E -Octa-3, 5-diene-1, 3, 4-tricarboxylic acid-3, 4-anhydride (ODTAA) was found by a selective IMP-1 MBL inhibitory activity from microbial metabolites. First total synthetic route was established by Suzuki-Miyaura cross-coupling reaction, Julia- Kocienski olefination, and singlet oxygen oxidation. The introduction of catechol improved the antimicrobial activity against IMP-1 MBL-producing E. coli and P. aeruginosa . β-Carbonyl-α, β-unsaturated carboxylic acid was suggested as a pharmacophore for selective IMP-1 MBL inhibitory activity. Abstract: 3 Z, 5 E -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.