Tetrazole-based inhibitors of the bacterial enzyme N-succinyl-L,L-2,6-diaminopimelic acid desuccinylase as potential antibiotics

Journal Article · 08 February 2023 · Bioorganic and Medicinal Chemistry Letters

DOI: https://doi.org/10.1016/j.bmcl.2023.129177 · OSTI ID:1994199

DiPuma Jr., Thomas  ^[1]; Thabthimthong, Teerana  ^[1]; Kelley, Emma H.  ^[1]; Konczak, Katherine  ^[1]; Beulke, Megan  ^[1]; Herbert, Claire  ^[1]; S. Habeeb Mohammad, Thahani  ^[1]; Starus, Anna ^[1]; Nocek, Boguslaw ^[2]; Olsen, Kenneth W. ^[1]; Holz, Richard C. ^[3]; Becker, Daniel P.  ^[1]

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1. Loyola University Chicago, IL (United States)
2. Argonne National Laboratory (ANL), Argonne, IL (United States). Biosciences Division
3. Colorado School of Mines, Golden, CO (United States)

Based on a hit from a high-throughput screen, a series of phenyltetrazole amides was synthesized and assayed for inhibitory potency against DapE from Haemophilus influenzae (HiDapE). The inhibitory potency was modest but confirmed, with the most potent analog containing an aminothiazole moiety displaying an IC₅₀ = 50.2 ± 5.0 μM. Finally, docking reveals a potential binding mode wherein the amide carbonyl bridges both zinc atoms in the active site, and the tetrazole forms key hydrogen bonds with Arg330.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: USDOE; National Science Foundation (NSF); Michael and Dorothy Carbon Fellowship
• Grant/Contract Number: AC02-06CH11357
• OSTI ID: 1994199
• Journal Information: Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Vol. 83; ISSN 0960-894X
• Publisher: ElsevierCopyright Statement
• Country of Publication: United States
• Language: English