Direct Staudinger–Phosphonite Reaction Provides Methylphosphonamidates as Inhibitors of CE4 De‐N‐acetylases |
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| Authors: | Rishikesh Ariyakumaran Varvara Pokrovskaya Dustin J Little P Lynne Howell Mark Nitz |
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| Affiliation: | 1. Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 (Canada);2. Program in Molecular Structure and Function, The Hospital for Sick Children and Department of Biochemistry, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8 (Canada) |
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| Abstract: | De‐N‐acetylases of β‐(1→6)‐D ‐N‐acetylglucosamine polymers (PNAG) and β‐(1→4)‐D ‐N‐acetylglucosamine residues in peptidoglycan are attractive targets for antimicrobial agents. PNAG de‐N‐acetylases are necessary for biofilm formation in numerous pathogenic bacteria. Peptidoglycan de‐N‐acetylation facilitates bacterial evasion of innate immune defenses. To target these enzymes, transition‐state analogue inhibitors containing a methylphosphonamidate have been synthesized through a direct Staudinger–phosphonite reaction. The inhibitors were tested on purified PgaB, a PNAG de‐N‐acetylase from Escherichia coli, and PgdA, a peptidoglycan de‐N‐acetylase from Streptococcus pneumonia. Herein, we describe the most potent inhibitor of peptidoglycan de‐N‐acetylases reported to date (Ki=80 μM ). The minimal inhibition of PgaB observed provides insight into key structural and functional differences in these enzymes that will need to be considered during the development of future inhibitors. |
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| Keywords: | de‐N‐acetylase inhibitors methylphosphonamidate Staudinger reaction transition states |
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