Azetidine-2,4-diones (4-oxo-β-lactams) as Scaffolds for Designing Elastase Inhibitors

Jalmira Mulchande, Rita C. Guedes, Wing Yin Tsang, Michael I. Page, Rui Moreira, Jim Iley

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


A new class of inhibitors 4-oxo-β-lactams (azetidine-2,4-diones), containing the required structural elements for molecular recognition, inhibit porcine pancreatic elastase (PPE) but show a dramatically lower reactivity toward hydroxide compared with the analogous inhibitors 3-oxo-β-sultams. Inhibition is the result of acylation of the active site serine and electron-withdrawing substituents at the N-(4-aryl) position in 3,3-diethyl-N-aryl derivatives increasing the rate of enzyme acylation and generating a Hammett ρ-value of 0.65. Compared with a ρ-value of 0.96 for the rates of alkaline hydrolysis of the same series, this is indicative of an earlier transition state for the enzyme-catalyzed reaction. Docking studies indicate favorable noncovalent interactions of the inhibitor with the enzyme. Compound 2i, the most potent inhibitor against PPE, emerged as a very potent HLE inhibitor, with a second-order rate for enzyme inactivation of ∼5 × 105 M-1 s-1.

Original languageEnglish
Pages (from-to)1783-1790
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number6
Early online date22 Feb 2008
Publication statusPublished - 2008


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