β-Lactam antibiotics are among the most valued drug classes and act via covalent inhibition of penicillin-binding proteins. Until recently, it was regarded that β-lactams were ineffective against Mycobacterium tuberculosis (Mtb), due to β-lactamase activity and the presence of transpeptidases in the cell wall. We have identified cephalosporin analogues active against Mtb; however, these compounds are unstable in mouse plasma. To probe this observation and develop structurally distinct analogues, we have prepared a library of benzazetidines containing features of our hit compounds. While benzazetidines and β-lactams both contain a highly strained four-membered nitrogen heterocycle, azetidines are not prone to covalent binding via the classic β-lactam ring-opening mechanism. A summary of our synthetic efforts and screening results against Mtb of this rare and underexploited heterocyclic scaffold will be presented.

Strained amine heterocycles as non-hydrolyzable β-lactam surrogates: Mechanistic probes for Mycobacterium tuberculosis

256th National Meeting (2018)

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