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(27) SB 660618

Bicyclic hydroxamic acids

Researchers at Novartis, Senju and Hoffman-La Roche have reported structurally related bicyclic hydroxamic acids as potent PDF inhibitors [106-108]. In 2001, screening efforts at Hoffman-LaRoche identified hydrazide (28)

as a 27 uM inhibitor of E. coli PDF, and this molecule was subsequently co-crystallised with E. coli Ni2 + -PDF. Interestingly, the urea carbonyl of (28) was not involved in any hydrogen bonding interactions with the enzyme. In attempts to improve potency, hydroxamic acid analogues of both urea (29) and sulfonylurea (30) containing compounds were prepared. While these modifications greatly improved the enzyme inhibitory activity (^500-fold), antibacterial activity was poor except against M. catarrhalis (MIC = 1-4 mg/mL) [106].

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