Antibacterial Mimics of Natural Products by Side-Chain Functionalization of Bicyclic Tetramic Acids

Abstract

Tetramic acids with unsaturated acyl chains are widely found in natural products possessing a range of biological activities, and bicyclic tetramates represent a suitable scaffold to prepare simple mimics of such complex molecules. An efficient route to functionalize the C(6)-acyl group of a bicyclic tetramate was developed and utilized to prepare a small chemical library with a range of saturated and unsaturated side-chains. The analogues with lipophilic residues possessed highly potent antibacterial activity, which was selective for Gram-positive bacteria, and the best compound was 37-fold more potent than the cephalosporin C control and with an appropriate therapeutic window.

Mediation of metal chelation in cysteine-derived tetramate systems

“…Each of products 23–30 was obtained as an approximately equal ratio mixture of C2′′ R / S diastereomers (Table S3, ESI † ). Consistent with previous observations, 58 the side chain tricarbonyl system existed in the keto-form, indicated by the presence of an H-2′′ singlet in 1 H NMR spectra. Exclusive formation of the cis diastereomer was found in all cases except for 27ii.…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…Notwithstanding the fact that this compound has every ring carbon functionalised, it was found to undergo highly selective Grignard displacement at the Weinreb amide and gave alkyl systems 74a,b,d. 122 However, when the Grignard was unsaturated (e.g., an alkynyl…”

“…134 It has recently been reported that substituted tetramic acids, tetronic acids and dihydropyridin-2-ones are potent inhibitors of undecaprenyl pyrophosphate synthase (UPPS), 135 and we found that some of our compounds showed dual activity against UPPS and ribonucleic acid polymerase (RNAP). 130 Of interest is that the hydroxylated pyroglutamates of type 28, 32 and 36 showed better Gram-negative activity, 56,57,[121][122][123] and broader activity was found for spiro systems 48 although alkylated and arylated pyroglutamates were fully inactive. 105,125 It is clear that these systems offer considerable promise for the development of antibacterial agents.…”

Synthesis, characterization and antimicrobial activity of N-acetyl-3-acetyl-5-benzylidene tetramic acid-metal complexes. X-ray analysis and identification of the Cd(II) complex as a potent antifungal agent

“…These structures have inspired synthetic and medicinal chemists to focus on the tetramic acids and the endless possibilities of derivatizing them in order to reach novel antibiotic compounds [17]. Various structure activity relationship studies on antimicrobial activities have been published, often with impressive results [18][19][20][21][22]. In one of these works [21], it has been shown that some copper(II) tetramic acid complexes exhibit higher activity than their parent compounds.…”