A detailed study of antibacterial 3-acyltetramic acids and 3-acylpiperidine-2,4-diones.
Inspired by the core fragment of antibacterial natural products such as streptolydigin, 3-acyltetramic acids and 3-acylpiperidine-2,4-diones have been synthesised from the core heterocycle by direct acylation with the substituted carboxylic acids using a strategy which permits ready access to a structurally diverse compound library. The antibacterial activity of these systems has been established against a panel of Gram-positive and Gram-negative bacteria, with activity mostly against the former, which in some cases is very potent. Data consistent with modes of action against undecaprenylpyrophosphate synthase (UPPS) and/or RNA polymerase (RNAP) for a small subset of the library has been obtained. The most active compounds have been shown to exhibit binding at known binding sites of streptolydigin and myxopyronin at UPPS and RNAP. These systems offer potential for their antibacterial activity, and further demonstrate the use of natural products as biologically validated starting points for drug discovery.
Chemistry Research Laboratory, University of Oxford, Mansfield Rd, Oxford, OX1 3TA (UK).
Yong-Chul
YC
Jeong
Zsolt
Z
Bikadi
Eszter
E
Hazai
Mark G
MG
Moloney
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000617:Aminoglycosides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D007783:Lactones; C100307:streptolydigin; C040322:myxopyronin A; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase; D012321:DNA-Directed RNA Polymerases
antibacterial agents; drug discovery; synthesis; tetramates