title: Design, synthesis and structure-activity relationships of substituted oxazole-benzamide antibacterial inhibitors of FtsZ.
abstract: The design, synthesis and structure-activity relationships of a series of oxazole-benzamide inhibitors of the essential bacterial cell division protein FtsZ are described. Compounds had potent anti-staphylococcal activity and inhibited the cytokinesis of the clinically-significant bacterial pathogen Staphylococcus aureus. Selected analogues possessing a 5-halo oxazole also inhibited a strain of S. aureus harbouring the glycine-to-alanine amino acid substitution at residue 196 of FtsZ which conferred resistance to previously reported inhibitors in the series. Substitutions to the pseudo-benzylic carbon of the scaffold improved the pharmacokinetic properties by increasing metabolic stability and provided a mechanism for creating pro-drugs. Combining multiple substitutions based on the findings reported in this study has provided small-molecule inhibitors of FtsZ with enhanced in vitro and in vivo antibacterial efficacy.
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Stokes
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Baker
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Chauhan
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Davies
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Maruti
authors.initials: M
authors.lastname: Gavade
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Dushyant
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Lancett
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Macdonald
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Leanne
authors.initials: L
authors.lastname: Macleod
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Anu
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, VIC 3168, Australia.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Mitchell
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Narendra
authors.initials: N
authors.lastname: Nayal
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Yashodanand Nandan
authors.initials: YN
authors.lastname: Nayal
authors.affiliation: Biota Scientific Management Pty Ltd, 10/585 Blackburn Road, Notting Hill, VIC 3168, Australia.
authors.forename: Gary R W
authors.initials: GR
authors.lastname: Pitt
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Mahipal
authors.initials: M
authors.lastname: Singh
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Jubilant Chemsys Ltd, B-34, Sector-58, Noida 201301, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom.
authors.forename: Lloyd G
authors.initials: LG
authors.lastname: Czaplewski
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Oxfordshire OX5 1PF, United Kingdom. Electronic address: d.haydon@biota.com.au.
authors.forename: David J
authors.initials: DJ
authors.lastname: Haydon
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001549:Benzamides; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D010080:Oxazoles; C037689:benzamide
keywords: 3-Methoxybenzamide; Antibacterial; Cell division; FtsZ; MRSA