title: Discovery and in vivo evaluation of alcohol-containing benzothiazoles as potent dual-targeting bacterial DNA supercoiling inhibitors.
abstract: A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia. Electronic address: j.palmer@biota.com.au.
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Lorraine C
authors.initials: LC
authors.lastname: Axford
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Barker
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: James M
authors.initials: JM
authors.lastname: Bennett
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Blair
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: David T
authors.initials: DT
authors.lastname: Davies
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ford
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Carlie T
authors.initials: CT
authors.lastname: Gannon
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Lancett
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Logan
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lunniss
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Offermann
authors.affiliation: Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
authors.forename: Gary R W
authors.initials: GR
authors.lastname: Pitt
authors.affiliation: Jubliant Chemsys Ltd, B-34, Sector 58, Noida 201301, India.
authors.forename: B Narasinga
authors.initials: BN
authors.lastname: Rao
authors.affiliation: Jubliant Chemsys Ltd, B-34, Sector 58, Noida 201301, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Jubliant Chemsys Ltd, B-34, Sector 58, Noida 201301, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Shukla
authors.affiliation: Jubliant 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, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Stokes
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: Helena B
authors.initials: HB
authors.lastname: Thomaides-Brears
authors.affiliation: Jubliant Chemsys Ltd, B-34, Sector 58, Noida 201301, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Haydon
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004269:DNA, Bacterial / Q000737:chemistry* / Q000187:drug effects*; D004278:DNA, Superhelical / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006193:Haemophilus influenzae / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013210:Staphylococcus; D013329:Structure-Activity Relationship
chemical_list: D000438:Alcohols; D000900:Anti-Bacterial Agents; D052160:Benzothiazoles; D004269:DNA, Bacterial; D004278:DNA, Superhelical
keywords: Antibacterial; DNA gyrase; Dual-targeting; In vivo; Synthesis; Topoisomerase