title: Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses.
abstract: A synthetic reexamination of a series of ketodihydronicotinic acid class antibacterial agents was undertaken in an attempt to improve their therapeutic potential. A convenient new synthesis was developed involving hetero Diels-Alder chemistry producing 74 new analogs in a multiple parallel synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the disappointing activity against bacteria that some of the analogs exhibited.
authors.affiliation: Department of Medicinal Chemistry, Chemical Methodology and Library Development Center of Excellence, Kansas University, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Laursen
authors.forename: John
authors.initials: J
authors.lastname: Nielsen
authors.forename: Torsten
authors.initials: T
authors.lastname: Haack
authors.forename: Srinivas
authors.initials: S
authors.lastname: Pusuluri
authors.forename: Sunil
authors.initials: S
authors.lastname: David
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Yibin
authors.initials: Y
authors.lastname: Zeng
authors.forename: Zhunkun
authors.initials: Z
authors.lastname: Ma
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Doyle
authors.forename: Lester A
authors.initials: LA
authors.lastname: Mitscher
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000890:Anti-Infective Agents; D009539:Nicotinic Acids; D011728:Pyridones