title: Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors.
abstract: A set of novel pantothenamide-type analogues of the known Staphylococcus aureus pantothenate kinase (SaPanK) inhibitors, N-pentyl, and N-heptylpantothenamide, was synthesized in three series. The first series of analogues (1-3) were designed as molecular probes of the PanK binding site to elucidate important structure-activity relationships (SAR). The second series of analogues (4-16) were designed using structural information obtained from the Escherichia coli PanK (EcPanK) structure by targeting the pantothenate binding site and the adjacent phenylalanine-lined lipophilic pocket. Insight into the antimicrobial effect of N-pentylpantothenamide (N5-Pan) through its conversion to the antimetabolite ethyldethia-CoA and further incorporation into an inactive acyl carrier protein analogue drove the development of the third series of analogues (17-25) to enhance this effect using substrate-like substitutions. Each of the analogues was screened for enzyme inhibition activity against a panel of pantothenate kinases consisting of EcPanK, Aspergillus nidulans (AnPanK), SaPanK, and the murine isoform (MmPanK1alpha). Series 1 demonstrated only modest inhibitory activity, but did reveal some important SAR findings including stereospecific binding. Series 2 demonstrated a much higher inhibition rate for the entire series and significant inhibition was seen with analogues containing alkyl substituents. Series 3 demonstrated the most preferential inhibition profile, with the highest inhibitory activity against the SaPanK and MmPanK1alpha. The MmPanK1alpha protein was inhibited by a broad spectrum of the compounds, whereas the E. coli enzyme showed greater selectivity. The overall activity data from these analogues suggest a complex and non-enzyme specific SAR for pantothenamide substrate/inhibitors of the different PanK enzymes.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, 38163, USA.
authors.forename: Kristopher G
authors.initials: KG
authors.lastname: Virga
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Roberta
authors.initials: R
authors.lastname: Leonardi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ivey
authors.forename: Kirk
authors.initials: K
authors.lastname: Hevener
authors.forename: Hee-Won
authors.initials: HW
authors.lastname: Park
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D001665:Binding Sites; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase