Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors

Kristopher G. Virga, Yong Mei Zhang, Roberta Leonardi, Robert A. Ivey, Kirk Hevener, Hee Won Park, Suzanne Jackowski, Charles O. Rock, Richard E. Lee

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 (MmPanK1α). 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 MmPanK1α. The MmPanK1α 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.

Original languageEnglish (US)
Pages (from-to)1007-1020
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number4
DOIs
StatePublished - Feb 15 2006

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Enzyme inhibition
Structure-Activity Relationship
Escherichia coli
Staphylococcus aureus
Enzymes
Binding Sites
Acyl Carrier Protein
Antimetabolites
Molecular Probes
Aspergillus nidulans
Aspergillus
Substrates
Coenzyme A
Phenylalanine
Protein Isoforms
Substitution reactions
pantothenate kinase
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors. / Virga, Kristopher G.; Zhang, Yong Mei; Leonardi, Roberta; Ivey, Robert A.; Hevener, Kirk; Park, Hee Won; Jackowski, Suzanne; Rock, Charles O.; Lee, Richard E.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 4, 15.02.2006, p. 1007-1020.

Research output: Contribution to journalArticle

Virga, KG, Zhang, YM, Leonardi, R, Ivey, RA, Hevener, K, Park, HW, Jackowski, S, Rock, CO & Lee, RE 2006, 'Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors', Bioorganic and Medicinal Chemistry, vol. 14, no. 4, pp. 1007-1020. https://doi.org/10.1016/j.bmc.2005.09.021
Virga, Kristopher G. ; Zhang, Yong Mei ; Leonardi, Roberta ; Ivey, Robert A. ; Hevener, Kirk ; Park, Hee Won ; Jackowski, Suzanne ; Rock, Charles O. ; Lee, Richard E. / Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 4. pp. 1007-1020.
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