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

Structure–activity relationships were determined for three series of pantothenamide-type pantothenate kinase inhibitors through their evaluation in vivo against a panel of four PanK enzymes and for antimicrobial activity. 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.