Discovery of Aminopyridine-Based Inhibitors of Bacterial Enoyl-ACP Reductase (FabI)

Abstract

Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

“…The most salient features that had emerged from the atomic structures of ENR-NAD(H) complexed with triclosan and with other inhibitors like diazoborines, imidazoles, and aminopyridines were: 1) p-p stacking interaction between one of the aromatic rings of the inhibitors with the nicotinamide ring of the cofactor NADH and 2) a Hydrogen bond between the active site residue-Tyr277 and the inhibitor (15,(38)(39)(40). Our previous work to identify new scaffolds of inhibitors against PfENR, based on the above key features of interactions of the inhibitor with active-site residues and NADH led to the discovery of a new class of inhibitors.…”

Chalcomoracin and Moracin C, New Inhibitors of <i>Staphylococcus aureus</i> Enoyl-Acyl Carrier Protein Reductase from <i>Morus alba</i>

“…Several synthetic FabI inhibitors, including 1,4-disubstituted imidazoles, 10) aminopyridines, 11) naphthyridinones, 12,13) and thiopyridines 14) have been reported in previous studies. Cephalochromin, 15) vinaxanthone, 16) epigallocatechin gallate (EGCG), 17) and flavonoids 18) have all been identified as natural FabI inhibitors.…”

“…Disposition of the two hydroxyl and prenyl groups was deduced from the two proton singlet at 6.78 (2H, s, H-2′,6′). The above spectral data were compared with those in the literature, 10,11) and compounds 1 and 2 were identified as chalcomoracin and moracin C, respectively.…”

“…Therefore, inhibitors of S. aureus FabI may prove to be interesting lead compounds for the development of effective antibacterial drugs. Several synthetic [10][11][12][13][14] and natural [15][16][17][18] FabI inhibitors have been reported, but since some compounds showed toxicity and their structures are not so diverse for further study, Fab I inhibitors with new scaffold and low toxicity are desired. Since S. aureus is the most common pathogen and especially multidrugs-resistant S. aureus such as methicillin-resistant S. aureus (MRSA) is becoming increasingly prevalent in community-acquired infections, 19) new antibacterial with new mode of action like S. aureus FabI inhibitors is urgently needed.…”

3-Substituted Indole Inhibitors Against Francisella tularensis FabI Identified by Structure-Based Virtual Screening

“…Six known FabI inhibitors that were cocrystallized with other FabI were collected and used as query molecules. The molecules were obtained from PDBs 2OP0 (P. falciparum), 53 3OIG (B. subtilis), 54 1I2Z (E. coli), 55 1LX6 (E. coli), 56 1LXC (E. coli), 56 and 1MFP (E. coli) 57 (Supporting Information Figure S2). The top 2000 most similar molecules were selected and subjected to hierarchical virtual screening protocol in the Glide program.…”