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Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).

Miller WH, Seefeld MA, Newlander KA, Uzinskas IN, Burgess WJ, Heerding DA, Yuan CC, Head MS, Payne DJ, Rittenhouse SF, Moore TD, Pearson SC, Berry V, DeWolf WE, Keller PM, Polizzi BJ, Qiu X, Janson CA, Huffman WF
J Med Chem 45 3246-56 (2002)
Cited: 61 times
EuropePMC logo PMID: 12109908

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.

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Reviews citing this publication (18)

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  36. Characterization of protein-ligand binding interactions of enoyl-ACP reductase (FabI) by native MS reveals allosteric effects of coenzymes and the inhibitor triclosan. Joyner PM, Tran DP, Zenaidee MA, Loo JA. Protein Sci 31 568-579 (2022)
  37. Synthesis and anticholinesterase activity of 2-substituted-N-alkynylindoles. Prochnow T, Maroneze A, Back DF, Jardim NS, Nogueira CW, Zeni G. Org Biomol Chem 16 7926-7934 (2018)
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