Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.
J Med Chem
; 61(8): 3325-3349, 2018 04 26.
Article
em En
| MEDLINE
| ID: mdl-29551072
ABSTRACT
In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.jmedchem.7b01691 ] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas de Escherichia coli
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Inibidores Enzimáticos
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Compostos Heterocíclicos com 2 Anéis
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Antibacterianos
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Nucleotidiltransferases
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article