Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B.
Eur J Med Chem
; 125: 500-514, 2017 Jan 05.
Article
en En
| MEDLINE
| ID: mdl-27689732
ABSTRACT
Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50 value of 16 and 0.5 µM respectively.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_neglected_diseases
/
3_zoonosis
Asunto principal:
Adenosina Trifosfato
/
Girasa de ADN
/
Escherichia coli
/
Inhibidores de Topoisomerasa II
/
Antibacterianos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2017
Tipo del documento:
Article
País de afiliación:
Eslovenia