Parallel solid-phase synthesis and evaluation of inhibitors of Streptomyces coelicolor type II dehydroquinase.
A series of 1-substituted and 4-substituted benzyl analogues of the known inhibitor (1S,3R,4R)-1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid has been synthesized and tested as inhibitors of Streptomyces coelicolor type II dehydroquinase. The solid-phase syntheses of 18 new analogues are reported. The most potent inhibitor, 2-nitrobenzyloxy analogue 5i, has K(i) of 8 microM, more than 30 times lower than the K(M) of the substrate and approximately 4 times more potent than the original inhibitor. The binding modes of the synthesized analogues in the active site were studied by molecular docking with GOLD 2.0.
González-Bello
Concepción
C
Departamento de Química Orgánica y Unidad Asociada al C.S.I.C., Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain. cgb1@lugo.usc.es
Lence
Emilio
E
Toscano
Miguel D
MD
Castedo
Luis
L
Coggins
John R
JR
Abell
Chris
C
D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D012765:Shikimic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013302:Streptomyces / Q000737:chemistry*; D013329:Structure-Activity Relationship
C480611:1,3,4-trihydroxy-5-cyclohexene-1-carboxylic acid; D001593:Benzyl Compounds; D003510:Cyclohexanes; D012765:Shikimic Acid; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase