Diarylpropane-1,3-dione derivatives as TetR-inducing tetracycline mimetics: Synthesis and biological investigations.
Synthesis, biological investigations and molecular docking studies of nonantibiotic and nontetracyclic inducers that feature a minimal key motif of the natural lead tetracycline are presented. The diarylpropane-1,3-dione motif was identified as the minimal substructure responsible for TetR induction by tetracyclines. The first nontetracyclic surrogates of the natural tetracyclines displayed significant inducing effects for TetR(BD)S135L, whereby the chlorohydroxyphenyl-substituted beta-diketone 31 displayed the highest activity. Interestingly, antibiotic activity could not be detected for 31. Homology modeling based on the X-ray structure of 7-chlorotetracycline bound to TetR indicated analogous binding modes for the natural inducer and the synthetic diarylpropane-1,3-dione derivatives.
Kormann
Christian
C
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Erlangen, Germany.
Pimenta
Irina
I
Löber
Stefan
S
Wimmer
Cornelius
C
Lanig
Harald
H
Clark
Timothy
T
Hillen
Wolfgang
W
Gmeiner
Peter
P
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047188:Chalcones / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D047188:Chalcones; D012097:Repressor Proteins; D013754:Tetracyclines; C034811:tetracycline resistance-encoding transposon repressor protein