Beta-triketone inhibitors of plant p-hydroxyphenylpyruvate dioxygenase: modeling and comparative molecular field analysis of their interactions.
p-Hydroxyphenylpyruvate dioxygenase (HPPD) is the target site of beta-triketone herbicides in current use. Nineteen beta-triketones and analogues, including the naturally occurring leptospermone and grandiflorone, were synthesized and tested as inhibitors of purified Arabidopsis thaliana HPPD. The most active compound was a beta-triketone with a C(9) alkyl side chain, not reported as natural, which inhibited HPPD with an I(50) of 19 +/- 1 nM. This is significantly more active than sulcotrione, which had an I(50) of 250 +/- 21 nM in this assay system. The most active naturally occurring beta-triketone was grandiflorone, which had an I(50) of 750 +/- 70 nM. This compound is of potential interest as a natural herbicide because it can be extracted with good yield and purity from some Leptospermum shrubs. Analogues without the 1,3-diketone group needed to interact with Fe(2+) at the HPPD active site were inactive (I(50)s > 50 microM), as were analogues with prenyl or ethyl groups on the triketone ring. Modeling of the binding of the triketones to HPPD, three-dimensional QSAR analysis using CoMFA (comparative molecular field analysis), and evaluation of the hydrophobic contribution with HINT (hydropathic interactions) provided a structural basis to describe the ligand/receptor interactions.
Dayan
Franck E
FE
US Department of Agriculture, Natural Products Utilization Research Unit, Agricultural Research Service, University, Mississippi 38677, USA. fdayan@olemiss.edu
Singh
Nidhi
N
McCurdy
Christopher R
CR
Godfrey
Colette A
CA
Larsen
Lesley
L
Weavers
Rex T
RT
Van Klink
John W
JW
Perry
Nigel B
NB
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017360:Arabidopsis / Q000737:chemistry / Q000201:enzymology*; D001665:Binding Sites; D003512:Cyclohexanones / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006540:Herbicides / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D010940:Plant Proteins / Q000737:chemistry*; D011485:Protein Binding
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D006540:Herbicides; D010940:Plant Proteins; D015111:4-Hydroxyphenylpyruvate Dioxygenase