ABSTRACT
BACKGROUND: 4-Hydroxyphenylpyruvate dioxygenase (HPPD) (EC 1.13.11.27) has been identified as one of the most promising target sites for herbicide discovery. To discover novel HPPD inhibitors with high herbicidal activity and improved crop selectivity, a series of novel triketone-containing quinazoline-2,4-dione derivatives possessing a variety of substituents at the N-1 position of the quinazoline-2,4-dione ring were designed and synthesised. RESULTS: The results of in vitro tests and greenhouse experiments indicated that some analogues showed good HPPD inhibitory activity, with promising broad-spectrum herbicidal activity at a rate of 150 g AI ha(-1) . Most surprisingly, compound 11 h, 1-ethyl-6-(2-hydroxy-6-oxocyclohex-1-enecarbonyl)-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione, showed the highest HPPD inhibition activity, with a Ki value of 0.005 µM, about 2 times more potent than mesotrione (Ki = 0.013 µM). Further greenhouse experiments indicated that compounds 11d and 11 h displayed strong and broad-spectrum post-emergent herbicidal activity even at a dosage as low as 37.5 g AI ha(-1) , which was superior to mesotrione. More importantly, compounds 11d and 11 h were safe for maize at a rate of 150 g AI ha(-1) , and compound 11d was safe for wheat as well. CONCLUSION: The present work indicated that the triketone-containing quinazoline-2,4-dione motif could be a potential lead structure for further development of novel herbicides.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase/antagonists & inhibitors , Arabidopsis Proteins/antagonists & inhibitors , Arabidopsis/drug effects , Herbicides/pharmacology , Quinazolines/pharmacology , 4-Hydroxyphenylpyruvate Dioxygenase/chemistry , Arabidopsis/chemistry , Arabidopsis/enzymology , Arabidopsis Proteins/chemistry , Herbicides/chemical synthesis , Herbicides/chemistry , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity RelationshipABSTRACT
4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting 4-hydroxyphenylpyruvate acid to homogentisate, is an important target for treating type I tyrosinemia and alkaptonuria due to its significant role in tyrosine catabolism. However, only one commercial drug, NTBC, also known as nitisinone, has been available for clinical use so far. Herein, we have elucidated the structure-based design of a series of pyrazolone-quinazolone hybrids that are novel potent human HPPD inhibitors through the successful integration of various techniques including computational simulations, organic synthesis, and biochemical characterization. Most of the new compounds displayed potent inhibitory activity against the recombinant human HPPD in nanomolar range. Compounds 3h and 3u were identified as the most potent candidates with Ki values of around 10 nM against human HPPD, about three-fold more potent than NTBC. Molecular modeling indicated that the interaction between the pyrazolone ring and ferrous ion, and the hydrophobic interaction of quinazolone with its surrounding residues, such as Phe347 and Phe364, contributed greatly to the high potency of these inhibitors. Therefore, compounds 3h and 3u could be potentially useful for the treatment of type I tyrosinemia and other diseases with defects in tyrosine degradation.
