Pyrazole–Isoindoline-1,3-dione Hybrid: A Promising Scaffold for 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Abstract

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC₅₀ values against the recombinant <i>Arabidopsis thaliana</i> HPPD (<i>At</i>HPPD) ranging from 0.0039 μM to over 1 μM. Most promisingly, compound <b>4ae</b>, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1<i>H</i>-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest <i>At</i>HPPD inhibitory activity with a <i>K</i>_i value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (<i>K</i>_i = 44 nM) and slightly more potent than mesotrione (<i>K</i>_i = 4.56 nM). In addition, the cocrystal structure of the <i>At</i>HPPD-<b>4ae</b> complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of <b>4ae</b>. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.