Synthesis and bioactivity studies of triketone-containing quinazoline-2,4-dione derivatives

Abstract

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important enzyme in the catabolism of tyrosine, catalyzing the conversion of 4-hydroxyphenyl pyruvic acid (HPPA) into homogentisic acid (HGA), belonging to the 2-his-1-carboxylate facial triad family of non-heme iron(II) enzymes. As an important enzyme in regulating the biosynthesis of tocopherols and plastoquinone in plants, HPPD is an important target for herbicides discovery. Previously, we have found that triketone-containing quinazoline-2,4-dione motif can be used as a novel lead structure for herbicides discovery. In this continuous work, we synthesized a total number of 24 new triketone-containing quinazoline-2,4-dione derivatives. The new compounds 9a~9x were prepared by using 5-methyl-2-nitrobenzoic acid as the starting material, followed by oxidation, esterification and reduction reactions, the main intermediate dimethyl 4-aminoisophthalate could be obtained in a yield of 83%, then by another six steps of reactions the target compounds could be smoothly synthesized. All the title compounds were characterized by 1H NMR, 13C NMR and HRMS spectrum data. To explore the biology activity of these compounds, their in vitro Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity and in vivo herbicidal activity were evaluated. The results of AtHPPD inhibitory experiments indicated that, most of the synthesized compounds showed "good" to "the excellent" HPPD-inhibiting activities. To our delight that, compound 9i with a Ki value of 0.005 μmol/L is about two times more potent than that of mesotrione (Ki=0.013 μmol/L). The results of greenhouse experiments showed that, most of the synthesized compounds displayed at least 80% inhibition against one of six weeds tested at the rate of 150 g ai/ha. To our surprise that, compound 9g showed over 85% inhibition against four of six tested weeds even at a rate as low as 37.5 g ai/ha. In addition, it was also safe for rice and wheat by post-emergent application at the rate of 150 g ai/ha. Furthermore, we also obtained some structure-activity relationships, the SAR indicated that too electron-withdrawing groups in 3,5-positions of benzene ring (3-position of quinazoline-2,4-dione) were detrimental to activity, too sterically bulk groups at R4 were also detrimental to activity. Thus, compound 9g emerged as a new lead compound for herbicidal discovery.