含喹唑啉二酮片段的新型三酮类化合物的合成及生物活性
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摘要
对羟苯基丙酮酸双氧化酶(EC 1.13.11.27,HPPD)是一个重要的除草剂作用靶标.为了寻找具有高效除草活性的新型HPPD抑制剂,在前期研究的基础上设计合成了24个含有喹唑啉二酮结构的三酮类化合物9a~9x.所合成的化合物均经过1H NMR,13C NMR和HRMS的表征.以来源于拟南芥的HPPD(At HPPD)为测试对象进行酶抑制活性筛选,结果表明所合成的大部分化合物对At HPPD均表现出了较好的抑制效果,其中化合物9i的Ki值为0.005μmol/L,显著优于商品化对照药剂硝磺草酮(Ki=0.013μmol/L).进一步温室盆栽筛选结果表明,多数化合物在150 g ai/ha的剂量下对六种供试杂草中的至少一种表现出80%以上的防效,特别是化合物9g在37.5 g ai/ha的低剂量下对所测试的六种杂草中的四种仍表现出了大于85%的抑制效果,同时9g在150 g ai/ha的剂量下对水稻和小麦均表现出了很好的作物安全性,可以作为先导化合物供进一步深入研究.
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, 13 C NMR and HRMS spectrum data. To explore the biology activity of these compounds, their in vitro Arabidopsis thaliana HPPD(At HPPD) inhibitory activity and in vivo herbicidal activity were evaluated. The results of At HPPD 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.
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, 13 C NMR and HRMS spectrum data. To explore the biology activity of these compounds, their in vitro Arabidopsis thaliana HPPD(At HPPD) inhibitory activity and in vivo herbicidal activity were evaluated. The results of At HPPD 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.
引文
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[6]Beaudegnies,R.;Edmunds,A.J.F.;Fraser,T.E.M.;Hall,R.G.;Hawkes,T.R.;Mitchell,G.;Schaetzer,J.;Wendeborn,S.;Wibley,J.Bioorg.Med.Chem.2009,17,4134.
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[8]Zhou,Y.Y.;Li,Z.M.World Pest.2013,35,1.(周蕴赟,李正名,世界农药,2013,35,1.)
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