Synthesis and Bioactivity Studies of Triketone-Containing Quinazoline-2,4-dione Derivatives
Synthesis and Bioactivity Studies of Triketone-Containing Quinazoline-2,4-dione Derivatives
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含三酮的喹唑啉-2,4-二酮衍生物的合成及生物活性研究
DOI：
10.6023/a14110805
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发表时间：
2015-01
影响因子：
2.5
通讯作者：
Yang Guangfu
中科院分区：
文献类型：
--
作者：
Wang Dawei;Lin Hongyan;Cao Runjie;Yang Shenggang;Chen Tao;He Bo;Chen Qiong;Yang Wenchao;Yang Guangfu
4-羟基苯基丙酮酸双加氧酶（EC 1.13.11.27， HPPD）是酪氨酸分解代谢的重要酶，催化4-羟基苯基丙酮酸（HPPA）转化为均质酸（HGA），属于非血红素铁（II）酶的2-his-1-羧酸面三元家族。HPPD作为调控植物生育酚和质体醌生物合成的重要酶，是除草剂研究的重要靶点。在此之前，我们已经发现含有三酮的喹唑啉-2,4-二酮基序可以作为除草剂发现的新型先导结构。在这一连续工作中，我们共合成了24个新的含三酮的喹唑啉-2,4-二酮衍生物。以5-甲基-2-硝基苯甲酸为原料，经氧化、酯化、还原反应，制得主要中间体4-氨基间苯二甲酸二甲酯，收率达83%，再经过6步反应，可顺利合成目标化合物9a~9x。所有标题化合物均通过H NMR、C NMR和HRMS谱数据进行了表征。为了探究这些化合物的生物学活性，我们对其体外对拟南芥HPPD （AtHPPD）的抑制活性和体内除草活性进行了评价。AtHPPD抑制实验结果表明，大多数合成的化合物具有“良好”到“优异”的抑制hppd活性。令人欣喜的是，当Ki值为0.005 μmol/L时，化合物9i的效价约为mesotrione （Ki=0.013 μmol/L）的2倍。温室试验结果表明，在150克/公顷的剂量下，大多数合成的化合物对6种杂草中的一种具有至少80%的抑制作用。令我们惊讶的是，即使在37.5 g /ha的速率下，化合物9g对6种测试杂草中的4种也有超过85%的抑制作用。此外，苗期后施用150 g /ha对水稻和小麦也是安全的。此外，我们还得到了一些构效关系，SAR表明苯环上3,5位（喹唑啉-2,4-二酮的3位）吸电子基团过多对活性有害，R位的空间体积基团过多也对活性有害。因此，化合物9g成为除草剂新发现的先导化合物。
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 H NMR, C 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 R were also detrimental to activity. Thus, compound 9g emerged as a new lead compound for herbicidal discovery.