CN114957135B - 一种偶氮嘧啶类化合物的应用 - Google Patents
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
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Abstract
本发明公开了一种偶氮嘧啶类化合物的应用,涉及生物技术领域。本发明发现具有通式(I)结构的偶氮嘧啶类化合物对几丁质酶具有优异的抑制活性以及优异的杀虫活性,尤其是对亚洲玉米螟、秀丽线虫几丁质酶有较高的抑制活性;对农业害虫玉米螟、小菜蛾、桃蚜有很强的杀虫活性。该结构的化合物可用于几丁质酶抑制剂或杀虫剂,具有很高的农药研究价值,在农药学领域有广泛的应用前景。
Description
技术领域
本发明涉及生物技术领域,特别是涉及一种偶氮嘧啶类化合物的应用。
背景技术
几丁质是由N-乙酰氨基葡萄糖通过β-1,4糖苷键连接的直链多糖,其在自然界中含量极为丰富,并广泛存在于昆虫的外骨骼、线虫的卵壳、真菌的细胞壁中。几丁质的合成和水解代谢对昆虫、线虫、真菌的生长发育过程具有至关重要的作用。在几丁质水解过程中,几丁质先由18家族几丁质酶水解为几丁寡糖,再由20家族β-N-乙酰己糖胺酶水解为N-乙酰氨基己糖。
几丁质酶参与多种生物体的生命活动,在细胞分裂、病原入侵、昆虫蜕皮和免疫预防等方面发挥着重要的用途。抑制昆虫的几丁质酶会导致昆虫不能正常生长发育蜕皮而死亡,抑制线虫的几丁质酶会导致线虫的生长停滞,干扰真菌几丁质酶的表达水平会影响真菌的分裂过程。因此,针对几丁质酶开展新型抑制剂的发掘工作对于农业病虫害的防治具有重要的意义。
几丁质作为农业害虫外骨骼和肠壁等组织的重要组成部分,且农业害虫的正常生长发育过程离不开几丁质的代谢,而人和高等动植物不含几丁质。因此,催化几丁质水解过程中几丁质酶被公认为是重要的绿色杀虫剂靶酶,开展基于昆虫几丁质酶为靶标的抑制剂开发具有重要的应用前景。
发明内容
本发明的目的是提供一种偶氮嘧啶类化合物的应用,以解决上述现有技术存在的问题,实现对几丁质酶良好的抑制效果和杀虫效果。
为实现上述目的,本发明提供了如下方案:
本发明提供一种如式(I)所示结构的偶氮嘧啶类化合物及其药学上可接受的盐在抑制几丁质酶活性或防治农业害虫方面的应用:
其中:R1-R5独立的选自H、C1-C4烷基、卤素、OCH3、CN、NHAc或NO2中的一种;
R6、R7独立的选自H、NHCH3、NHC2H5、N(CH3)2、N(C2H5)2或卤素中的一种;
R8选自H、卤素、NHCH3、NHC2H5、 中的一种。
式(I)所示化合物的制备方法包括以下步骤:
将式(II)所示化合物(1当量)与亚硝酸钠(0.5~3当量)和盐酸(0.5~10当量)在(-20℃~30℃)温度下反应(0.2~5h)得到式(III)所示化合物;
将式(III)所示化合物(1当量)与式(IV)所示化合物(0.5~3当量)在碱性水溶液中(10~300当量,所用的碱为氢氧化钠、碳酸氢钠、乙酸钠、碳酸钠、碳酸钾、醋酸钾、醋酸铵其中的一种或两种,碱的浓度为质量分数1%~70%,反应pH为7.2~14)于(-20℃~30℃)温度下反应(0.5~72h)得到式(V)所示化合物;
将式(V)所示化合物(1当量)在碱性条件下(所用碱为氢氧化钠、碳酸氢钠、乙酸钠、碳酸钠、碳酸钾、醋酸钾、三乙胺、二异丙基乙基胺其中的一种,0.5~5当量)与含有R8基团的胺类化合物(0.5~5当量)于(0℃~100℃)温度下在溶剂(乙腈或DMF)中反应(0.5~48h)得到如示(I)目标化合物。
进一步地,所述几丁质酶为糖基水解酶18家族几丁质酶。
进一步地,所述几丁质酶包括亚洲玉米螟几丁质酶h(OfChi-h)或秀丽隐杆线虫几丁质酶I(CeCht1)。
进一步地,用于抑制玉米螟几丁质酶h的活性时,反应体系中所述偶氮嘧啶类化合物的终浓度不低于1μM;当用于抑制秀丽隐杆线虫几丁质酶I的活性时,反应体系中所述偶氮嘧啶类化合物的终浓度不低于1μM。
进一步地,当式(I)所示结构的偶氮嘧啶类化合物用于防治农业害虫时,农业害虫为桃蚜或玉米螟。
本发明公开了以下技术效果:
本发明发现具有通式(I)结构的偶氮嘧啶类化合物对几丁质酶具有优异的抑制活性以及优异的杀虫活性,尤其是对亚洲玉米螟几丁质酶h(OfChi-h)、秀丽隐杆线虫几丁质酶I(CeCht1)有较高的抑制活性;对农业害虫玉米螟、小菜蛾、桃蚜有很强的杀虫活性。该结构的化合物可用于几丁质酶抑制剂或杀虫剂,具有很高的农药研究价值,在农药学领域有广泛的应用前景。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为化合物HAU-D2的核磁氢谱图(400MHz,CDCl3);
图2为化合物HAU-D2的核磁碳谱图(101MHz,CDCl3);
图3为化合物HAU-D10对OfChi-h的IC50值;
图4为化合物HAU-D10对CeCht1的IC50值;
图5为化合物HAU-D13对OfChi-h的IC50值;
图6为化合物HAU-D13对CeCht1的IC50值;
图7为化合物HAU-D15对OfChi-h的IC50值;
图8为化合物HAU-D15对CeCht1的IC50值。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入,用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时,以本说明书的内容为准。
在不背离本发明的范围或精神的情况下,可对本发明说明书的具体实施方式做多种改进和变化,这对本领域技术人员而言是显而易见的。由本发明的说明书得到的其他实施方式对技术人员而言是显而易见的。本发明说明书和实施例仅是示例性的。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
本发明实施例中的几丁质酶OfChi-h和CeCht1如下述参考文献给出:Liu,T.;Chen,L.;Zhou,Y.;Jiang,X.;Duan,Y.;Yang,Q.,Structure,Catalysis,and Inhibitionof OfChi-h,the Lepidoptera-exclusive Insect Chitinase.J.Biol.Chem.2017,292(6),2080-2088.
Chen,Q.;Chen,W.;Kumar,A.;Jiang,X.;Janezic,M.;Zhang,K.Y.J.;Yang,Q.,Crystal Structure and Structure-Based Discovery of Inhibitors of the NematodeChitinase CeCht1.J.Agric.Food.Chem.2021,69(11),3519-3526.
以化合物HAU-D2为例,对本发明化合物的制备及鉴定进行说明:
实施例1
化合物HAU-D2,R1=R2=R4=R5=H,R3=Br,R6=R7=N(CH3)2,R8=NHCH2COOC2H5的制备及结构鉴定。
(1)在10mL的烧瓶中,加入4-溴苯胺(462mg,2.7mmol)和2MHCl(2mL),将溶液冷却至0℃,并加入亚硝酸钠(201mg)。将反应混合物在0℃搅拌30分钟以获得重氮盐化合物,其无需进一步纯化即可使用,产率95%。
(2)将6-氯-N2,N2,N4,N4-四甲基嘧啶-2,4-二胺(450mg,2.2mmol)溶解在NaOAc溶液(10%,25mL)和NaOH溶液(5%,2mL)中,在0℃下,缓慢滴加(1)中所得重氮盐溶液滴,并在室温搅拌15小时。将水层用CH2Cl2(3×30mL)萃取,Na2SO4干燥,真空浓缩,柱色谱(石油醚/EtOAc,30:1v/v)纯化,得到橘红色固体485mg,产率56%。
结构确证数据如下:1H NMR(400MHz,CDCl3)δ7.60–7.53(m,2H,ArH),7.49–7.42(m,2H,ArH),3.09(s,6H,2NCH3),2.88(s,6H,2NCH3);13C NMR(101MHz,CDCl3)δ160.17,156.96,156.21,150.48,131.10,122.16,121.91,120.53,40.18,36.27;HRMS(ESI)calcd forC14H17BrClN6(M+H+)383.0387,found 383.0395.
(3)在50mL的圆底烧瓶中加入(2)中所得产物(76.4mg,0.2mmol)、甘氨酸乙酯(30.9mg,0.3mmol)和无水碳酸钾(41.4mg,0.3mmol),与无水乙腈(3mL)中回流10h,减压浓缩并通过快速柱色谱法(石油醚/EtOAc,30:1v/v)纯化,得到黄色固体化合物57mg,产率63%。
结构确证数据如下:1H NMR(400MHz,CDCl3)δ11.48(t,J=4.9Hz,1H,NH),7.54–7.43(m,4H,ArH),4.30–4.22(m,4H,2CH2),3.36(s,6H,2NCH3),3.17(s,6H,2NCH3),1.30(t,J=7.1Hz,3H,CH2CH3 );13C NMR(101MHz,CDCl3)δ170.53,162.45,159.44,155.22,152.37,131.96,122.17,119.56,113.45,61.11,43.27,42.38,36.82,14.31;HRMS(ESI)calcd forC18H25BrN7O2(M+H+)450.1253,found 450.1251.
图1为化合物HAU-D2的核磁氢谱图(400MHz,CDCl3);图2为化合物HAU-D2的核磁碳谱图(101MHz,CDCl3)。
实施例2
偶氮嘧啶类化合物对几丁质酶OfChi-h和CeCht1的抑制率测定。具体步骤如下:
实验组:设置3组平行实验组。在30℃反应温度下,100μL的反应体系中加入2nmol/L几丁质酶、10μM化合物(或1μM化合物)和50μM底物Mu-(GlcNAc)2在20mM的pH=6.0的磷酸盐缓冲液中孵育30min;加入0.5M碳酸钠溶液终止反应,反应液用360nm波长的激发光进行激发后测定450nm波长下的吸光值。
正对照:设置3组平行正对照。在30℃反应温度下,100μL的反应体系中加入2nmol/L几丁质酶、50μM底物Mu-GlcNAc在20mM的pH=6.0的磷酸盐缓冲液中孵育30min;加入0.5M碳酸钠溶液终止反应,反应液用360nm波长的激发光进行激发后测定450nm波长下的吸光值。
根据以下公式计算化合物的酶抑制活性
抑制百分数=(正对照-实验组)/正对照*100
结果如表1所示,表1列举了代表性的21个化合物的编号、化学结构及其对OfChi-h和CeCht1的酶抑制活性。
表1
实施例3
偶氮嘧啶类化合物对OfChi-h和CeCht1的半数抑制浓度IC50值的测定:
具体步骤如下:在30℃反应温度下,100μL的反应体系中加入2nmol/L几丁质酶、具有适宜浓度梯度的化合物和50μM底物Mu-(GlcNAc)2在20mM的pH=6.0的磷酸盐缓冲液中孵育30min;加入0.5M碳酸钠溶液终止反应,反应液用360nm波长的激发光进行激发后测定450nm波长下的吸光值。采用Graphpad Prism处理数据绘图,结果如图3-图8所示(图3-图8中横坐标为化合物浓度的对数,纵坐标为化合物对几丁质酶的抑制率百分数)。对应表1中的化合物HAU-D10、HAU-D13、HAU-D15对OfChi-h的IC50值分别为1.029μM、0.676μM、0.282μM;对应表1中的化合物HAU-D10、HAU-D13、HAU-D15对CeCht1的IC50值分别为0.558μM、0.344μM、0.181μM。显示出偶氮嘧啶类化合物HAU-D10、HAU-D13、HAU-D15对OfChi-h和CeCht1具有优良的抑制活性。
实施例4
偶氮嘧啶类化合物的杀虫活性测定:
采用浸虫法测试偶氮嘧啶类化合物对玉米螟虫的杀虫活性。将三龄玉米螟幼虫浸入浓度为500μg/mL的化合物药液中5-10秒,用滤纸吸取多余药液,然后将试虫转至正常条件下饲养48h,检查结果,统计死亡率。选用氟铃脲为阳性对照。
采用点滴法测试偶氮嘧啶类化合物对桃蚜的杀虫活性。用微量点滴器将浓度为500μg/mL的化合物母液点滴于蚜虫的腹部,之后将试虫置于正常条件下饲养,并在24h后统计死虫数,并计算死亡率。选用氟铃脲为阳性对照。
校正死亡率(%)=(样品死亡率-空白对照死亡率)/(1-空白对照死亡率)*100。
表2偶氮嘧啶类化合物的杀虫活性测试结果
由上述可以看出,本发明式(I)结构偶氮嘧啶类化合物对几丁质酶具有优秀的酶抑制活性,对几丁质酶的抑制活性数据(包括抑制剂的抑制率、半数抑制浓度IC50)结果表明,表1所示代表性的21个偶氮嘧啶类化合物表现出对几丁质酶OfChi-h和CeCht1的抑制活性。特别是,对应表1中的化合物HAU-D10、HAU-D13、HAU-D15、HAU-D16、HAU-D19、HAU-D20在10μM的测试浓度下对OfChi-h的抑制率均大于90%;对应表1中的所有化合物在10μM的测试浓度下对CeCht1的抑制活性均大于90%;对应表1中的化合物HAU-D14、HAU-D15、HAU-D21在1μM的测试浓度下对OfChi-h的抑制率分别为70%、71%、73%;对应表1中的化合物HAU-D13、HAU-D14在1μM的测试浓度下对CeCht1的抑制率分别为98%、97%。对应表1中的化合物HAU-D10、HAU-D13、HAU-D15对OfChi-h的IC50值分别为1.029μM、0.676μM、0.282μM;对应表1中的化合物HAU-D10、HAU-D13、HAU-D15对CeCht1的IC50值分别为0.558μM、0.344μM、0.181μM。
此外,结构式(I)所示的化合物对农业害虫有较强的杀虫活性。对应表2中的化合物HAU-D7、HAU-D8、HAU-D10、HAU-D13、HAU-D20的对玉米螟的杀虫活性优于对照药氟铃脲;对应表1中的化合物HAU-D1、HAU-D3、HAU-D10在500μg/mL的浓度下对桃蚜的杀虫活性大于80%。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (3)
1.偶氮嘧啶类化合物及其药学上可接受的盐在制备抑制几丁质酶活性的药物中的应用,其特征在于,所述偶氮嘧啶类化合物选自以下结构的化合物:
所述几丁质酶包括亚洲玉米螟几丁质酶h或秀丽隐杆线虫几丁质酶I。
2.根据权利要求1所述的应用,其特征在于,用于抑制亚洲玉米螟几丁质酶h的活性时,反应体系中所述偶氮嘧啶类化合物的终浓度不低于1μM;当用于抑制秀丽隐杆线虫几丁质酶I的活性时,反应体系中所述偶氮嘧啶类化合物的终浓度不低于1μM。
3.偶氮嘧啶类化合物及其药学上可接受的盐在制备防治农业害虫的药物中的应用,其特征在于,所述农业害虫为桃蚜或玉米螟;
所述偶氮嘧啶类化合物选自以下结构的化合物:
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