CN113880777A - 一类含二硫醚结构的喹唑啉酮类衍生物的制备方法及其应用 - Google Patents
一类含二硫醚结构的喹唑啉酮类衍生物的制备方法及其应用 Download PDFInfo
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- CN113880777A CN113880777A CN202111104865.9A CN202111104865A CN113880777A CN 113880777 A CN113880777 A CN 113880777A CN 202111104865 A CN202111104865 A CN 202111104865A CN 113880777 A CN113880777 A CN 113880777A
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- quinazolinone
- substituted
- disulfide
- unsubstituted
- mercapto
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- 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
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
Abstract
本发明涉及一类含二硫醚结构的喹唑啉酮类衍生物的制备方法及其应用。该化合物具有如通式(I)所示的结构:
Description
技术领域
本发明涉及农药学技术领域,是一类含二硫醚结构的喹唑啉酮类衍生物的制备方法及其应用。
背景技术
植物细菌性病害是最具破坏性的植物病害之一,不仅影响了农业的健康稳定发展,同时也对食品安全构成了重大威胁。其中,水稻白叶枯病菌(Xanthomonas oryzaepv.oryzae,Xoo)、柑橘溃疡病菌(Xanthomonas axonopodis pv.citri,Xac)、猕猴桃溃疡病菌(Pseudomonas syringae pv.Actinidiae,Psa)、茄青枯雷尔氏菌(Ralstoniasolanacearum,Rs)等造成的细菌性病害使每年的农业损失达数亿美元。
施用化学农药一直是防治植物细菌性病害的主要措施,它具有杀菌谱广、见效快、成本低等优点,与此同时,随着科学技术的升级和更新,在过去的半个多世纪里,农药的使用量从上世纪60年代的1千克每公顷减少到了当前的10克每公顷,这不仅是作物保护的巨大成就,同样的,对于环境保护而言更是如此。然而长期施用化学农药不可避免的导致了农药残留及环境污染问题,人体健康和生态平衡都受到了极大挑战,此外,很多商品化农药已经出现了不同程度上的抗药性问题,因此急需寻找用于抗植物病原细菌的高活性、低抗性化合物,并在此基础上创制自主知识产权的绿色新农药,为农作物细菌性病害防控提供候选药物。
喹唑啉酮类化合物是普遍存在于自然界中的一类天然活性物质,天然存在的喹唑啉酮化合物具有多种生物活性,如:抗菌、抗肿瘤、抗惊厥、抗疟疾、抗炎等,以喹唑啉酮为母体结构进行衍生也发现了很多具有较好抗菌活性的化合物;此外,二硫醚类衍生物具有广泛的生物活性,例如抗细菌、抗真菌、抗肿瘤,其中二硫醚类抗菌化合物—大蒜素(allicin),其杀菌的独特作用方式引起了广泛的关注和研究。
为寻找高效、抵抗性的杀菌活性化合物,本发明以喹唑啉酮为母体结构,将具有生物活性的二硫键引入到此体系中,合成了一系列2-取代二硫烷基-4(3H)-喹唑啉酮类衍生物,考察其杀菌生物活性,为新农药的研发和创制提供一定的科学基础。
喹唑啉酮类衍生物的生物活性研究进展如下:
2018年,Megahed[Megahed M,Fathalla W,Alsheikh A A.Synthesis andAntimicrobial Activity of Methyl2-(2-(2-Arylquinazolin-4-yl)oxy)AcetylaminoAlkanoates[J].Journal of Heterocyclic Chemistry.2018,55(12):2799-2808.]等合成了数十个喹唑啉酮类衍生物,测定了这些化合物对大肠杆菌、白色念珠菌和金黄色葡萄球菌的抑菌活性。生物活性结果表明:部分甘氨酸衍生物、缬氨酸衍生物、羧酸衍生物与对照抗生素相比,对三种病原菌均具有显著的抗菌活性。
2019年,Gatadi[Gatadi S,Gour J,Shukla M,et al.Synthesis and evaluationof new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives aspotent antibacterial agents effective against multidrug resistantStaphylococcus aureus[J].Bioorganic chemistry.2019,83:569-579.]等合成了一系列3-苯甲酸、3-苯甲酰胺的喹唑啉酮类衍生物,初步活性筛选表明:大部分化合物在对金黄色葡萄球菌表现出较好抑制活性的同时(MIC=0.25-8μg/mL),对Vero(非洲绿猴肾细胞)细胞表现为低细胞毒性,具有良好的选择性指数(Si>10)。
2019年,Mostafavi[Mostafavi H,Islami M R,Khabazzadeh H,et al.Synthesisof New Quinazolin-4-(3H)-one Derivatives and Evaluation of Their BiologicalActivities[J].ChemistrySelect.2019,4(11):3169-3174.]等以对甲苯磺酸为催化剂、邻氨基苯酰胺衍生物和醛为原料,采用一锅法合成了一系列含偶氮吡啶基和4-氨基苯甲酰胺基的新型喹唑啉酮衍生物,以磺胺甲噁唑、环丙沙星为对照药,测定了合成化合物对肺炎克雷伯氏菌、大肠杆菌、金黄色葡萄球菌、蜡样芽孢杆菌和白色念珠菌的抗菌活性,结果表明:几乎所有化合物都对蜡样芽孢杆菌和白色念珠菌有较好的抗菌活性。
二硫醚类化合物的生物活性研究进展如下:
2008年,Turos[Turos E,Revell K D,Ramaraju P,et al.Unsymmetric aryl–alkyl disulfide growth inhibitors of methicillin-resistant Staphylococcusaureus and Bacillus anthracis[J].Bioorganic&medicinal chemistry.2008,16(13):6501-6508.]等人合成了一系列不对称的二硫醚类衍生物,研究发现系列化合物对金黄色葡萄球菌、耐甲氧西林葡萄球菌、炭疽杆菌及大肠杆菌均有不同程度的抑制作用,就前三株致病菌的构效关系研究发现:当芳环上有吸电子取代基时活性较好,其中,间位和对位取代的活性优于邻位取代;若取代苯环与硫原子间插入了碳原子,则活性下降;此外,若芳环上有亲水性取代基时,活性降低;直链烷基的链长增加,活性增加,且支链取代的活性优于直链取代。而对于大肠杆菌而言,烷基为甲基或乙基时活性较好。这些结果表明:有利于降低二硫键中硫的电荷密度,即增加亲核取代反应活性的取代基有利于抗菌活性的增加,同时,为保证化合物的活性,分子结构中需引入亲脂性基团,便于化合物透过细胞膜。
2018年,Sheppard[Sheppard J G,McAleer J P,Saralkar P,et al.Allicin-inspired pyridyl disulfides as antimicrobial agents for multidrug-resistantStaphylococcus aureus[J].Europeanjournalofmedicinalchemistry.2018,143:1185-1195.]等人设计合成了一系列含吡啶基的二硫醚类衍生物,测定了目标化合物对多种耐药性金黄色葡萄球菌的抑制活性,在菌体的生理条件下,系列化合物中的吡啶基会形成季铵盐,从而降低了硫的电子云密度,利于二硫键与游离巯基的交换反应,这成为活性改善的结构前提。研究发现部分目标化合物不仅具有较好的抑菌活性,与万古霉素联用时还实现了协同抗菌作用,增加了化合物的抑菌效果,同时对人体正常细胞表现为低毒。初步作用机制研究发现,这些化合物不仅造成了菌体膜的破坏,同时降低了细菌的代谢水平、抑制了菌体的生长。
2016年,Sheppard[Sheppard J G,Long T E.Allicin-inspired thiolatedfluoroquinolones as antibacterials against ESKAPE pathogens[J].Bioorganic&medicinal chemistry letters.2016,26(22):5545-5549.]等人将硫醚引入环丙沙星(CIP)的母体结构中,制备了一系列N-烷基氟喹诺酮硫醚类衍生物,就目标化合物对ESKAPE(Enterococcus spp.,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacterbaumannii,Pseudomonas aeruginosa,and Enterobacter spp)的抗菌活性及初步机制进行了研究,活性测定结果与预期一致,活性化合物丙基硫代氟喹诺酮对MSSA(甲氧西林敏感型金黄色葡萄球菌,methicillin-susceptible S.aureus)及MRSA两种菌株的抑制活性均优于CIP,该活性化合物与谷胱甘肽(GSH)复合物的质谱结果中存在目标化合物、GS-S-Pr(丙基)、CIP及GSH的离子碎片峰,这初步印证了活性化合物的作用机制可能是S-烷基与谷胱甘肽的结合。此外,在发生取代反应的同时释放出环丙沙星,进一步增强了目标化合物的抑菌活性。
发明内容
本发明的目的之一提供了一类含二硫醚结构的喹唑啉酮类衍生物。
本发明的另一目的在提供了制备上述化合物及其制备方法。
本发明还有一目的是提供了上述化合物或所述组合物的用途。
本发明另一目的是提供了利用上述化合物或所述组合物防治农业病虫害的方法。
为实现上述目的,本发明采用了下述技术方案:
一类含二硫醚结构的喹唑啉酮类衍生物,该化合物具有如通式(Ⅰ)所示的结构:
其中,
R选自任意取代或未取代的烷基、任意取代或未取代的环烷基及任意取代或未取代的芳基。
进一步优选地,R选自烷基、环烷基、取代或未取代的芳基;
优选地,R选自C2-C10烷基、C5-C6环烷基、取代或未取代的C6-C7芳基,其中,所述取代指的是被C1-C10烷基、C1-C10烷氧基、氨基、羟基、卤素、硝基、三氟甲基中的一个或一个以上取代;
更优选地,R选自乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、环戊基、环己基、己基、庚基、辛基、壬基、葵基、取代或未取代的苯基、取代或未取代的苄基,其中,所述取代指的是被C1-C10烷基、C1-C10烷氧基、氨基、羟基、卤素、硝基、三氟甲基中的一个或一个以上取代;
最优选地,R选自乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、环戊基、环己基、己基、庚基、辛基、壬基、葵基、苯基、4-甲基苯基、4-甲氧基苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-氟苯基、3-氟苯基、4-氟苯基、苄基、2-甲氧基苄基、3-甲氧基苄基、4-甲氧基苄基、2-甲基苄基、3-甲基苄基、4-甲基苄基。
所述的一类含二硫醚结构的喹唑啉酮类衍生物,包含下述化合物:
本发明还提供了所述的一类含二硫醚结构的喹唑啉酮类衍生物的制备方法,包括下述步骤:
所述的化合物或所述的组合物可用于防治农业病虫害,优选地,所述农业病虫害为植物细菌性病害;更优选地,所述农业病虫害为植物叶枯病、植物溃疡病和植物细菌性青枯病;最优选地,所述农业病虫害为水稻白叶枯病、柑橘溃疡病、猕猴桃溃疡病、细菌性青枯病。
此处用到的术语“烷基”是包括具有特定数目碳原子的支链和直链饱和烃基。例如“C2-10烷基”(或亚烷基)目的是C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外,例如“C2-10烷基”表示具有2到10个碳原子的烷基。烷基可为非取代或取代的,以使一个或多个其氢原子被其它化学基团取代。烷基的实施例包括但不限于乙基(Et)、丙基(如正丙基和异丙基)、丁基(如正丁基、异丁基、叔丁基)、戊基(如正戊基、异戊基、新戊基)、己基、庚基、辛基、壬基、葵基及其类似物。并且,当提到己基、庚基、辛基时,除包括正己基、正庚基、正辛基之外,还包括其所有同分异构体。
此处用到的术语“取代的”指的是在指定原子或基团上的任意一个或多个氢原子以选择的指定基团取代,前提是不超过指定原子的一般化合价。如果没有其它说明,取代基命名至中心结构。例如,可以理解的是当(环烷基)烷基是可能的取代基,该取代基至中心结构的连接点是在烷基部分中。当提到取代时,特别是多取代时,指的是多个取代基在指定基团上的各个位置上取代,如二氯苯基指的是1,2-二氯苯基、1,3-二氯苯基和1,4-二氯苯基。
取代基和或变量的组合是允许的,仅当这些组合产生稳定的化合物或有用的合成中间体。稳定的化合物或稳定结构暗示所述化合物以有用的纯度从反应混合物分离出来时是足够稳定的,随之配制形成有效的治疗试剂。
术语“芳基”指的是在环部分具有6个碳原子的单环芳香烃基,如苯基。
术语“卤素”或“卤素原子”指的是氯、溴、氟。
优选地,C2-C10烷基指的是乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基及其同分异构体;
当提到取代基时,如烯基、炔基、烷基、卤素、芳基、杂芳基、烷氧基、环烷基、羟基、氨基、巯基、膦基时,或这些取代基具体的为某个具体的烯基、炔基、烷基、卤素、芳基、杂芳基、烷氧基、环烷基、羟基、氨基、巯基、膦基时,指的是一个到三个上述取代基。如甲基苯基指的是一个到三个甲基取代的苯基。
本发明的有益效果:通过采用上述技术方案,本发明以喹唑啉酮结构为基础,合成了一类含二硫醚结构的喹唑啉酮类衍生物,且发现该化合物对部分植物致病病原细菌具有良好的抑制作用,如水稻白叶枯病菌(Xanthomonas oryzae pv.oryzae,Xoo)、柑橘溃疡病菌(Xanthomonas axonopodis pv.citri,Xac)、猕猴桃溃疡病菌(Pseudomonas syringaepv.Actinidiae,Psa)、茄青枯雷尔氏菌(Ralstonia solanacearum,Rs)等均具有良好的抑制效果,为新农药的研发和创制提供了一定的科学基础。
具体实施方式
下面通过实施例对本发明作进一步说明。应该理解的是,本发明实施例所述方法仅仅是用于说明本发明,而不是对本发明的限制,在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。实施例中用到的所有原料和溶剂均为市售产品。
实施例1:2-(乙基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
(1)2-巯基-4(3H)-喹唑啉酮的制备
向250mL的圆底烧瓶中依次加入1.65g氢氧化钾、100mL无水乙醇,搅拌溶解后,滴加4.42mL二硫化碳,随后升温至30℃,半小时后,加入10g2-氨基苯甲酰胺,补加约60mL无水乙醇,升温至90℃回流,约5h后TLC显示原料点消失,反应结束,冷却至室温,有白色固体析出、抽滤,滤饼用冰水溶解、盐酸调节PH至中性,析出大量固体,烘干得6.28g白色固体,收率为47.96%。
(2)乙基硫氯的制备
圆底瓶中加入8mL二氯甲烷和0.62g(9.98mmol)乙基硫醇,冰浴下滴加2.69g(19.96mmol)磺酰氯,冰浴条件下反应1h,旋蒸除去溶剂,用乙酸乙酯/石油醚的混合溶剂溶解后直接用于下一步反应。
(3)2-(乙基二硫醚)-4(3H)-喹唑啉酮的制备
圆底烧瓶中加入40mL乙酸乙酯/石油醚的混合溶剂、0.8g(4.49mmol)2-巯基-4(3H)-喹唑啉酮,将上步反应产物滴加进反应体系,常温搅拌过夜,加入约50mL石油醚搅拌、抽滤,饱和碳酸氢钠/碳酸钠水溶液多次洗涤,乙酸乙酯/石油醚混合溶剂过柱,得到白色目标产物,产率63.55%。
实施例2:2-(丙基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;丙基硫氯的制备及2-(丙基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、丙基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例3:2-(异丙基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;异丙基硫氯的制备及2-(异丙基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、异丙基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例4:2-(丁基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;丁基硫氯的制备及2-(丁基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、丁基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例5:2-(异丁基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;异丁基硫氯的制备及2-(异丁基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、异丁基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例6:2-(仲丁基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;仲丁基硫氯的制备及2-(仲丁基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、仲丁基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例7:2-(叔丁基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;叔丁基硫氯的制备及2-(叔丁基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、叔丁基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例8:2-(3-甲基-2-丁基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;3-甲基-2-丁基硫氯的制备及2-(3-甲基-2-丁基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、3-甲基-2-丁基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例9:2-(戊基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;戊基硫氯的制备及2-(戊基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、戊基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例10:2-(异戊基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;异戊基硫氯的制备及2-(异戊基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、异戊基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例11:2-(己基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;己基硫氯的制备及2-(己基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、己基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例12:2-(环己基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;环己基硫氯的制备及2-(环己基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、环己基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例13:2-(庚基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;庚基硫氯的制备及2-(庚基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、庚基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例14:2-(辛基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;辛基硫氯的制备及2-(辛基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、辛基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例15:2-(苄基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;苄基硫氯的制备及2-(苄基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、苄基硫醇及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例16:2-(4-甲基苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;4-甲基苯基硫氯的制备及2-(4-甲基苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、4-甲基苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例17:2-(4-氟苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;4-氟苯基硫氯的制备及2-(4-氟苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、4-氟苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例18:2-(4-氯苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;4-氯苯基硫氯的制备及2-(4-氯苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、4-氯苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例19:2-(4-溴苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;4-溴苯基硫氯的制备及2-(4-溴苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、4-溴苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例20:2-(4-甲氧基苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;4-甲氧基苯基硫氯的制备及2-(4-甲氧基苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、4-甲氧基苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例21:2-(3-氟苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;3-氟苯基硫氯的制备及2-(3-氟苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、3-氟苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例22:2-(2-氟苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;2-氟苯基硫氯的制备及2-(2-氟苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、2-氟苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例23:2-(2-氯苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;2-氯苯基硫氯的制备及2-(2-氯苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、2-氯苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
实施例24:2-(2-溴苯基二硫醚)-4(3H)-喹唑啉酮衍生物的合成
2-巯基-4(3H)-喹唑啉酮的制备见实施例1;2-溴苯基硫氯的制备及2-(2-溴苯基二硫醚)-4(3H)-喹唑啉酮的制备参照实施例1,其中磺酰氯、2-溴苯硫酚及2-巯基-4(3H)-喹唑啉酮的投料摩尔比为4:2:1。
表1部分化合物的核磁共振氢谱和碳谱数据
表2部分目标化合物的理化性质
药理实施例1:
采用浊度法测试目标化合物对植物病原菌的抑制率,试验对象为水稻白叶枯病菌(Xoo)、猕猴桃溃疡病菌(Psa)、茄青枯雷尔氏菌(Rs)、柑橘溃疡病菌(Xac),培养基中加入等体积DMSO作为空白对照,以叶枯唑(Bismerthiazol,90%)和申嗪霉素(Shenqinmycin,99.3%)为阳性对照药。挑取适量NA固体培养基上的水稻白叶枯病菌、柑橘溃疡病菌和猕猴桃溃疡病菌放入NB培养基中,于28℃、250rpm恒温摇床中振荡培养至对数生长期备用;用灭菌试管配置4mL不同浓度(例:100、50ppm)的含毒(化合物或药剂)NB液体培养基,分别向这些试管中加入40μL已培养好的病原细菌,在28℃、250rpm恒温摇床中振荡,培养时间约为12-24h。分别从各试管中移取200μL的菌液用于测定OD595值,同时测定对应浓度的含毒无菌NB液体培养基的OD595值。
校正OD值=含菌培养基OD值-无菌培养基OD值;
抑制率%=[(校正后对照培养基菌液OD值-校正含毒培养基OD值)/校正后对照培养基菌液OD值]×100
本发明实施例辅以说明本发明的技术方案,但实施例的内容并不局限于此,部分目标化合物实验结果如下表所示。
表3一类含二硫醚结构的喹唑啉酮类衍生物对水稻白叶枯病菌的抑制活性
——:low activity
表4一类含二硫醚结构的喹唑啉酮类衍生物对柑橘溃疡病菌的抑制活性
——:low activity
表5一类含二硫醚结构的喹唑啉酮类衍生物对猕猴桃溃疡病菌的抑制活性
——:low activity
表6一类含二硫醚结构的喹唑啉酮类衍生物对烟草青枯病菌的抑制活性
——:low activity
上述离体实验结果表明:该系列化合物与对照药叶枯唑和申嗪霉素相比,对水稻白叶枯病菌、柑橘溃疡病菌、猕猴桃溃疡病菌和烟草青枯病菌都具有较好的抑制活性;以对水稻白叶枯病菌的抑制活性数据为例,大部分化合物在测试浓度下的抑制作用优于叶枯唑,与申嗪霉素相当,其中化合物1-9、11-13、16-17、21、23在较低浓度25ppm下仍能实现大于90%的抑制效果,与申嗪霉素的抑制效果相当,而相同浓度下叶枯唑的抑制率仅为30%左右。初步离体活性数据为进一步的研究提供了较好支撑,该系列化合物可进一步进行活体实验、结构优化和初步作用机制研究,以期为新农药创制提供一定基础。
Claims (10)
2.根据权利要求1所述的含二硫醚结构的喹唑啉酮类衍生物,其特征在于:R选自烷基、环烷基、取代或未取代的芳基。
3.根据权利要求1所述的含二硫醚结构的喹唑啉酮类衍生物,其特征在于:R选自C2-C10烷基、C5-C6环烷基、取代或未取代的C6-C7芳基,其中,所述取代指的是被C1-C10烷基、C1-C10烷氧基、氨基、羟基、卤素、硝基、三氟甲基中的一个或一个以上取代。
4.根据权利要求3所述的含二硫醚结构的喹唑啉酮类衍生物,其特征在于:R选自乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、环戊基、环己基、己基、庚基、辛基、壬基、葵基、取代或未取代的苯基、取代或未取代的苄基,其中,所述取代指的是被C1-C10烷基、C1-C10烷氧基、氨基、羟基、卤素、硝基、三氟甲基中的一个或多个取代。
6.一种组合物,其特征在于含有权利要求1-4任一所述的化合物,以及农业上用的助剂或杀菌剂。
7.如权利要求1-4任一所述的化合物,或权利要求6所述的组合物在制备防治植物细菌病害方面药物中的应用。
8.根据权利要求7所述的应用,其特征在于:优选地,所述农业病虫害为植物细菌性病害。
9.根据权利要求7所述的应用,其特征在于:所述农业病虫害为植物叶枯病、植物溃疡病和植物细菌性青枯病。
10.根据权利要求7所述的应用,其特征在于:所述农业病虫害为水稻白叶枯病、柑橘溃疡病、猕猴桃溃疡病、细菌性青枯病。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0276825A1 (en) * | 1987-01-30 | 1988-08-03 | Nisshin Flour Milling Co., Ltd. | 4 (3H)-Quinazolinone derivatives, processes for their preparation and pharmaceutical compositions |
CN102643247A (zh) * | 2011-02-21 | 2012-08-22 | 中国科学院上海药物研究所 | 一类二硫醚类化合物及其制备方法和用途 |
CN102775360A (zh) * | 2012-03-06 | 2012-11-14 | 南开大学 | 含三唑环的不对称二硫醚类化合物及其合成方法和用途 |
CN111285814A (zh) * | 2020-03-25 | 2020-06-16 | 贵州大学 | 一种含腙结构单元的喹唑啉酮化合物或其立体异构体、或其盐或其溶剂化物 |
CN111285860A (zh) * | 2020-03-25 | 2020-06-16 | 贵州大学 | 一类含二硫烷基杂环结构的吲哚衍生物或其立体异构体、或其盐或其溶剂化物 |
-
2021
- 2021-09-22 CN CN202111104865.9A patent/CN113880777A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0276825A1 (en) * | 1987-01-30 | 1988-08-03 | Nisshin Flour Milling Co., Ltd. | 4 (3H)-Quinazolinone derivatives, processes for their preparation and pharmaceutical compositions |
CN102643247A (zh) * | 2011-02-21 | 2012-08-22 | 中国科学院上海药物研究所 | 一类二硫醚类化合物及其制备方法和用途 |
CN102775360A (zh) * | 2012-03-06 | 2012-11-14 | 南开大学 | 含三唑环的不对称二硫醚类化合物及其合成方法和用途 |
CN111285814A (zh) * | 2020-03-25 | 2020-06-16 | 贵州大学 | 一种含腙结构单元的喹唑啉酮化合物或其立体异构体、或其盐或其溶剂化物 |
CN111285860A (zh) * | 2020-03-25 | 2020-06-16 | 贵州大学 | 一类含二硫烷基杂环结构的吲哚衍生物或其立体异构体、或其盐或其溶剂化物 |
Non-Patent Citations (2)
Title |
---|
徐文方: "《新药设计原理与方法》", 31 July 1997, 中国医药科技出版社 * |
郭宗儒: "《药物分子设计》", 30 April 2005, 科学出版社 * |
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