CN115850284A - 一类8-氟-9-脂肪胺取代色胺酮衍生物、其制备方法及应用 - Google Patents
一类8-氟-9-脂肪胺取代色胺酮衍生物、其制备方法及应用 Download PDFInfo
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- CN115850284A CN115850284A CN202211455969.9A CN202211455969A CN115850284A CN 115850284 A CN115850284 A CN 115850284A CN 202211455969 A CN202211455969 A CN 202211455969A CN 115850284 A CN115850284 A CN 115850284A
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- fatty amine
- tryptanthrin
- substituted
- fluoro
- derivative
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Images
Abstract
Description
技术领域
本发明涉及化工技术领域,具体来说涉及一类8-氟-9-脂肪胺取代色胺酮衍生物的制备方法及其在抑菌活性的应用。
背景技术
色胺酮(tryptanthrin)是一种从多种天然物质中分离得到的吲哚喹唑啉生物碱,其来源包括中国菘蓝(Isatis tinctoria)、日本槐蓝(Polygonum tinctorium)、马蓝(Strobilanthescusia)、靛蓝(Strobilanthesformosanus)和靛木夹竹桃(Wrightiatinctoria)。色胺酮及其衍生物具有广泛的生物活性,包括抗真菌、抗肿瘤、抗炎、抗病毒、抗原生动物、抗氧化和抗微生物的作用,具有较好的研究和应用价值。色胺酮及其衍生物,其结构含有共轭芳香环的四元稠杂环分子,分子之间紧密堆积和π-π作用,导致较难溶解,降低化合物的暴露量,影响药效的发挥。
先导化合物的发现及结构优化是创新药物研究成败的核心问题之一,在先导化合物结构优化过程中,化合物的水溶性起着至关重要的作用,良好的水溶性可以提升化合物的类药性质,提高药物在生物体内的吸收、分布、代谢、排泄(ADME)等药代动力学特性。通过成盐修饰、引入极性基团、降低脂溶性等一系列化学结构修饰来改善色胺酮及其衍生物的溶剂性,以期获得具备高活性、低毒性、良好的药代动力学性质等各项优良性质的理想药物分子
当分子含有较大或较多的芳香体系时,通过引入一个或更多的极性片段来调节水溶性,其中各种链状和环状的胺是一种常用的极性基团,这个策略成功的关键在于引入合适的极性基团而不影响化合物的其他重要指标,如活性和安全性等。吗啉环和哌嗪环的应用是该策略的典型代表,其目的是增加化合物的水合作用,促进溶解的热力学过程,最终有效提高化合物的生物活性。
2019年,Yang等[Yang D.,Zhang S.N.,Fang,X.,Guo L.L.,Hu N.,Guo Z.L.,LiX.S.,Yang S.S.,He J.C.,Kuang C.X.,Yang Q.N-Benzyl/Aryl SubstitutedTryptanthrin as Dual Inhibitors ofIndoleamine2,3-Dioxygenase and Tryptophan2,3-Dioxygenase.[J]J.Med.Chem.2019,62,9161-9174.]设计合成一系列新型的N-苄基/芳基取代的色胺酮,并在酶活性和细胞水平上的IDO1,TDO和IDO2抑制能力进行了评估。发现在这些N-苄基/芳基取代的色胺酮衍生物中,N-苄基取代的化合物显示出更高的IDO1、IDO2和TDO抑制活性,尤其甲基哌嗪苄基取代的化合物表现的更为突出,由于其改善了物理化学性质,大大增强了酶和细胞的活性。
2020年,Li等[Li Y.Y.,Zhang S.N.,Wang R.,Cui M.H.,Liu W.,Yang Q.,KuangC.X.Synthesis of novel tryptanthrin derivatives as dual inhibitors ofindoleamine2,3-dioxygenase 1and tryptophan2,3-dioxygenase.Bioorg.Med.Chem.Lett.2020,30,127159.]合成了12种含醛基、三氮唑、N-苄基环烷酸、N-苄基环烷酸、肉桂酸酯、肉桂酸、硼酸酯、和硼酸等一系列增大色胺酮溶解性的衍生物。生物活性测试显示,所有化合物均表现出IDO1抑制活性,肉桂酸衍生物(IC50=0.12μm)显示出比具有8-氟色胺酮(IC50=0.534μm)更好的IDO1抑制活性。在TDO抑制活性方面表现更为突出,肉桂酸衍生物(IC50=0.03μm)相对于8-氟色胺酮(IC50=0.937μm)抑制效力增加32倍。
2020年,Hao等,[Hao,Y.N.,Guo,J.C.,Wang,Z.W.,Liu,Y.X.,Li,Y.Q.,Ma,D.J.,&Wang,Q.M.Discovery of Tryptanthrins as Novel Antiviral and Anti-Phytopathogenic-Fungus Agents.[J]J.Agric.Food Chem.2020,68,5586-5595]考察了色胺酮衍生物对烟草花叶病毒(TMV)和14种植物性病原真菌抑制活性的影响。发现7位四氢吡咯取代色胺酮对TMV具有较高的抗病毒活性,色胺酮6位和14位氢化还原产物对植物真菌表现出较好的抑菌活性,尤其对苹果轮纹病菌(Physalosporapiricola)具有较好的选择性抑菌活性。
2020年,Kirpotina等[Kirpotina L.N.,Schepetkin I.A.,Hammaker D.,KuhsA.,Khlebnikov A.I.,Quinn M.T.Therapeutic Effects of TryptanthrinandTryptanthrin-6-Oxime in Modelsof Rheumatoid Arthritis.[J]FRONT PHARMACOL,2020,11,1145].研究发现色胺酮肟作为NK1和JNK3潜在治疗靶标,评估了色胺酮和色胺酮肟的体外抗炎作用,色胺酮肟能够有效抑制FLS,SW982滑膜细胞和THP-1单核细胞的IL-6分泌,在治疗类风湿关节炎方面具有相对更大的治疗潜力。同时,使用SwissADME工具分析色胺酮和色胺酮肟的ADME特性,在H-键受体和供体的数量上显著不同,从而影响JNK结合亲和力和结合位点内的位置。
2020年,Popov等[Popov A.,Klimovich A.,Stysyova O.,Moskovkin T.,ShchekotikhinA.,Grammatikova N.,Dezhenkova L.,KaluzhnyD.,Deriabin P.,Gerasimenko A.,Udovenko A.,StonikV.Design,synthesis and biomedical evaluationof mostotrin,a new water solubletryptanthrinderivativegram-positive bacteria[J]Int.J.Mol.Med.2020,46,1335-1346]通过色胺酮6位衍生化反应,利用分子内氢键的参与下形成了一个附加的假循环的五元环化合物,设计合成了Mostotrin(MT)衍生物,大大提高了水溶性,其在水中的溶解度比其色胺酮至少高出五个数量级,对肿瘤细胞系HCT-116、MCF-7和K-562的细胞毒性活性比色胺酮母体结构高出5到10倍,但对正常细胞的毒性却大大降低。同时联用用药实验结果表明,该类化合物还具有与已知的抗肿瘤药物联合用于治疗肿瘤疾病的前景。
2022年,Wang等[Palabindela R.,GudaR.,Gondru Ramesh G.,MyadaraveniP.,Banothu D.,Ravi G.,Korra R.,Mekala H.,Kasula M.Novel tryptanthrin hybridsbearing aminothiazoles aspotential EGFR inhibitors:Design,synthesis,biologicalscreening,molecular docking studies,and ADME/Tpredictions.J.Heterocyclic Chem.2022,59,1533-1550.]通过色胺酮与硫代氨基硫脲以及不同取代的α-溴-4-取代苯乙酮化合物反应,合成了一系列新型的具有生物活性的噻唑类色胺酮衍生物,并进行了三种人类癌细胞系(MCF-7,A549和HeLa)的体外抗癌活性测定,结果表现出优异的抗肿瘤活性。ADME预测出的水溶性结果表明,所有化合物都具有良好的水溶性,其值在从3.43到4.17的范围内。
发明内容
本发明的目的之一提供了一类8-氟-9-脂肪胺取代色胺酮衍生物。
本发明还有一目的是提供了一种含有上述化合物或其异构体,或其盐类,或其溶剂化合物及组合物。
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。
本发明还有一目的是提供了上述化合物或所述组合物的防治农业植物细菌病害方法。
为实现上述目的,本发明采用了下述技术方案:
一类8-氟-9-脂肪胺取代色胺酮衍生物,该类化合物具有如通式(Ⅰ)所示的结构:
其中,
R1为独立地选自氢,硝基,C1-C4烷氧基,C1-C4烷烃基,卤素,三氟甲基,三氟甲氧基,氨基,羟基,氰基,羧基,甲砜基,磺酸基,或上述取代基团任意组合的二取代、三取代、四取代的衍生物。
R为脂肪胺,进一步独立地选自低碳脂肪胺(C2~C8)类、高级脂肪胺(C8~C22)类、氨基酸类和哌嗪类,包含伯胺、仲胺、叔胺,季铵盐,无机盐。
所述的脂肪胺再进一步包括甲基哌嗪、乙基哌嗪、环丙基哌嗪、酰胺哌嗪类衍生物、磺酰胺类衍生物、哌嗪杂环取代衍生物、哌嗪嘌呤取代衍生物、哌嗪嘌呤糖苷衍生物等。
所述的一类8-氟-9-脂肪胺取代色胺酮衍生物,选自下述化合物:
本发明还提供了所述的一类8-氟-9-脂肪胺取代色胺酮衍生物的制备方法,其包括下述步骤:
一类组合物,其含有所述的化合物或其立体异构体或其盐类或其溶剂化合物,以及农业上用的助剂或杀菌制剂。
所述的化合物或所述的组合物用于防治农业病害,优选地,所述农业病害为植物细菌性病害;更优选地,所述农业病害为植物叶枯病,溃疡病和青枯病;最优选地,所述农业病害为水稻白叶枯病、柑橘溃疡病、猕猴桃溃疡病和烟草青枯病。
术语“卤素”或“卤素原子”指的是氟、氯、溴和碘。
如果没有其它说明,本发明的化合物理解为包括游离态和其盐。术语“盐”表示以无机和/或有机酸和碱形成酸式和/或碱式盐。
通过采用上述技术方案,本发明以3,4二氟苯胺为起始原料,经过酰胺肟中间体后,在浓硫酸的作用下加热关环反应得到5,6二氟靛红;将其他取代靛红衍生物在二氯甲烷中通过间氯过氧苯甲酸氧化重排反应,制备取代的靛红酸酐衍生物;5,6二氟靛红与取代靛红酸酐通过优化的Bergman反应,获得取代的8,9-二氟色胺酮类衍生物;最后,以碳酸钾为催化剂在NMP溶剂作用下加入相应的脂肪胺,加热搅拌获得色胺酮8-氟9-脂肪胺取代色胺酮衍生物。通过对植物病原细菌的活性测试结果,发现该类化合物还具较好的抑制植物病菌生物活性,针对水稻白叶枯病(Xoo)、柑橘溃疡病(Xac)、猕猴桃溃疡病(Psa)和烟草青枯病(Rs)具有良好的抑制作用,为以天然源生物碱色胺酮为先导化合物基础,将具有较好柔性的脂肪胺化合物引入到色胺酮结构,能大大增大色胺酮脂溶性和水溶性,生物活性也获得了大大提高,为开发高效低毒的绿色农药提供一种研究方向。
附图说明
图1为盆栽柑橘叶片保护活性测试结果。
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
(1)5,6二氟靛红的制备
在500mL圆底三口烧瓶中,事先加入220mL蒸馏水,加热至50℃,添加无水硫酸钠(0.1mol)搅拌至完全溶解,用5%的稀盐酸完全溶解3,4-二氟苯胺溶液(0.1mol),然后逐滴滴加到反应体系中,继续滴加盐酸羟胺水溶液(0.3mol),回流5-8h,TLC监测,待反应完全,冷却,真空抽滤,干燥,得到酰胺肟中间体2。
在250mL圆底三口烧瓶中,将中间体化合物2(0.1mol)分批次加入到90%的浓硫酸中,90℃加热搅拌3-5h后冷却至室温,快速搅拌下加入500mL的冰水混合物中,关环反应30min,抽滤,水洗,真空抽滤,干燥,获得产物5,6二氟靛红。
(2)取代靛红酸酐的制备
在250mL圆底三口烧瓶中,将取代靛红衍生物(0.1mol)悬浮于二氯甲烷中,在冰浴条件下分批次加入间氯过氧苯甲酸(0.12mol),然后室温搅拌3-5h,TLC监测,反应结束后,过滤,饱和碳酸氢钠洗涤,通过Baeyer-Villiger氧化重排反应,得到浅黄色固体,产率72%-83%。
(3)8,9-二氟取代色胺酮衍生物的制备
在250mL圆底三口烧瓶中,将上述制备的5,6-二氟靛红(0.1mol)和取代靛红酸酐(0.1mol)在甲苯溶剂中以三乙胺为催化剂,加热回流3-5h,TLC监测,反应结束后,旋干溶剂,柱层析分离,得到8,9-二氟取代色胺酮衍生物,产率60%-85%。
(4)目标化合物9-((3-(二甲氨基)丙基)氨基)-8-氟吲哚[2,1-b]喹唑啉-6,12-二酮的制备
在50mL圆底三口烧瓶中,加入8,9-二氟取代色胺酮(0.01mol)和N,N-二甲基-1,3-丙二胺(0.01mol)),加入反应溶剂N-甲基吡咯烷酮(NMP)(25mL),以碳酸钾(0.03mol)为催化剂,90℃加热搅拌3-5h后冷却至室温,加入甲醇3.0mL,静置30min,析出固体,真空抽滤,干燥,柱层析分离,得到9-((3-(二甲氨基)丙基)氨基)-8-氟吲哚[2,1-b]喹唑啉-6,12-二酮,产率86%。
其他目标化合物8-氟-9-脂肪胺取代色胺酮衍生物,采用8,9-二氟取代色胺酮、相对应的取代脂肪胺以及其他试剂原料,参照实施例步骤(4)的合成方法。
合成的部分8-氟-9-脂肪胺取代色胺酮衍生物的结构及核磁共振氢谱、碳谱和高分辨质谱数据如表1所示,物化性质如表2所示。
表1部分化合物的核磁共振氢谱、碳谱及高分辨质谱数据。
表1 8-氟-9-脂肪胺取代色胺酮衍生物1H NMR、13C NMR和ESI-HRMS数据
表2部分目标化合物的理化性质
表2 8-氟-9-脂肪胺取代色胺酮衍生物的理化性质
药理实施例1:
抗植物病原菌性测试。
采用浊度法测试8-氟-9-脂肪胺取代色胺酮衍生物对植物病原菌细菌的抑制率,测试病原菌为水稻白叶枯病菌(Xoo)、柑橘溃疡病菌(Xac)、猕猴桃溃疡病菌(Psa)和烟草青枯菌(Rs)。空白对照为DMSO,阳性对照为叶枯唑和噻菌酮。恒温摇床在28℃和180rpm条件下,将Xoo、Xac、Psa和Rs病原菌接种于固体培养基(NA)中,使用时在28℃/180rpm恒温摇床中振荡培养到对数生长期备用。将被测试化合物和阳性对照药配置不同浓度的含毒NB液体培养基,分别加入40μL生长至对数期的含植物病原菌的NB培养基液体,在28℃/180rpm恒温摇床中振荡,水稻白叶枯病菌培养约36小时,猕猴桃溃疡菌和柑橘溃疡菌培养约48小时,待摇床中对照组的OD值在生长对数期时,通过酶标仪在595nm处分别测定空白对照组、阳性对照药和化合物OD值。
校正OD值和抑制率的计算公式如下:
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表3所示。
表3 8-氟-9-脂肪胺取代色胺酮衍生物对四种植物病原菌细菌的抑制活性
测试结果为三次测定平均值。
上述实验活性数据表明,所测试的8-氟-9-脂肪胺取代色胺酮衍生物对植物病原菌细菌均具有较好的抑制活性,该测试浓度下大部分化合物的初筛抑制活性优于阳性对照化合物叶枯唑和噻菌酮,可作为潜在的抑制植物病原菌细菌的候选药物,具有较好的研究和应用价值。
药理实施例2:
盆栽柑橘叶片保护活性测试。
准备好建康的柑橘盆栽植株,用无菌水叶将叶片清洗干净并自然干燥,分别使用消毒过的注射器在每个柑橘叶的中间部位均匀地形成18个小伤口。配制测试化合物14和阳性对照药20%悬浮剂的噻唑铜(TC),药物浓度均为200μg/mL,加入药物等量的DMSO水剂作为空白对照。然后,将被测试水剂均匀喷洒在柑橘叶片上,自然晾干后,置于温度为28℃,设置光照16h,黑暗8h,在湿度保在80%至95%的光照培养箱内培养24h。随后,将新活化的Xac悬浮液(OD595=0.5)均匀地涂在叶片伤口处,同样的培养条件在人工气候箱中培养14天,观察测试药物的保护效果。
盆栽柑橘叶片保护活性测试结果表明,化合物14具有较好的保护活性,与阳性对照药TC(20%悬浮剂)的保护效果相当。在200μg/mL的浓度下,对柑橘叶面溃疡斑的扩展具有相对明显的阻断作用,并且在一些伤口处没有出现明显的结痂。因此,化合物14可能是一种具有潜在的预防柑橘细菌性溃疡感染的小分子化合物。
Claims (8)
2.根据权利要求1所述的一类8-氟-9-脂肪胺取代色胺酮衍生物,其特征在于:所述的脂肪胺包含低碳脂肪胺(C2~C8)类、高级脂肪胺(C8~C22)类和哌嗪类。
3.根据权利要求1所述的一类8-氟-9-脂肪胺取代色胺酮衍生物,其特征在于:包含其立体异构体或其盐类或其溶剂化合物,R1为独立地选自氢,硝基,C1-C4烷氧基,C1-C4烷烃基,卤素,三氟甲基,三氟甲氧基,氨基,羟基,氰基,羧基,甲砜基,磺酸基,或上述取代基团任意组合的二取代、三取代、四取代的衍生物;R为脂肪胺。
5.一类组合物,其特征在于含有权利要求1-3任一所述的化合物或其立体异构体或其盐类或其溶剂化合物,以及农业上用的助剂或杀菌制剂。
6.权利要求1-3任一所述的化合物或其立体异构体或其盐类或其溶剂化合物、或权利要求5所述的组合物在制备农业病菌病害药物的应用。
7.根据权利要求6所述的应用,其特征在于:所述的病菌病害为植物病原菌细菌病害。
8.根据权利要求7所述的应用,其特征在于:所述的植物病原菌为水稻白叶枯病菌(Xanthomonas oryzaepv.oryzae,Xoo)、柑橘溃疡病菌(Xanthomonascampestrispv.citri,Xac)、猕猴桃溃疡菌(seudomonassyringaepv.actinidiae,Psa)和烟草青枯菌(Ralstoniasolanacearum)。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995013807A1 (en) * | 1993-11-19 | 1995-05-26 | Pathogenesis Corporation | INDOLO[2,1-b]QUINAZOLINE-6,12-DIONE ANTIBACTERIAL COMPOUNDS AND METHODS OF USE THEREOF |
CN105330666A (zh) * | 2015-11-27 | 2016-02-17 | 西北大学 | 色胺酮新衍生物、合成方法及其药用用途 |
CN110437233A (zh) * | 2019-06-21 | 2019-11-12 | 同济大学 | 一种含烯酸的色胺酮衍生物及其制备方法和应用 |
CN114805353A (zh) * | 2022-01-11 | 2022-07-29 | 贵州大学 | 氮杂色胺酮类衍生物的合成及在防治植物病原菌细菌、真菌杀菌剂及抗植物病毒制剂的应用 |
CN115197227A (zh) * | 2022-08-09 | 2022-10-18 | 贵州大学 | 一类色胺酮1位或3位取代芳香硫醚衍生物、其制备方法及应用 |
-
2022
- 2022-11-21 CN CN202211455969.9A patent/CN115850284A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995013807A1 (en) * | 1993-11-19 | 1995-05-26 | Pathogenesis Corporation | INDOLO[2,1-b]QUINAZOLINE-6,12-DIONE ANTIBACTERIAL COMPOUNDS AND METHODS OF USE THEREOF |
CN105330666A (zh) * | 2015-11-27 | 2016-02-17 | 西北大学 | 色胺酮新衍生物、合成方法及其药用用途 |
CN110437233A (zh) * | 2019-06-21 | 2019-11-12 | 同济大学 | 一种含烯酸的色胺酮衍生物及其制备方法和应用 |
CN114805353A (zh) * | 2022-01-11 | 2022-07-29 | 贵州大学 | 氮杂色胺酮类衍生物的合成及在防治植物病原菌细菌、真菌杀菌剂及抗植物病毒制剂的应用 |
CN115197227A (zh) * | 2022-08-09 | 2022-10-18 | 贵州大学 | 一类色胺酮1位或3位取代芳香硫醚衍生物、其制备方法及应用 |
Non-Patent Citations (4)
Title |
---|
BAOLONG HOU,等: "Synthesis and evaluation of tryptanthrins as antitumor agents", 《TETRAHEDRON》, vol. 99, 21 September 2021 (2021-09-21), pages 132454, XP086839606, DOI: 10.1016/j.tet.2021.132454 * |
DAN YANG,等: "N‑Benzyl/Aryl Substituted Tryptanthrin as Dual Inhibitors of Indoleamine 2, 3-Dioxygenase and Tryptophan 2, 3-Dioxygenase", 《J. MED. CHEM.》, vol. 62, 3 October 2019 (2019-10-03), pages 9161 - 9174 * |
GRACE SHIAHUY CHEN,等: "Specific stabilization of DNA triple helices by indolo[2, 1-b]-quinazolin-6, 12-dione derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 17, 27 December 2006 (2006-12-27), pages 1769 - 1772, XP005895408, DOI: 10.1016/j.bmcl.2006.12.079 * |
VARUN,等: "Isatin and its derivatives: a survey of recent syntheses, reactions, and applications", 《MED. CHEM. COMMUN.》, vol. 10, 31 December 2019 (2019-12-31), pages 351 - 368 * |
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