CN115925706B - 一类哌嗪乙酰-螺[吡咯烷-2,3’-喹啉]-2’-酮类衍生物的设计合成与应用 - Google Patents

一类哌嗪乙酰-螺[吡咯烷-2,3’-喹啉]-2’-酮类衍生物的设计合成与应用 Download PDF

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CN115925706B
CN115925706B CN202210732656.7A CN202210732656A CN115925706B CN 115925706 B CN115925706 B CN 115925706B CN 202210732656 A CN202210732656 A CN 202210732656A CN 115925706 B CN115925706 B CN 115925706B
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吉庆刚
吴胡
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Southwest University
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Abstract

本发明公开了一类1‑(2‑(4‑苯甲酰基)哌嗪‑1‑基)乙酰基)‑1',4'‑二氢‑2'H‑螺[吡咯烷‑2,3'‑喹啉]‑2'‑酮类化合物的设计合成及应用，所述化合物的结构如通式1所示：1式中R为3‑CH3C6H4,4‑CH3C6H,3‑BrC6H4,4‑O2NC6H4,3‑CH3OC6H4,3‑FC6H4,4‑FC6H4,‑C6H5,4‑C2H5C6H4,2‑ClC6H4,2.6‑FC6H3,2.5‑ClC6H3,2‑IC6H4,2‑Cl‑5‑O2NC6H3,3‑O2NC6H等。经生物活性测试实验证明，化合物对几丁质合成酶抑制活性明显，对白色念珠菌、黄曲霉菌、新型隐球菌和烟曲霉菌及其耐药变异株表现出较好的抑制活性，可用于制备抗真菌的药物。

Description

一类哌嗪乙酰-螺[吡咯烷-2,3’-喹啉]-2’-酮类衍生物的设 计合成与应用
技术领域
本发明属药物化学领域，涉及新型哌嗪乙酰-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物，具体涉及一种1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物的设计合成及其在抗真菌及耐药真菌方面的应用。
背景技术
据报道，随着感染艾滋病毒、肺结核、肺炎和癌症的人口越来越多，侵袭性真菌感染成为了这些免疫性缺陷患者死亡的主要原因。造成这种严重困境的主要因素在于当前抗真菌治疗的欠缺。临床用于侵袭性感染治疗主要是四类抗真菌药物(唑类、多烯类、嘧啶类和棘白菌素)，尽管它们存在一定的抗菌疗效，但这些药物具有内脏毒性和生物利用率低等缺点。因此抗真菌药物的稀缺，加上真菌耐药性的迅速蔓延，凸显了迫切需要新药来应对日益严重的真菌感染问题。
相比于人体细胞，真菌细胞中存在着一种特殊的细胞器，细胞壁。当药物靶向真菌细胞壁时，可能不会对宿主细胞产生不良副作用，这是开发新型抗真菌剂中最理想的结果。几丁质是真菌细胞壁的必要成分，细胞壁在维持细胞形态和功能方面起着重要作用，几丁质的合成必须有几丁质合成酶的参与。研究表明阻断几丁质合酶对几丁质的合成会导致细胞壁发生变化和功能异常，最终导致真菌死亡。所以几丁质合成酶抑制剂被认为是理想的抗真菌药物。
喹诺酮类化合物中3,4-二氢喹啉-2(1H)酮骨架存在于很多具有生物活性的天然产物药物分子和功能材料中，目前临床上广泛将它们应用在抗病毒、抗菌、抗炎、血管舒张和抗精神疾病治疗中。Chem-Eur.J.2009,15:7238-7245；J.Med.Chem.2002,45:4954-4957；J.Med.Chem.1985,28:1511-1516.
由于吡咯烷片段已广泛应用于药物化学领域，且与3,4-二氢喹啉-2(1H)酮以螺环形式杂交，其中螺环被设计为分子的附加物。螺环的主要优点是其固有的三维结构性质，使其能够在三个维度上发挥作用，从而增加与目标相互作用的机会。此外，螺环分子比线性支架具有更好的水溶性和代谢稳定性，在构象上更灵活，用于设计抑制酶、调节受体和抑制蛋白质-蛋白质相互作用和转运蛋白的螺环类化合物均已被报道。Bioorg.Med.Chem.Lett.2014,24:3672-3682.
含氮杂环化合物在许多天然产物与药物合成分子中占据着重要地位，美国FDA批准药物的数据库中显示，氮杂环是最常见的药物碎片且哌嗪类在氮杂环衍生物中占有59％。在药物化学中通过引入弱碱性哌嗪环进行改性，以提高药物的水溶性、结合亲和力和选择性等理化性质。哌嗪片段目前已经广泛存在抗感染、神经科学、皮肤科、胃肠道、代谢、抗肿瘤和眼科治疗领域。J.Med.Chem.2014,57:10257-10274；J.Med.Chem.2018,61:10935-10956；J.Med.Chem.2018,61:7004-7031.
为了寻找新型的几丁质合成酶抑制剂，本发明设计合成了1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物，以多氧霉素B和氟康唑为对照，测定了该类化合物对几丁质合成酶的抑制作用，并测定了其在抗真菌，抗细菌方面的活性，拓展了螺环化合物和喹啉酮类化合物的应用研究。到目前为止，本发明所涉及的新型化合物在抑制几丁质合成酶活性方面还未见报道，所以将其作为几丁质合成酶的抑制剂，可用于开发成新型的抗真菌制剂。
发明内容
本发明的目的之一在于提供一类1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物；本发明的目的之二在于提供一类1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物的制备方法；本发明的目的之三在于提供所述的一类1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物在制备抗真菌/抗细菌药物中的应用。
为达到上述目的，本发明提供如下技术方案：
1.本发明所述的1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物结构如通式1所示：
其中R为3-CH3C6H4,4-CH3C6H,3-BrC6H4,4-O2NC6H4,3-CH3OC6H4,3-FC6H4,4-FC6H4,-C6H5,4-C2H5C6H4,2-ClC6H4,2.6-FC6H3,2.5-ClC6H3,2-IC6H4,2-Cl-5-O2NC6H3,3-O2NC6H4。
具体地说，通式1所示的1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物为下述化合物的任意一种。
上述1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物的合成方法，按如下进行：如Scheme1所示。
具体地说，上述Scheme1反应条件如下：
(a)溶剂为二氯甲烷和无水乙醇，螺[吡咯烷-2,3'-喹啉]-2'-酮、氯乙酰氯和三乙胺摩尔比为1:1:2.5，在二氯甲烷溶剂后，室温下反应1小时，反应结束后，浓缩溶剂，蒸馏水洗涤固体，得到棕黄色固体。将中间体与哌嗪二盐酸盐反应，无水乙醇为溶剂，在60℃下回流搅拌3小时，浓缩溶剂后得到粗品，过柱洗脱剂EA/MeOH(V/V，1/1)，得棕色固体
(b)化合物3a-o与1-(2-(哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮的摩尔比为1：1，45℃反应48小时，二氯甲烷为溶剂,1-丙基膦酸酐为缩合剂，三乙胺为催化剂。
本领域普通技术人员均可按上述公开的制备方法制得相应的化合物。
上述1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物在制备抗真菌或细菌，真菌是白色念珠菌(ATCC 76615)、黄曲霉菌(ATCC 16870)、烟曲霉菌(GIMCC 3.19)、新型隐球菌(ATCC 32719)；细菌是大肠杆菌(JM109)、耐甲氧西林金黄色葡萄球菌(N 3.15)、枯草杆菌(ATCC 6633)、铜绿色假单胞菌(ATCC9027)、金黄色葡萄球菌(ATCC 25923)、变形杆菌(ATCC 8427)。
附图说明
附图1测试化合物浓度为300μg/ml时的几丁质合成酶抑制率
具体实施方式
为了加深对本发明的理解，下面将结合实施例对本发明作进一步详述，该实施例仅用于解释本发明，并不构成对本发明保护范围的限定，但本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。
除非另有说明，所有化学品和材料试剂均为商业级，并通过标准方法干燥和纯化，无需进一步纯化。所有反应均通过使用预涂硅胶板的分析薄层色谱(TLC)进行监测，并使用UV灯在254nm波长处进行显色观察，部分使用碘和溴苯酚氯显色。1HNMR和13C NMR光谱在Bruker AV 600MHz光谱仪上记录，以CDCl3或DMSO-d6作为溶剂，TMS作为内标。化学位移以δppm为单位报告，耦合常数(J)以Hz表示，s、d、t、q、m、分别表示单峰、双重峰、三重峰、四重峰和多重锋，高分辨率质谱(HRMS)是使用Bruker impactⅡ所获得。熔点在显微熔点仪(X-4型)上测量。
实施例1:化合物2的制备：
向50mL的圆底烧瓶中依次加入螺[吡咯烷-2,3'-喹啉]-2'-酮(1g，5mmoL)、无水二氯甲烷10mL，待固体溶解后，再向瓶中加入三乙胺(1.26g，12.5mmoL)和5mmoL的氯乙酰氯，将反应在室温搅拌一小时，TLC检测反应结束后，在旋转蒸发仪器上旋干二氯甲烷，再用蒸馏水洗涤固体，得到棕黄色固体。另取50mL圆底烧瓶，将哌嗪二盐酸盐(2.86g，18mmoL)、无水哌嗪(0.86g，10mmoL)和20mL的无水乙醇，在60℃下将反应回流搅拌3小时，向混合物体系中加入上述棕黄色固体，继续搅拌回流16小时，TLC检测反应完毕后，浓缩溶剂后得到粗品，过柱洗脱剂EA/MeOH(V/V，1/1)，得棕色固体。
实施例2:目标产物的制备
向各取代苯甲酸(1.2mmol)的10mL无水二氯甲烷溶液中加入三乙胺(4mmol)和1-丙基膦酸酐(2.15mmol)，搅拌30分钟后，加入1-(2-(哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1.2mmol)至以上反应。然后将混合物加热回流18小时。反应完成后，将溶液减压浓缩。残留物溶于乙酸乙酯中，依次用蒸馏水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，层柱析得固体产物1a,化合物1b-1o的合成方法同上。
化合物1a-1o的物理常数及光谱数据如下所示。
1-(2-(4-(3-甲基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1a)
产率39.7％；黄色固体；熔点：271～273℃；HPLC RT 13.8min purity 97.64％.1HNMR(600MHz,CDCl3)δ9.12(s,1H),7.92(d,J＝7.9Hz,1H),7.33～7.29(m,1H),7.23(d,J＝7.8Hz,2H),7.08(t,J＝7.7Hz,2H),6.95(t,J＝7.3Hz,1H),6.79(d,J＝7.7Hz,1H),4.21(d,J＝15.5Hz,1H),3.93～3.70(m,4H),3.53(d,J＝3.8Hz,2H),3.33(q,J＝14.7Hz,2H),2.81～2.63(m,4H),2.61(d,J＝15.5Hz,1H),2.40(s,3H),2.07～2.00(m,4H).13C NMR(151MHz,CDCl3)δ171.76,170.55,167.83,138.34,136.41,135.77,130.34,128.38,128.28,127.64,127.47,123.92,122.91,122.41,115.09,66.18,61.33,53.03,48.50,35.33,35.31,23.42,21.34,21.21.HRMS(ESI):calcd for C26H31N4O3[M+H]+,447.2391,found,447.2390.
1-(2-(4-(4-甲基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1b)产率36.4％；黄色固体；熔点：272～274℃；HPLC RT 11.45min purity97.60％.1H NMR(600MHz,CDCl3)δ8.80(s,1H),7.28(d,J＝7.9Hz,2H),7.17(d,J＝7.7Hz,2H),7.05～6.98(m,2H),6.87(t,J＝7.4Hz,1H),6.70(d,J＝7.8Hz,1H),4.15(d,J＝15.4Hz,1H),3.85～3.65(m,4H),3.48(d,J＝4.2Hz,2H),3.25(q,J＝,14.6Hz,2H),2.73～2.57(m,4H),2.54(d,J＝15.5Hz,1H),2.35(s,3H),2.02～1.93(m,4H).13C NMR(151MHz,CDCl3)δ171.35,170.53,167.81,139.75,136.54,132.86,129.03,128.37,127.45,127.18,122.78,122.41,115.02,66.19,61.51,53.13,48.51,35.39,35.34,23.41,21.34.HRMS(ESI):calcd for C26H31N4O3[M+H]+,447.2391,found,447.2391.
1-(2-(4-(3-溴苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1c)
产率40.0％；白色固体；熔点：275～276℃；HPLC RT 10.70min purity 98.09％.1H NMR(600MHz,CDCl3)δ7.98(s,1H),7.54(d,J＝7.8Hz,2H),7.31(d,J＝7.5Hz,1H),7.28(d,J＝7.2Hz,1H),7.12～7.05(m,2H),6.93(t,J＝7.4Hz,1H),6.70(d,J＝7.8Hz,1H),4.16(d,J＝15.4Hz,1H),3.85～3.67(m,4H),3.46(d,J＝15.9Hz,2H),3.27(q,J＝14.7Hz,2H),2.64(d,J＝15.1Hz,4H),2.57(d,J＝15.5Hz,1H),2.08～1.99(m,4H).13C NMR(151MHz,CDCl3)δ170.98,168.57,167.84,137.78,136.33,132.73,130.11,130.08,128.51,127.56,125.58,122.97,122.64,122.43,114.81,66.25,61.29,53.02,48.46,35.42,35.35,23.44.HRMS(ESI):calcd for C25H28BrN4O3[M+H]+,511.1339,found,511.1338.1-(2-(4-(4-硝基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1d)产率43.5％；黄色固体；熔点：273～275℃；HPLC RT 8.58min purity 98.23％.1H NMR(600MHz,CDCl3)δ8.30(s,1H),8.19(d,J＝8.3Hz,2H),7.50(d,J＝8.3Hz,2H),6.99(s,2H),6.84(t,J＝7.3Hz,1H),6.63(d,J＝8.0Hz,1H),4.09(d,J＝15.4Hz,1H),3.68(m,4H),3.34(d,J＝15.3Hz,2H),3.22(q,J＝14.8Hz,2H),2.61(d,J＝16.4Hz,4H),2.50(d,J＝15.5Hz,1H),1.91(m,4H).13C NMR(151MHz,CDCl3)δ171.13,167.92,167.75,148.40,141.97,136.40,128.49,128.10,127.47,123.86,122.91,122.39,114.86,66.27,61.11,52.98,48.46,35.38,35.32,23.44.HRMS(ESI):calcd for C25H28N5O5[M+H]+,478.2085,found,478.2085.
1-(2-(4-(3-甲氧基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1e)产率37.2％；白色固体；熔点：275～277℃；HPLC RT 10.25minpurity 97.66％.1H NMR(600MHz,CDCl3)δ8.40(s,1H),7.22(t,J＝8.0Hz,1H),6.98(d,J＝4.3Hz,2H),6.95(d,J＝8.4Hz,2H),6.83(d,J＝7.7Hz,2H),6.64(d,J＝7.9Hz,1H),4.09(d,J＝15.4Hz,1H),3.91～3.77(m,2H),3.74(s,3H),3.67～3.58(m,2H),3.45～3.32(m,2H),3.21(q,J＝14.6Hz,2H),2.69～2.52(m,4H),2.49(d,J＝15.5Hz,1H),1.95～1.86(m,4H).13C NMR(151MHz,CDCl3)δ171.20,170.07,167.75,159.68,137.10,136.44,129.56,128.43,127.50,122.88,122.41,119.10,115.61,114.91,112.39,66.22,61.39,55.36,48.49,35.37,35.35,23.42.HRMS(ESI):calcd for C26H31N4O4[M+H]+,463.2340,found,463.2341.1-(2-(4-(3-氟苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1f)
产率45.6％；淡黄色固体；熔点：268～270℃；HPLC RT 8.75min purity 99.09％.1H NMR(600MHz,CDCl3)δ8.04(s,1H),7.30(d,J＝7.8Hz,1H),7.10(d,J＝7.5Hz,1H),7.07～6.96(m,4H),6.87(t,J＝7.4Hz,1H),6.64(d,J＝7.7Hz,1H),4.09(d,J＝15.4Hz,1H),3.82～3.60(m,4H),3.48～3.33(m,2H),3.23(q,J＝14.8Hz,2H),2.75～2.53(m,4H),2.51(d,J＝15.5Hz,1H),1.97～1.89(m,4H).13CNMR(151MHz,CDCl3)δ171.10,168.83,167.69,161.73,136.29,130.30,128.51,127.57,123.00,122.71,122.41,116.64,114.86,114.44,114.29,66.27,61.11,52.98,48.46,35.39,35.35,29.67,23.44.HRMS(ESI):calcd forC25H28FN4O3[M+H]+,451.2140,found,451.2140.
1-(2-(4-(4-氟苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1g)
产率47.3％；淡黄色固体；熔点：269～271℃；HPLC RT 8.28min purity 97.06％.1H NMR(600MHz,CDCl3)δ7.93(s,1H),7.31(d,J＝7.6Hz,2H),7.00(d,J＝7.8Hz,4H),6.86(t,J＝7.1Hz,1H),6.62(d,J＝7.2Hz,1H),4.10(d,J＝15.4Hz,1H),3.83～3.57(m,4H),3.51～3.30(m,2H),3.20(q,J＝14.6Hz,2H),2.74～2.47(m,5H),1.98～1.88(m,4H).13CNMR(151MHz,CDCl3)δ170.91,167.83,167.81,162.14,136.34,135.85,130.39,130.13,129.64,128.51,127.83,127.54,122.93,122.47,114.75,66.22,61.49,48.48,46.66,41.59,35.43,35.38,23.44.HRMS(ESI):calcd for C25H28FN4O3[M+H]+,451.2140,found,451.2140.
1-(2-(4-苯甲酰基哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1h)
产率41.9％；白色固体；熔点：265～268℃；HPLC RT 8.67min purity 95.48％.1HNMR(600MHz,CDCl3)δ8.10(s,1H),7.45(t,J＝7.7Hz,2H),7.40(d,J＝7.3Hz,2H),7.36(t,J＝7.9Hz,1H),7.07(d,J＝7.3Hz,2H),6.92(t,J＝7.4Hz,1H),6.70(d,J＝7.7Hz,1H),4.16(d,J＝15.4Hz,1H),3.89～3.67(m,4H),3.57～3.40(m,2H),3.29(q,J＝14.7Hz,2H),2.78～2.59(m,4H),2.56(d,J＝15.5Hz,1H),1.99～1.89(m,4H).13C NMR(151MHz,CDCl3)δ171.00,170.35,167.66,136.36,135.78,129.71,128.48,128.46,127.54,127.06,122.94,122.42,114.83,66.26,61.24,53.10,48.48,35.40,35.36,29.68,23.43.HRMS(ESI):calcdfor C25H29N4O3[M+H]+,433.2234,found,433.2231.
1-(2-(4-(4-乙基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1i)
产率44.0％；黄色固体；熔点：269～272℃；HPLC RT 13.90min purity 96.11％.1H NMR(600MHz,CDCl3)δ8.52(s,1H),7.25(d,J＝7.9Hz,2H),7.14(d,J＝7.8Hz,2H),6.97(t,J＝8.1Hz,2H),6.82(t,J＝7.4Hz,1H),6.64(d,J＝7.7Hz,1H),4.09(d,J＝15.4Hz,1H),3.80～3.60(m,4H),3.53～3.47(m,2H),3.19(q,J＝14.6Hz,2H),2.68～2.48(m,6H),2.49(d,J＝15.5Hz,1H),1.95～1.88(m,4H),1.16(t,J＝7.6Hz,3H).13C NMR(151MHz,CDCl3)δ171.30,170.56,167.88,146.05,136.49,133.09,128.40,127.87,127.47,127.24,122.83,122.43,114.94,66.20,61.54,53.18,48.50,35.35,28.73,23.42,15.33.HRMS(ESI):calcdfor C27H33N4O3[M+H]+,461.2547,found,461.2544.
1-(2-(4-(2-氯苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1j)
产率42.6％；白色固体；熔点：270～272℃；HPLC RT 7.60min purity 99.16％.1HNMR(600MHz,CDCl3)δ7.79(s,1H),7.32(d,J＝7.2Hz,1H),7.28～7.20(m,3H),7.03(t,J＝7.6Hz,1H),7.00(d,J＝6.9Hz,1H),6.86(t,J＝7.3Hz,1H),6.61(d,J＝7.7Hz,1H),4.10(d,J＝15.3Hz,1H),3.79～3.65(m,4H),3.42(d,J＝16.1Hz,2H),3.33(q,J＝15.7Hz,2H),2.75(d,J＝14.7Hz,4H),2.52(d,J＝16.5Hz,1H),1.97～1.89(m,4H).13C NMR(151MHz,DMSO)δ170.59,167.61,165.95,137.86,130.92,129.87,129.61,128.77,128.38,128.05,127.67,127.55,122.62,122.33,114.99,65.65,61.33,52.80,52.36,48.58,46.73,35.65,34.89,23.34.HRMS(ESI):calcd for C25H28ClN4O3[M+H]+,467.1844,found,467.1838.
1-(2-(4-(2,6-二氟苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1k)产率36.8％；黄色固体；熔点：272～275℃；HPLC RT 10.69minpurity 97.80％.1H NMR(600MHz,CDCl3)δ8.28(s,1H),7.37～7.29(m,1H),7.07(d,J＝7.4Hz,2H),6.96～6.87(m,3H),6.69(d,J＝7.7Hz,1H),4.16(d,J＝15.4Hz,1H),3.94～3.80(m,3H),3.71～3.66(m,1H),3.37(t,J＝14.5Hz,2H),3.25(q,J＝14.6Hz,2H),2.73～2.58(m,4H),2.56(d,J＝15.5Hz,1H),2.03～1.94(m,4H).13CNMR(151MHz,CDCl3)δ169.12,165.76,158.03,157.76,156.10,134.44,128.99,126.46,125.49,120.88,120.47,112.86,111.83,109.84,109.68,64.23,59.48,50.95,46.50,44.76,39.85,33.38,21.44.HRMS(ESI):calcd for C25H27F2N4O3[M+H]+,469.2046,found,469.2041.
1-(2-(4-(2,5-二氯苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1l)产率45.7％；白色固体；熔点：276～278℃；HPLC RT 8.25minpurity 99.03％.1H NMR(600MHz,CDCl3)δ7.50(s,1H),7.33(d,J＝8.4Hz,1H),7.31～7.26(m,2H),7.14(t,J＝7.5Hz,1H),7.08(d,J＝7.2Hz,1H),6.95(t,J＝7.4Hz,1H),6.68(d,J＝7.7Hz,1H),4.18(d,J＝15.4Hz,1H),3.94～3.77(m,3H),3.74～3.67(m,1H),3.37～3.31(m,1H),3.31～3.21(m,3H),2.75～2.61(m,3H),2.57(d,J＝15.4Hz,2H),2.06～1.94(m,4H).13C NMR(151MHz,CDCl3)δ168.72,165.79,163.35,135.23,131.30,128.84,128.83,128.21,126.73,126.55,125.86,125.58,120.98,120.48,112.67,64.25,59.38,50.83,46.46,39.69,33.47,33.37,21.45.HRMS(ESI):calcd for C25H27Cl2N4O3[M+H]+,501.1455,found,501.1448.
1-(2-(4-(2-碘苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1m)
产率39.5％；白色固体；熔点：277～279℃；HPLC RT 10.70min purity 97.42％.1H NMR(600MHz,CDCl3)δ8.22(s,1H),7.82(d,J＝8.0Hz,1H),7.37(t,J＝7.5Hz,1H),7.19(d,J＝7.5,1H),7.20～7.01(m,3H),6.91(t,J＝7.3Hz,1H),6.69(d,J＝7.7Hz,1H),4.16(d,J＝15.5Hz,1H),3.90～3.65(m,4H),3.45(d,J＝15.1Hz,2H),3.36(q,J＝15.3Hz,2H),2.80(d,J＝15.7Hz,4H)2.53(d,J＝15.5Hz,1H),2.02～1.97(m,4H).13C NMR(151MHz,CDCl3)δ171.11,169.24,167.78,142.24,139.23,136.38,130.17,128.46,128.35,127.51,127.09,122.90,122.44,114.85,92.47,66.21,61.52,52.93,52.79,48.49,46.79,41.53,35.38,35.36,23.44.HRMS(ESI):calcd for C25H28IN4O3[M+H]+,559.1201,found,559.1188.
1-(2-(4-(2-氯-5-硝基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1n)产率52.6％；黄色固体；熔点：282～284℃；HPLC RT 9.024minpurity 96.98％.1H NMR(600MHz,CDCl3)δ8.26(d,J＝1.3Hz,1H),7.99(s,1H),7.73(d,J＝7.6Hz,1H),7.63～7.57(m,1H),7.09(d,J＝7.7Hz,2H),6.92(t,J＝7.1Hz,1H),6.70(d,J＝7.7Hz,1H),4.16(d,J＝15.5Hz,1H),3.97～3.65(m,4H),3.46(d,J＝14.2Hz,2H),3.30(d,J＝14.8Hz,2H),2.78～2.59(m,3H),2.57(d,J＝15.5Hz,2H),2.05～1.95(m,4H).13C NMR(151MHz,CDCl3)δ168.72,165.79,163.35,135.23,131.30,128.84,128.83,128.21,126.73,126.55,125.86,125.58,120.98,120.48,112.67,64.25,59.38,50.83,46.46,39.69,33.47,33.37,21.45.HRMS(ESI):calcd for C25H27ClN5O5[M+H]+,512.1695,found,512.1695.1-(2-(4-(3-硝基苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮(1o)产率42.8％；黄色固体；熔点：273～274℃；HPLC RT 8.60minpurity 97.24％.1H NMR(600MHz,CDCl3)δ8.19(t,J＝7.0,2H),7.73(s,1H),7.62～7.56(m,1H),7.16～7.04(m,2H),6.94(t,J＝7.7Hz,1H),6.69(d,J＝7.8Hz,1H),4.16(d,J＝15.4Hz,1H),3.94～3.77(m,3H),3.07～3.62(m,1H),3.35～3.21(m,4H),2.81～2.60(m,4H),2.57(d,J＝15.5Hz,1H),2.05～1.95(m,4H).13C NMR(151MHz,CDCl3)δ169.81,166.68,163.37,145.71,136.37,136.19,135.27,129.82,127.54,126.57,123.85,122.27,121.99,121.42,113.75,65.28,60.19,51.93,51.75,47.46,45.71,40.84,34.41,34.34,22.44.HRMS(ESI):calcd for C25H28N5O5[M+H]+,478.2085,found,478.2078.
实施例3：本发明1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物抗微生物活性实验。
本发明的目标化合物的抗真菌活性都在96孔板中使用两倍肉汤稀释法进行评估，所有合成的化合物用DMSO溶解后，用无菌水稀释成所需药液浓度，将96孔板，移液枪头、棉花和玻璃仪器等物品高压灭菌，用移液枪移取配置好的菌液溶液100uL到96孔板中，通过获取最小抑菌浓度(MIC)值来评估抗菌效果。抗真菌实验用氟康唑，多氧霉素B作阳性药物；抗细菌实验用诺氟沙星，氯霉素作为参比对照。放有细菌、真菌的96孔板在37℃下培养24小时,观察现象。结果见附表1，2
附表1、本发明1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1’,4’-二氢-2’H-螺[吡咯烷-2,3’-喹啉]-2’-酮类化合物抗细菌微生物活性数据(MIC ug/mL)
附表2、本发明1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1’,4’-二氢-2’H-螺[吡咯烷-2,3’-喹啉]-2’-酮类化合物抗真菌微生物活性数据(MIC ug/mL)
上述活性数据结果表明，本发明新化合物对选定的真菌(除了部分化合物对抗新型隐球菌)具有较明显的抑菌作用。化合物1d、1f、1k和1n对白色念珠菌(ATCC 76615)表现出优异的抗真菌活性，MIC值为2μg/mL，是氟康唑的一半，它们的抗真菌能力优于多氧霉素B。MIC值为4μg/mL的化合物1f、1n和1o对黄曲霉(ATCC 16870)的抑制效果最强，其MIC值优于氟康唑和多氧霉素B。化合物1f、1g、1l和1o的MIC值为8μg/mL，与多氧霉素B对抗烟曲霉(GIMCC 3.19)相比，具有同样优异的抗菌效力。MIC值为8μg/mL的化合物1d、1f和1l对新型隐球菌(ATCC 32719)显示出与氟康唑相同的抗真菌活性，且优于多氧霉素B。
实施例4：本发明1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物几丁质酶抑制活性实验
在低速和高速离心下从热带酵母中提取几丁质合成酶，这种酶可以与几丁质素合成所必需的底物UDP-GlcNAC特异性结合，以产生几丁质，然后所得几丁质可以与预先负载到96孔板的WGA结合，其他物质被50mM pH 7.5TriS-HCl缓冲液洗掉；其次，加入WGA与HRP缀合的WGA-HRP与固定的几丁质结合，此时可通过相应的检测剂3,3’,5,5’-四甲基联苯胺(TMB)检测HRP活性，每孔加入50mL 2M H2SO4溶液终止反应，并在ELISA检测仪检测器下记录OD450值,每组平行测试两组,抑菌率计算公式：抑菌率＝(B0-Bn)/(B0-OD0)。结果见附图1和附表3。
附表3测试化合物的IC50值
所有化合物均显示出对CHS的抑制作用，抑制率范围为46％～84％。化合物1d、1k、1n和1o在15种化合物中表现出最高的抑制效果，其抑制率分别为80.2％、83.4、82.9％和81.1％，与多氧霉素B大致相当(IP值为86.1％)。此外，化合物1f、1g对CHS表现出良好的抑制作用，IP超过70％。化合物1b、1c、1e、1i、1j、1l和1m都显示出中等效力，IP范围为50％至70％之间。化合物的IC50值分布在0.10和0.88之间。化合物1d、1k、1n和1o在300μg/mL浓度下表现出优异的抑制活性，IC50值分别为0.11、0.11、0.10和0.12mM，抑制效果与其IP值一致，表现出良好的抑制作用。化合物1f、1g和1l的IC50值分别为0.14mM、0.13mM和0.18mM，也与其IP值一致，显示出中等效力。
实施例5：本发明1-(2-(4-苯甲酰基)哌嗪-1-基)乙酰基)-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物抗真菌药性评估实验
附表4化合物的MIC值(μg/mL)和体外对耐药真菌的控制。
从表4所示的结果来看，所选化合物对耐米卡芬净的白色念珠菌表现出中等至良好的抗真菌活性，它们的MIC值范围为32-128μg/mL，而米卡芬净的MIC值超过256μg/mL。表明这些化合物与米卡芬净有着不同的抗真菌靶点。使用耐氟康唑真菌评价这些化合物的抗真菌活性，结果表明，这些化合物对耐药真菌具有中等至优异的抗真菌活性，MIC值远低于其对照药物的值，说明靶点在于几丁质合成酶的药物可用于目前临床上出现的耐药性问题。

Claims (3)

1.一种通式1所示的化合物：
通式1所示的化合物为下述化合物的任意一种：
2.如权利要求1所述化合物在制备抗病原微生物药物中的应用，所述微生物为大肠杆菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌、枯草杆菌、变形杆菌、铜绿色假单胞菌；白色念珠菌、新型隐球菌、黄曲霉菌、烟曲霉菌中的一种。
3.如权利要求1所述化合物在制备几丁质合成酶抑制剂药物中的应用。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824669A (zh) * 2018-12-21 2019-05-31 西南大学 哌啶螺环酒石酸类化合物制备及应用
CN110713459A (zh) * 2019-12-04 2020-01-21 西南大学 一类喹啉酮富马来酰胺衍生物的设计合成与应用
JP2020147544A (ja) * 2019-03-15 2020-09-17 日本曹達株式会社 キノリン化合物および農園芸用殺菌剤
CN113264949A (zh) * 2021-05-31 2021-08-17 西南大学 一类螺苯并噁嗪哌啶α,β-不饱和酮类衍生物的设计合成与应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174267B2 (en) * 2015-06-12 2021-11-16 The Regents Of The University Of California Spiroindolinones and therapeutic uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109824669A (zh) * 2018-12-21 2019-05-31 西南大学 哌啶螺环酒石酸类化合物制备及应用
JP2020147544A (ja) * 2019-03-15 2020-09-17 日本曹達株式会社 キノリン化合物および農園芸用殺菌剤
CN110713459A (zh) * 2019-12-04 2020-01-21 西南大学 一类喹啉酮富马来酰胺衍生物的设计合成与应用
CN113264949A (zh) * 2021-05-31 2021-08-17 西南大学 一类螺苯并噁嗪哌啶α,β-不饱和酮类衍生物的设计合成与应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Hu Wu等.Design, synthesis, and biological evaluation of novel spiro[pyrrolidine- 2,30-quinolin]-20-one derivatives as potential chitin synthase inhibitors and antifungal agents.《European Journal of Medicinal Chemistry》.2022,第233卷114208（1-11）. *

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