CN116143782B - 一类螺[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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CN116143782B
CN116143782B CN202111388256.0A CN202111388256A CN116143782B CN 116143782 B CN116143782 B CN 116143782B CN 202111388256 A CN202111388256 A CN 202111388256A CN 116143782 B CN116143782 B CN 116143782B
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Abstract

本文公开了N‑4‑氧代‑4‑(2'‑氧代‑1',4'‑二氢‑2'H‑螺[吡咯烷‑2,3'‑喹啉]‑1‑基)丁‑2‑烯酰胺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：

Description

一类螺[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
本发明属化学领域，涉及新型螺[吡咯烷-2,3'-喹啉]-2'-酮类化合物及其应用，具体涉及一种N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物的设计合成及在抗微生物上的应用。
背景技术
真菌感染在人类健康领域中是一种比较常见的现象，具有高发病率和至死率的侵袭性真菌感染每年影响着全球数百万人的生命。在过去几十年里，伴随着免疫缺陷患者人数的增加，抗生素，抗肿瘤等药物的大量使用，使得侵袭性真菌感染的发病率和死亡率的明显增加。现有抗真菌药物具有毒副作用大，易产生耐药性等问题。因此临床上迫切需要新的抗真菌药物，以应对日益严重的真菌感染问题。
几丁质是一种β-(1,4)-N-乙酰-D-氨基葡萄糖胺的聚合物(GlcNAc),是真菌细胞壁独具必要成分，并在维持细胞形态和功能方面起重要作用。几丁质合酶抑制剂可阻断几丁质合成过程，导致细胞壁通透性发生变化和细胞形态异常，最终导致真菌死亡。在哺乳动物细胞中不存在几丁质合成酶以及几丁质生物合成途径，所以几丁质合成酶及该酶活性的调节机制被认为是理想抗真菌药物的理想靶标。
螺环化合物是一类具有刚性结构的多环化合物，因其独特的结构特征及显著的生物活性备受研究者的广泛关注。一方面它具有构想更灵活的线性支架所特有的吸收和渗透性；另一方面相比平面芳香环螺环结构更加灵活，能适应多种蛋白质为靶标。目前螺环化合物具有抗菌、抗肿瘤、抗抑郁、抗糖尿病以及抗癌等生物活性。据报道，在某些药物设计案例中，含有螺环的分子比含有扁平芳环的分子具有更多的益处。这类化合物的研究文章可见：Bioorg. Med. Chem .Lett.2014,24(16):3673-3682；PNAS,1992, 89(2): 519-523；Mol.Microbiol.1996, 20(3):667-679；Bioorg. Med. Chem.2012, 20(19): 5678-5698；Bioorg. Med. Chem. Lett. 2009, 19(2): 332-335；Eur. J.Med. Chem.2019,182:111669。
3,4-二氢喹啉-2(1H)-酮衍生物代表了一类重要的含氮杂环化合物，其骨架广泛存在于天然产物、药物分子和功能材料中。其独特的内酰胺结构可与多种酶产生氢键相互作用，使其表现出广谱的生物活性。许多具有这种核心骨架的化合物用于抗肿瘤、抗病毒、抗菌、镇痛和抗炎。这类化合物的研究文章可见：Chem. Eur. J. 2009, 15(29): 7238-7245；J. Med. Chem.2002, 45(23): 4954-4957；J. Med. Chem.1985, 28(10): 1511-1516。
为了寻找新型的几丁质合成酶抑制剂，本发明设计合成了N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物，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以及优良的抗微生物等方面还未见报道，可以将其作为几丁质合成酶的抑制剂，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N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物；本发明的目的之二在于提供一类N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺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N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物在制备抗细菌/抗真菌药物中的应用。
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N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物结构如通式1所示：
其中R为苯基、取代苯基、萘基。具体地说，通式1所示的N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物为下述化合物的任意一种：
上述N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物的合成方法，如Scheme1所示：
反应条件如下：
(a) 各种取代芳胺2a-2q和马来酸酐摩尔比为1:1.2，在二氯甲烷中室温反应2小时；
(b) 化合物3a-3q与螺[吡咯烷-2,3'-喹啉]-2'-酮的摩尔比为1：1.2， 以1-丙基膦酸酐为缩合剂，三乙胺为催化剂在二氯甲烷中45℃反应48小时即可得到。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N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物在制备抗细菌或真菌制剂中，所述的细菌是大肠杆菌(JM 109)、金黄色葡萄球菌(ATCC 25923)、耐甲氧西林金黄色葡萄球菌(N 3.15）、枯草杆菌(ATCC 6633)、变形杆菌(ATCC 6633)、铜绿色假单胞菌(ATCC 9027)；真菌为：白色念珠菌(ATCC 76615)、新型隐球菌(ATCC 32719)、黄曲霉菌(ATCC 16870)、烟曲霉菌(GIMCC 3.19)等。
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，部分使用碘和浓硫酸显色。1 HNMR 和13C NMR光谱在Bruker AV 600 MHz 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BrukerimpactⅡ所获得。熔点在显微熔点仪（X-4型）上测量。
实施例1:化合物3a-3q的制备：
在50ml圆底烧瓶中加入马来酸酐1.36g（1.39mmol）和2-氯苯胺（1.39mmol），向瓶中再加入30ml二氯甲烷作溶剂，室温反应2-3小时,有沉淀生成，过滤，用甲醇/乙酸乙酯重结晶。按相似合成方法，可得化合物3b-3q。
实施例2:目标产物的制备
3a（1.2mmol）溶于无水DCM（6mL）溶剂中，加入三乙胺（4mmol）和1-丙基膦酸酐（2.15mmol），搅拌30分钟后。加入螺[吡咯烷-2,3'-喹啉]-2'-酮（0.24g，1.2mmol）至上述反应溶液中，然后将混合物加热回流48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：N-（2-氯苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1a），产率50.3%；物理常数及光谱数据如下所示：白色粉末；熔点：233-235℃；1HNMR (600 MHz, CDCl3) δ 10.40 (s,1H), 8.34 (s,1H), 8.14 (d, J=7.9 Hz,1H), 7.23(d, J=7.9 Hz,1H), 7.13 (t, J=7.7 Hz,1H),7.05 (t, J=7.6Hz,1H), 6.99 (d,J=7.4Hz,1H), 6.94(t, J=7.5Hz,1H), 6.86 (t,J=7.4 Hz,1H),6.67(d, J=7.8 Hz,1H),6.47(d, J=13.0 Hz,1H), 6.21 (d, J=13.0 Hz,1H), 4.18 (d, J=15.4 Hz, 1H), 3.76–3.63 (m, 2H), 2.56 (d, J=15.5 Hz, 1H), 1.98-1.93 (m, 4H). 13C NMR(151 MHz,CDCl3) δ 169.55, 163.71,161.92, 135.29, 133.92, 132.16, 129.16, 128.31,127.46, 126.66,126.17, 124.27,123.98, 122.57, 122.00, 121.19, 114.10,65.40,48.60, 34.75, 33.95,22.22. HRMS (ESI): calcd for C22H21ClN3O3 [M+H]+, 410.1266,found, 410.1266.
化合物1b-1q的合成方法同上，其结构数据如下：
N-（邻甲苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1b）
产率48.7%；白色粉末；熔点：232-233℃；1HNMR (600 MHz, DMSO-d6) δ 10.12 (s,1H), 9.93 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 7.1 Hz, 1H), 7.18(t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.9 Hz, 2H), 7.08 (t, J = 6.8 Hz, 1H), 6.89(t, J = 7.3 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 12.2 Hz, 1H),6.33 (d, J = 12.2 Hz, 1H), 3.99 (d, J = 15.7 Hz, 1H), 3.65 – 3.54 (m, 2H),2.69 (d, J = 15.7 Hz, 1H), 2.22 (s, 3H), 1.85 (m, 4H). 13CNMR (151 MHz, DMSO-d6) δ 170.33, 165.20, 163.05, 137.75, 136.56, 133.74, 131.74, 130.81, 129.06,128.83, 127.69, 126.45, 125.63, 124.85, 122.60, 122.40, 115.05, 65.43, 49.23,36.31, 34.58, 23.18, 18.37.HRMS (ESI): calcd for C23H24N3O3 [M+H]+, 390.1812,found, 390.1811.
N-（2-硝基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1c）
产率40.6%；白色粉末；熔点：235-237℃；1HNMR (600 MHz, DMSO-d6) δ 10.65 (s,1H), 10.08 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.78 – 7.67 (m, 2H), 7.40 (t, J= 6.1 Hz, 1H), 7.12 (t, J = 7.1 Hz, 2H), 6.90 (t, J = 7.3 Hz, 1H), 6.85 (d, J= 7.7 Hz, 1H), 6.66 (d, J = 12.0 Hz, 1H), 6.31 (d, J = 12.0 Hz, 1H), 3.96 (d,J = 15.7 Hz, 1H), 3.60 – 3.48 (m, 2H), 2.66 (d, J = 15.8 Hz, 1H), 1.95 – 1.79(m, 4H). 13CNMR (151 MHz, DMSO-d6) δ 170.32, 164.75, 163.30, 142.93, 137.74,135.97, 134.50, 131.37, 128.75, 127.67, 126.91, 125.97, 125.92, 125.40,122.67, 122.47, 115.05, 65.28, 49.16, 36.36, 34.42, 23.16.HRMS (ESI): calcdfor C22H21N4O5 [M+H]+, 421.1506, found, 421.1506.
N-（4-甲氧基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1d）
产率42.0%；白色粉末；熔点：234-236℃；1H NMR (600 MHz, DMSO-d6) δ 10.21(s, 1H), 10.09 (s, 1H), 7.53 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 7.3 Hz, 1H),7.13 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.2 Hz, 3H), 6.85 (d, J = 7.8 Hz, 1H),6.53 (d, J = 12.0 Hz, 1H), 6.21 (d, J = 12.1 Hz, 1H), 4.03 (d, J = 15.7 Hz,1H), 3.73 (s, 3H), 3.59 – 3.52 (m, 2H), 2.73 (d, J = 15.7 Hz, 1H), 1.91 –1.81 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ 170.37, 165.30, 162.55, 155.99,137.79, 134.37, 132.40, 128.84, 128.12, 127.67, 122.69, 122.44, 121.44,115.02, 114.44, 65.25, 55.69, 49.09, 36.44, 34.63, 23.18.HRMS (ESI): calcdfor C23H24N3O4 [M+H]+, 406.1761, found, 406.1760.
N-（4-氟苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1e）
产率49.4%；白色粉末；熔点：231-233℃；1H NMR (600 MHz, DMSO-d6) δ 10.40(s, 1H), 10.10 (s, 1H), 7.65 (dd, J = 8.6, 5.0 Hz, 2H), 7.16 (t, J = 8.7 Hz,3H), 7.12 (d, J = 7.7 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 7.8 Hz,1H), 6.57 (d, J = 12.0 Hz, 1H), 6.23 (t, J = 11.2 Hz, 1H), 4.03 (d, J = 15.7Hz, 1H), 3.61 – 3.50 (m, 2H), 2.73 (d, J = 15.7 Hz, 1H), 1.93 – 1.80 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ 170.34, 165.11, 163.16, 138.21, 137.76, 134.90,129.13, 128.83, 127.97, 127.67, 122.63, 122.45, 121.42, 121.25, 115.06,65.33, 49.09, 36.40, 34.64, 23.19.HRMS (ESI): calcd for C22H21FN3O3 [M+H]+,394.1561, found, 394.1561
N-（3-甲氧基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1f）
产率53.6%；白色粉末；熔点：234-236℃；1HNMR (600 MHz, DMSO-d6) δ 10.33 (s,1H), 10.10 (s, 1H), 7.29 (s, 1H), 7.23 (t, J = 8.1 Hz, 1H), 7.18 (t,J = 8.1Hz, 2H), 7.14 (t, J = 7.7 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 7.8Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.57 (d, J = 12.0 Hz, 1H), 6.25 (d, J =12.1 Hz, 1H), 4.04 (d, J = 15.7 Hz, 1H), 3.74 (s, 3H), 3.60 – 3.51 (m, 2H),2.74 (d, J = 15.8 Hz, 1H), 1.93 – 1.81 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ170.35, 165.16, 163.09, 160.02, 140.39, 137.78, 134.72, 130.05, 128.84,128.13, 127.68, 122.99, 122.66, 122.44, 115.03, 112.31, 109.33, 105.96,65.28, 55.51, 49.08, 36.44, 34.64, 23.19.HRMS (ESI): calcd for C23H24N3O4 [M+H]+, 406.1761, found, 406.1761.
N-（4-氯-3-氟苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1g）
产率46.7%；白色粉末；熔点：234-235℃；1H NMR (600 MHz, DMSO-d6) δ 10.51(s, 1H), 10.10 (s, 1H), 7.94 (dd, J = 6.6, 2.2 Hz, 1H), 7.50 (dd, J = 8.2,3.3 Hz, 1H), 7.38 (t, J = 9.0 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 7.13 (t, J =7.6 Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.61 (d, J =12.0 Hz, 1H), 6.24 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 15.6 Hz, 1H), 3.62 –3.47 (m, 2H), 2.73 (d, J = 15.7 Hz, 1H), 1.94 – 1.80 (m, 4H).13CNMR (151 MHz,DMSO-d6) δ 170.32, 164.90, 163.37, 137.76, 136.53, 135.01, 128.86, 127.86,127.70, 122.61, 122.46, 121.23, 120.24, 119.69, 119.60, 117.54, 115.03,65.32, 49.07, 36.39, 34.65, 23.19.HRMS (ESI): calcd for C22H20ClFN3O3 [M+H]+,428.1172, found, 428.1167.
N-（4-溴苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1h）
产率44.2%；白色粉末；熔点：233-235℃；1HNMR (600 MHz, DMSO-d6) δ 10.47 (s,1H), 10.10 (s, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.17(d, J = 7.3 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.85(d, J = 7.8 Hz, 1H), 6.59 (d, J = 12.0 Hz, 1H), 6.24 (d, J = 12.0 Hz, 1H),4.02 (d, J = 15.6 Hz, 1H), 3.59 – 3.51 (m, 2H), 2.73 (d, J = 15.7 Hz, 1H),1.92 – 1.81 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ 170.33, 165.06, 163.20,138.63, 137.77, 134.98, 132.07, 128.85, 127.91, 127.69, 122.63, 122.46,121.79, 115.71, 115.04, 65.30, 49.08, 36.41, 34.62, 23.19. HRMS (ESI): calcdfor C22H21BrN3O3 [M+H]+, 454.0761, found, 454.0760.
N-（1-萘基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1i）
产率46.9%；白色粉末；熔点：233-235℃；1HNMR (600 MHz, DMSO-d6) δ 10.59 (s,1H), 10.11 (s, 1H), 8.12 (dd, J = 5.4, 3.0 Hz, 1H), 7.94 (dd, J = 5.9, 3.1Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.53 (t,J = 7.6Hz, 2H), 7.51 (d, J = 7.9 Hz, 1H), 7.12 (t, J = 6.2 Hz, 2H), 6.88 (t, J = 7.5Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 12.2 Hz, 1H), 6.48 (d, J =12.2 Hz, 1H), 4.01 (d, J = 15.6 Hz, 1H), 3.68 – 3.60 (m, 2H), 2.70 (d, J =15.7 Hz, 1H), 1.92 – 1.78 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ 170.33, 165.21,163.75, 137.74, 134.18, 133.97, 133.65, 129.13, 128.82, 128.63, 127.91,127.70, 126.53, 126.42, 126.06, 125.81, 123.08, 122.58, 122.46, 121.66,115.03, 65.45, 49.23, 36.34, 34.59, 23.20.HRMS (ESI): calcd for C26H24N3O3 [M+H]+, 426.1812, found, 426.1812.
N-（3,5-二甲基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1j）
产率59.1%；白色粉末；熔点：235-236℃；1HNMR ( 600 MHz, DMSO-d6) δ 10.19 (s, 1H), 10.10 (s, 1H), 7.24 (s, 2H), 7.18 (d, J = 7.3 Hz, 1H), 7.13 (t, J =7.7 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H) , 6.85 (d, J = 7.8 Hz, 1H), 6.71 (s,1H), 6.54 (d, J = 12.0 Hz, 1H), 6.23 (d, J = 12.1 Hz, 1H), 4.03 (d, J = 15.7Hz, 1H), 3.59 – 3.51 (m, 2H), 2.74 (d, J = 15.7 Hz, 1H), 2.24 (s, 6H), 1.92 –1.81 (m, 4H). 13CNMR (151 MHz, DMSO-d6) δ 170.35, 165.23, 162.89, 139.12,138.20, 137.78, 134.51, 128.85, 128.26, 127.69, 125.64, 122.66, 122.44,117.64, 115.02, 65.27, 49.09, 36.43, 34.71, 23.17, 21.57.HRMS (ESI): calcdfor C24H26N3O3 [M+H]+, 404.1969, found, 404.1968.
N-（间甲苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1k）
产率50.3%；白色粉末；熔点：232-233℃；1HNMR (600 MHz, DMSO-d6) δ 10.27 (s,1H), 10.10 (s, 1H), 7.43 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.8Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 6.89 (d, J = 6.6Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 12.0 Hz, 1H), 6.24 (d, J =12.0 Hz, 1H), 4.03 (d, J = 15.6 Hz, 1H), 3.59 – 3.52 (m, 2H), 2.73 (d, J =15.7 Hz, 1H), 2.28 (s, 3H), 1.91 – 1.81 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ170.35, 165.22, 162.95, 139.19, 138.42, 137.78, 134.62, 129.08, 128.85,128.16, 127.69, 124.78, 122.66, 122.44, 120.35, 117.13, 115.02, 65.27, 49.08,36.43, 34.66, 23.18, 21.66.HRMS (ESI): calcd for C23H24N3O3 [M+H]+, 390.1812,found, 390.1812.
N-（对甲苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1l）
产率47.5%；白色粉末；熔点：232-233℃；1HNMR (600 MHz, DMSO-d6) δ 10.27 (s,1H), 10.10 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.2 Hz, 1H), 7.13(t, J = 7.9 Hz, 3H), 6.90 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.54(d, J = 12.0 Hz, 1H), 6.23 (d, J = 12.1 Hz, 1H), 4.03 (d, J = 15.6 Hz, 1H),3.59 – 3.52 (m, 2H), 2.73 (d, J = 15.7 Hz, 1H), 2.25 (s, 3H), 1.91 – 1.81 (m,4H).13CNMR (151 MHz, DMSO-d6) δ 170.37, 165.28, 162.77, 137.78, 136.75,134.59, 133.02, 129.62, 128.86, 128.08, 127.68, 122.67, 122.45, 119.88,115.02, 65.25, 49.08, 36.43, 34.62, 23.18, 20.95.HRMS (ESI): calcd forC23H24N3O3 [M+H]+, 390.1812, found, 390.1810.
N-（2,4-二氯苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1m）
产率44.3%；白色粉末；熔点：232-234℃；1HNMR (600 MHz, DMSO-d6) δ 10.27 (s,1H), 10.11 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.44 (dd, J =8.7, 2.3 Hz, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.89(t, J = 7.3 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.66 (d, J = 12.2 Hz, 1H),6.38 (d, J = 12.2 Hz, 1H), 3.98 (d, J = 15.6 Hz, 1H), 3.61 – 3.54 (m, 2H),2.69 (d, J = 15.7 Hz, 1H), 1.92 – 1.80 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ170.23, 164.95, 163.37, 137.74, 134.36, 129.90, 129.42, 128.83, 128.15,128.06, 127.71, 127.45, 127.17, 122.55, 122.46, 115.04, 99.99, 65.42, 49.17,36.31, 34.54, 23.18.HRMS (ESI): calcd for C22H20Cl2N3O3 [M+H]+, 444.0876, found,444.0876.
N-（3-硝基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1n）
产率56.8%；白色粉末；熔点：235-237℃；1HNMR (600 MHz, DMSO-d6) δ 10.79 (s,1H), 10.10 (s, 1H), 8.63 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.1Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.5Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.66 (d, J =12.0 Hz, 1H), 6.30 (d, J = 12.0 Hz, 1H), 4.02 (d, J = 15.4 Hz, 1H), 3.62 –3.54 (m, 2H), 2.74 (d, J = 15.7 Hz, 1H), 1.94 – 1.81 (m, 4H).13CNMR (151 MHz,DMSO-d6) δ 170.30, 164.80, 163.89, 148.48, 140.42, 137.75, 135.23, 130.71,128.84, 127.91, 127.71, 125.82, 122.58, 122.47, 118.52, 115.04, 113.91,65.34, 49.08, 36.38, 34.68, 23.21.HRMS (ESI): calcd for C22H21N4O5 [M+H]+,421.1506, found, 421.1505.
N-（4-氯苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1o）
产率47.8%；白色粉末；熔点：233-235℃；1HNMR (600 MHz, DMSO-d6) δ 10.49 (s,1H), 10.11 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.16(d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.86(d, J = 7.8 Hz, 1H), 6.59 (d, J = 12.0 Hz, 1H), 6.25 (d, J = 12.0 Hz, 1H),4.04 (d, J = 15.9 Hz, 1H), 3.60 – 3.52 (m, 2H), 2.73 (d, J = 15.8 Hz, 1H),1.92 – 1.80 (m, 4H).13CNMR (151 MHz, DMSO-d6) δ 170.34, 165.11, 163.16,138.21, 137.76, 134.90, 129.13, 128.83, 127.97, 127.67, 122.63, 122.45,121.42, 121.25, 115.06, 65.33, 49.09, 36.40, 34.64, 23.19.HRMS (ESI): calcdfor C22H21ClN3O3 [M+H]+, 421.1506, found, 421.1505.
N-（2-甲氧基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1p）
产率48.6%；白色粉末；熔点：234-236℃；1HNMR (600 MHz, CDCl3) δ 10.03 (s,1H), 8.97 (s, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.01(t, J = 5.8 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.88(d, J = 7.9 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.49(d, J = 12.8 Hz, 1H), 6.24 (d, J = 12.8 Hz, 1H), 4.26 (d, J = 15.5 Hz, 1H),3.80 – 3.74 (m, 1H), 3.70 (d, J = 7.1 Hz, 3H), 3.69 – 3.66 (m, 1H), 2.60 (d,J = 15.6 Hz, 1H), 2.06 – 1.94 (m, 4H).13CNMR (151 MHz, CDCl3) δ 171.08,165.04, 162.70, 149.04, 136.38, 132.18, 130.53, 128.35, 127.73, 127.61,124.30, 122.92, 122.24, 120.81, 120.78, 115.26, 110.38, 66.11, 55.72, 49.45,35.88, 34.83, 23.25. HRMS (ESI): calcd for C23H24N3O4 [M+H]+, 406.1761, found,406.1760.
N-（4-氯-2,5-二甲氧基苯基）-4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺（1q）
产率54.3%；白色粉末；熔点：235-236℃；1H NMR (600 MHz, CDCl3) δ 10.60 (s,1H), 8.88 (s, 1H), 8.23 (s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.3Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.81 (s, 1H), 6.72 (d, J = 7.7 Hz, 1H),6.51 (d, J = 13.1 Hz, 1H), 6.25 (d, J = 13.1 Hz, 1H), 4.25 (d, J = 15.6 Hz,1H), 3.83 (s, 3H), 3.79 – 3.71 (m, 2H), 3.65 (s, 3H), 2.62 (d, J = 15.7 Hz,1H), 2.05 – 2.00 (m, 4H).13CNMR (151 MHz, CDCl3) δ 170.91, 164.84, 162.76,148.84, 143.33, 136.19, 133.47, 129.67, 128.39, 127.68, 127.33, 123.05,122.02, 116.26, 115.08, 112.83, 106.01, 66.33, 56.69, 56.60, 49.51, 35.82,35.00, 23.28.HRMS (ESI): calcd for C24H25ClN3O5 [M+H]+, 470.1477, found,470.1477。
实施例3：本发明N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物抗微生物活性实验
本发明的化合物用二甲基亚砜溶解后，用无菌水稀释成所需药液液浓度，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，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。结果见附表1、附表2：
附表1、化合物1a-1q抗细菌微生物活性数据（MIC µg/mL）
附表2、化合物1a-1q抗真菌活性数据（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（除了部分化合物抵抗新型隐球菌）具有较明显的抑菌作用。化合物1a, 1c, 1e, 1g, 1m, 1n, 1o, 对白色念珠菌(ATCC 76615)显示出优异的效力，它们的MIC值与氟康唑相当且低于多氧霉素 B。化合物1c、1g、1n 是针对黄曲霉 (ATCC 16870) 的高强度药剂，抑制效力优于氟康唑（MIC= 8μg/mL）。对于烟曲霉（GIMCC 3.19），与氟康唑相比，MIC值为4μg/mL的化合物1a、1c、1g、1n、1o显示出同等的效力。对于新型隐球菌 (ATCC 32719)，MIC值为8μg/mL 的化合物1a、1e、1g和1n显示出和氟康唑相同的抑制效力。
实施例4：本发明N- 4-氧代-4-(2'-氧代-1',4'-二氢-2'H-螺[吡咯烷-2,3'-喹啉]-1-基)丁-2-烯酰胺类化合物几丁质酶抑制活性实验
通过低速和高速离心从热带酵母中提取几丁质合酶，这酶可以与几丁质合成必需底物UDP-GlNAc特异性结合孵化产生几丁质，生成的几丁质再与预先附在96孔板上的WGA结合，然后用50 mM pH 7.5 Tris-HCl 缓冲液洗掉其他物质，加入WGA与HRP缀合的WGA-HRP以与固定的几丁质，此时HRP活性可用相应性检测剂TMB检测，通过向每个孔中加入50 mL2MH2SO4 终止反应。所有测试化合物均溶解在DMSO中制备为储备溶液，然后用50 mM pH 7.5Tris-HCl 缓冲液将化合物和酶配置至 600、300、150、75、37.5、18.75mg/mL，选择PolyoxinB作为阳性对照，使用Biotek ELx808 酶标仪检测96孔板上的OD 值，计算抑制率。每组平行测试两组。抑菌率计算公式：抑菌率= (B0 - Bn)/(B0 - OD0)，计算出化合物的IC50值，如附表3所示：
附表3化合物1a-1q抑制几丁质合成酶的IC50值
化合物1g和1n在所有化合物中表现出最高的抑制效力，抑制率分别为82.6%和83.4%，与多氧霉素B（P.B的值为86.1%）大致相当，此外，化合物1a、1c、1e、1m 和1o 都显示出对 CHS 有显著抑制，IP 超过 70%。化合物1d、1h、1i、1p、和1q 表现出中等效力，其 IP范围为 50% 至 70%。其他化合物的IP都在40%以上。这些测试化合物的IC50值分布在0.10和1.21之间。其中，化合物1n的 IC50值为 0.10 mM，表现出最好的抑制效力。化合物1a、1c、1e、1g、1m、1o的IC50值分别为0.12 mM、0.11mM、0.13mM、0.11mM、0.17mM、0.17mM，对CHS表现出较好的抑制效果。

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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