CN114907288B - 硝基苯类化合物在制备铜绿假单胞菌群体感应抑制剂中的应用 - Google Patents
硝基苯类化合物在制备铜绿假单胞菌群体感应抑制剂中的应用 Download PDFInfo
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- CN114907288B CN114907288B CN202210517348.2A CN202210517348A CN114907288B CN 114907288 B CN114907288 B CN 114907288B CN 202210517348 A CN202210517348 A CN 202210517348A CN 114907288 B CN114907288 B CN 114907288B
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明涉及式(I)所示硝基苯类化合物,其制备方法和在抑制革兰阴性病原菌铜绿假单胞菌群体感应系统的应用。本发明所述的小分子化合物通过抑制铜绿假单胞菌群体感应上游调控系统las系统中的LasR蛋白,可显著抑制铜绿假单胞菌群体感应系统,抑制细菌毒力因子的释放和生物膜的形成,从而减轻感染症状。
Description
技术领域
本发明属于医药化学领域,更具体地讲,本发明涉及硝基苯类化合物,其制备方法和在抑制革兰阴性病原菌铜绿假单胞菌群体感应系统的应用。
背景技术
铜绿假单胞菌(PA,Pseudomonas aeruginosa)是一种常见的引起严重院内获得性感染的条件致病菌,其感染率高居不下且逐年上升。PA的耐药机制十分复杂,其对临床上使用的多种抗生素极易产生耐药。生物被膜作为其主要耐药机制之一,成为抗PA药物研究的新热点。研究表明,群体感应(QS,Quorum Sensing)在PA生物被膜的形成中扮演着十分重要的角色,其调控PA胞外多糖以及藻酸盐等的形成,使细菌聚集形成生物被膜;同时,PA的QS系统调控毒力因子(如:弹性蛋白酶、鼠李糖脂、绿脓菌素等)的释放,从而影响PA的致病性。因此,基于PA的群体感应设计新型群体感应抑制剂(Quorum sensing inhibitors,QSI),通过介入细菌的群体感应调控系统,干扰细菌之间的信息交流,从而减弱细菌毒力因子的释放、生物被膜的形成等,这一作用使其不易诱导细菌耐药,有可能成为解决PA耐药性问题的突破口。(Protein Cell 2015,6(1):26–41;J.Med.Chem.,2020,63,10921-10945)
本发明的目的在于合成新型非天然的小分子细菌群体感应抑制剂,以用于革兰阴性菌铜绿假单胞菌所致疾病的治疗,为解决铜绿假单胞菌耐药性问题提供新的选择。
发明内容
本发明的目的是提供一类由式(I)所示硝基苯类化合物或其药用盐,
其中:
NO2处于X-Z-(CH2)nR1的邻位、间位或对位;
X代表O、NH或不存在;
Z代表羰基或者次甲基;
R1为具有4-8个碳原子的饱和或不饱和的直链、支链或环状的脂肪基,其中如果存在,任选1-3个次甲基被N(NH)、O或S取代;或者,R1代表马来酰亚胺基、取代或未取代的芳香(杂)环;
n代表0-10。
优选的,本发明所述的化合物选自:
2-吗啉基乙酸(3-硝基)苯酯
3-吗啉基丙酸(3-硝基)苯酯
2-吗啉基乙酸(4-硝基)苯酯
2-吗啉基乙酸(2-硝基)苯酯
2-硫代吗啉基乙酸(3-硝基)苯酯
2-吗啉基-N-(3-硝基)苯基乙酰胺
2-(4H-吡喃-4-基)-乙酸(3-硝基)苯酯
3-(4-三氟甲基苯基)丙酸(3-硝基)苯酯
3-(吡啶-3-基)丙酸(3-硝基)苯酯
6-马来酰亚胺基己酸(3-硝基)苯酯
4-(2-(3-硝基苯氧基)乙基)吗啉。
本发明的式(I)化合物的在药学上可接受的非毒性的药用盐,包括与无机酸,如盐酸、硫酸形成的盐,与有机酸,如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐,以及氨基酸,如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸,如甲磺酸、对甲苯磺酸形成的盐,其中优选盐酸盐。
本发明的式(I)化合物也可以溶剂化物(如水合物)的形式存在,因此,这些溶剂化物(如水合物)也包括在本发明的化合物之内。
本发明还涉及式(I)化合物的制备方法,如反应路线1所示。
反应路线1:
1)当R2为卤素时,式(Ⅱ)化合物与式(III)化合物在极性溶剂存在下并加入适量无机碱,室温搅拌3-5小时,得式(I)化合物;
2)当R2为COOH时,式(III)化合物在非极性溶剂存在下并加入羧酸活化试剂EDCI(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐)和HOBt(羟基苯并三唑),然后加入适量有机碱,于室温下搅拌0.5-1.5小时,后加入式(Ⅱ)化合物,室温搅拌反应3-5小时,得式(I)化合物。
其中,所述的非极性溶剂选自二氯甲烷、三氯甲烷、四氢呋喃、二氧六环中的一种或多种;所述的极性溶剂选自二甲基甲酰胺、二甲亚砜、乙腈中的一种或多种;所述的有机碱选自三乙胺、N,N-二甲基吡啶、吡啶中的一种或多种;所述的无机碱选自碳酸钾、碳酸钠、碳酸氢钠中的一种或多种。
本发明的另一个目的在于提供(I)化合物或其药用盐在制备铜绿假单胞菌群体感应抑制剂中的应用。
式(I)化合物或或其药用盐在制备抑制铜绿假单胞菌绿脓菌素的产生的药物中的应用。
式(I)化合物或或其药用盐在制备治疗革兰阴性菌铜绿假单胞菌所致疾病的药物中的应用。
本发明的另一个目的在于提供(I)化合物的药物组合物在制备铜绿假单胞菌群体感应抑制剂中的应用。
本发明的另一个目的在于提供含有(I)的化合物或其药用盐为活性成分的药物组合物。
本发明还提供含有本发明的化合作为活性成分的药物组合物。药物组合物含有的本发明化合物在组合物中的重量比为0.1~99.9%,药物可接受的载体在组合物中的重量比为0.1~99.9%。药物组合物以适合药用的制剂形式存在。
本发明的药物组合物可以制备成任何可药用的剂型。
药用的制剂为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂。其中,所述片剂为糖衣片剂、薄膜衣片剂、肠溶衣片剂或缓释片剂;所述胶囊剂为硬胶囊剂、软胶囊剂、缓释胶囊剂;所述粉针剂为冻干粉针剂。
本发明的药物组合物,作为制剂形式,每剂中含有的本发明化合物的有效量为0.1~1000mg,所述每剂指的是,每一制剂单位,如片剂的每片,胶囊的每粒,也可指每次服用剂量,如每次服用100mg。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂形式的固体药物制剂时,可使用固体载体。可使用的固体载体优选为选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质,或可为包封物质。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、可可脂等。由于它们易于给药,片剂,粉剂、扁囊剂和胶囊等代表最有利的口服固体制剂。
为了易于给药及剂量均一,将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位,每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式,如片剂、胶囊或装在小管或小瓶中的粉剂。
虽然剂量单位形式中所含活性成分的量可以变化,但一般根据所选择活性成分的效力,调节在1~800mg范围内。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般,开始治疗的量低于活性成分的最佳剂量,然后逐渐增加给药剂量,直到达到最佳治疗效果。为方便起见,总的日剂量可分为几部分,分数次给药。
附图说明
图1、化学发光报告体系。
图2.实施例1化合物对于LasR报告菌株化学发光抑制依赖于化合物浓度。
图3.A12抑制铜绿假单胞菌生物膜形成。
图4 A12抑制铜绿假单胞菌绿脓菌素的产生。
图5.A12处理抑制了很多群体感应调控基因的转录。(A)处理组和对照组之间的差异表达基因聚类热图。(B)具有代表性几个的QS调控基因。
图6.CCK8法测定A12的细胞毒性。哺乳细胞Vero被用于检测。
图7、A12处理延长了铜绿假单胞菌感染的线虫生命周期。
具体实施方式
以下实施例用于进一步解释和说明本发明,但不能用来限制本发明的范围。
实施例1、2-吗啉基乙酸(3-硝基)苯酯
将市售的化合物2-吗啉基乙酸(145mg,1.0mmol)溶于10mL二氯甲烷中,然后依次加入三乙胺(303mg,3.0mmol),EDCI(192mg,1.0mmol)和HOBt(135mg,1mmol)。室温反应0.5个小时后,加入3-硝基苯酚(139mg,1.0mmol),室温继续反应5个小时,TLC监测反应结束。后处理:反应液浓缩并进行柱层析(乙酸乙酯/石油醚=1/2)得120mg淡黄色固体(产率为45%)。1HNMR(500M,CDCl3):δ8.08(d,J=7.9Hz,1H),7.98–7.97(m,1H),7.54(t,J=8.0Hz,1H),7.44(d,J=8.1Hz,1H),3.75(d,J=4.9Hz,4H),3.50(s,2H),2.68(d,J=5.0Hz,4H).MS-ESI(m/z):267.1(M+H)+.
实施例2、3-吗啉基丙酸(3-硝基)苯酯
制备方法同实施例1,化合物3-硝基苯酚与3-吗啉基丙酸反应制得淡黄色色固体。收率:29%;1HNMR(500M,CDCl3):δ8.09(d,J=8.0Hz,1H),7.99–7.97(m,1H),7.55(t,J=8.2Hz,1H),7.44(d,J=7.6Hz,1H),3.72(q,J=4.4Hz,4H),2.83-2.77(m,4H),2.53(d,J=5.3Hz,4H).MS-ESI(m/z):281.1(M+H)+.
实施例3、2-吗啉基乙酸(4-硝基)苯酯
制备方法同实施例1,化合物4-硝基苯酚与2-吗啉基乙酸反应制得淡黄色固体。收率:23%;1HNMR(600M,CDCl3):δ8.26(d,J=9.1Hz,2H),7.29(d,J=9.1Hz,2H),3.78–3.77(m,4H),3.52(s,2H),2.70-2.68(m,4H)).MS-ESI(m/z):267.1(M+H)+.
实施例4、2-吗啉基乙酸(2-硝基)苯酯
制备方法同实施例1,化合物2-硝基苯酚与2-吗啉基乙酸反应制得淡黄色固体。收率:21%;1HNMR(600M,CDCl3):δ8.12(dd,J=8.2,1.6Hz,1H),7.67(td,J=7.9,1.6Hz,1H),7.42(td,J=7.9,1.3Hz,1H),7.25(dd,J=8.1,1.4Hz,1H),3.79–3.78(m,4H),3.61(s,2H),2.73(t,J=4.7Hz,4H)).MS-ESI(m/z):267.1(M+H)+.
实施例5、2-硫代吗啉基乙酸(3-硝基)苯酯
制备方法同实施例1,化合物2-硝基苯酚与2-硫代吗啉基乙酸反应制得淡黄色固体。收率:37%;1HNMR(500M,CDCl3):δ8.12(ddd,J=8.2,2.2,1.0Hz,1H),8.00(t,J=2.2Hz,1H),7.57(t,J=8.2Hz,1H),7.46(ddd,J=8.2,2.2,1.0Hz,1H),3.56(s,2H),2.98-2.95(m,4H),2.79-2.71(m,4H).MS-ESI(m/z):283.1(M+H)+.
实施例6、2-吗啉基-N-(3-硝基)苯基乙酰胺
制备方法同实施例1,化合物3-硝基苯胺与2-吗啉基乙酸反应制得淡黄色固体。收率:66%;1HNMR(500M,CDCl3):δ9.32(s,1H),8.36(s,1H),8.04(d,J=8.1Hz,1H),7.96(d,J=8.1Hz,1H),7.51(t,J=8.2Hz,1H),3.79(brs,4H),3.19(s,2H),2.64(brs,4H).MS-ESI(m/z):266.1(M+H)+.
实施例7、2-(4H-吡喃-4-基)-乙酸(3-硝基)苯酯
制备方法同实施例1,化合物3-硝基苯酚与2-(4H-吡喃-4-基)-乙酸反应制得淡黄色固体。收率:26%;1H NMR(500MHz,CDCl3)δ8.11(d,J=8.3Hz,1H),7.98(s,1H),7.56(t,J=8.1Hz,1H),7.44(d,J=8.2Hz,1H),3.99(d,J=7.2Hz,2H),3.45(t,J=11.7Hz,2H),2.55(d,J=7.2Hz,2H),2.18-2.14(m,1H),1.74(d,J=12.9Hz,2H),1.50-1.42(m,2H).MS-ESI(m/z):266.1(M+H)+.
实施例8、3-(4-三氟甲基苯基)丙酸(3-硝基)苯酯
制备方法同实施例1,化合物3-硝基苯酚与3-(4-三氟甲基苯基)丙酸反应制得淡黄色固体。收率:29%;1H NMR(500MHz,CDCl3)δ8.11(d,J=8.2Hz,1H),7.94(d,J=2.4Hz,1H),7.60(d,J=7.9Hz,2H),7.54(t,J=8.2Hz,1H),7.40-7.36(m,3H),3.15(t,J=7.5Hz,2H),2.97(t,J=7.6Hz,2H).MS-ESI(m/z):340.1(M+H)+.
实施例9、3-(吡啶-3-基)丙酸(3-硝基)苯酯
制备方法同实施例1,化合物3-硝基苯酚与3-(吡啶-3-基)丙酸反应制得淡黄色固体。收率:31%;1H NMR(500MHz,CDCl3)δ8.70-8.43(m,2H),8.08(d,J=8.2Hz,1H),7.91(s,1H),7.75-7.47(m,2H),7.47-7.19(m,2H),3.08(t,J=7.5Hz,2H),2.95(t,J=7.6Hz,2H).MS-ESI(m/z):273.1(M+H)+.
实施例10、6-马来酰亚胺基己酸(3-硝基)苯酯
制备方法同实施例1,化合物3-硝基苯酚与6-马来酰亚胺基己酸反应制得淡黄色固体。收率:45%;1H NMR(500MHz,CDCl3)δ8.03(d,J=8.2Hz,1H),7.92(d,J=2.6Hz,1H),7.50(t,J=8.2Hz,1H),7.39(d,J=8.2Hz,1H),6.65(d,J=2.4Hz,2H),3.49(t,J=7.1Hz,2H),2.55(t,J=7.4Hz,2H),1.76-1.71(m,2H),1.63-1.58(m,2H),1.43-1.30(m,2H).MS-ESI(m/z):333.1(M+H)+.
实施例11、4-(2-(3-硝基苯氧基)乙基)吗啉
3-硝基苯酚(139mg,1mmol)和4-(2-溴乙基)吗啉(193mg,1mmol)溶于10mL乙腈溶液中,然后加入碳酸钾(210mg,1.5mmol),室温搅拌6个小时后,过滤,滤液中加入10mL水,然后乙酸乙酯萃取。有机相浓缩并进行柱层析(乙酸乙酯/石油醚=1/2)得到白色固体;收率:75%.1HNMR(500M,CDCl3):δ7.83(dd,J=8.2,2.1Hz,1H),7.75(t,J=2.3Hz,1H),7.42(t,J=8.2Hz,1H),7.25–7.21(m,1H),4.18(t,J=5.6Hz,2H),3.75–3.73(m,4H),2.84(t,J=5.6Hz,2H),2.59(t,J=4.7Hz,4H).MS-ESI(m/z):253.1(M+H)+.
生物实施例
将实施例化合物1-11分别用二甲基亚砜溶解,配置128μg/mL的化合物母液进行活性评价;
为了更好的体现实施例化合物对铜绿假单胞菌群体感应系统LasR蛋白的抑制,首先利用高保真DNA聚合酶扩增铜绿假单胞菌PA14的lasR基因的编码区,并通过In-Fusion试剂盒(Takara)插入到质粒pET15b(NdeI酶切),构建LasR蛋白的表达质粒pET15b-lasR;此外,将lasB基因的启动子区扩增之后,插入到质粒pMS402(XhoI和BamHI酶切)上,得到了lasB启动子和化学发光报告基因luxCDABE转录融合表达质粒-pKD-lasB’-luxCDABE。将以上两个构建的质粒共转化E.coli BL21(DE3),得到化学发光报告菌株CW182。在LB培养基中添加LasR天然底物3OC12-HSL时,CW182会产生化学发光,且随时间逐渐增加,在接种后12小时出现一个化学发光高峰,然后发光强度开始下降。而且,报告菌株的发光强度随着天然底物浓度的增加而增加,但在添加100nM 3OC12-HSL后处于饱和状态;再提高3OC12-HSL浓度,化学发光强度也不再增加(见图1)。因此,为了测定实施例化合物与3OC12-HSL竞争性结合LasR,我们采用以下的报告体系:在含有报告菌株培养液的96孔板中,添加100nM 3OC12-HSL以及不同的化合物,以只添加3OC12-HSL为对照组,在37℃振板培养12小时后,利用酶标仪测定化学发光和OD600数值。化学发光单位/OD600被定义为相对发光单位;活性抑制率被定义为处理组相对发光单位占对照组相对发光单位的比值。
表1.
化合物 | 活性抑制(%) | 化合物 | 活性抑制率(%) |
实施例1(A12) | 92.34±5.08 | 实施例7 | 67.64±1.30 |
实施例2 | 87.09±2.81 | 实施例8 | 66.24±1.10 |
实施例3 | 82.34±2.00 | 实施例9 | 77.12±2.20 |
实施例4 | 61.64±2.30 | 实施例10 | 88.11±2.34 |
实施例5 | 91.55±2.20 | 实施例11 | 71.24±2.35 |
实施例6 | 45.11±2.34 |
实施例1化合物对报告菌株CW182的抑制活性
对实施例1化合物(A12)进行进一步活性评价,结果显示其IC50为5.94μg/mL,且具有剂量依赖关系。
实施例1化合物对野生型铜绿假单胞菌PAO1生物被膜抑制作用
铜绿假单胞菌生物被膜的形成受QS系统调控,实施例1化合物对LasR具有抑制活性,因此对生物被膜的形成也有抑制作用。将铜绿假单胞菌野生型菌株PAO1接种在丰富培养基LB中,37℃过夜培养。离心收集菌体后,用基本培养基M63洗涤和重悬菌体,将菌液按照1:100稀释到M63中,并分装到PVC材质的96孔板中,每孔100微升。将实施例化合物1倍比稀释后添加到孔中,每个处理设置8个复孔。将96孔板盖好后,在37℃静置培养48小时。倒去菌液,用无菌水洗涤2次去掉游离细菌,控干水分后,加入125微升0.1%的结晶紫溶液,在室温孵育15分钟;用无菌水清洗4次,再控干水分,在超净台风干2个小时;加入125微升30%醋酸溶解结晶紫;然后将125微升结晶紫溶液转移到新的平底96孔板中,用酶标仪测定550nm吸收值。实验重复2次。
实验结果表明实施例1化合物对PAO1生物被膜形成有抑制作用,且具有剂量依赖关系。在32μg/mL时就显著抑制生物膜形成。
实施例1化合物抑制铜绿假单胞菌绿脓菌素的产生
将铜绿假单胞菌野生型菌株PA14接种到丰富培养基LB中,37℃振荡培养18个小时,离心收集上清;500微升的上清和300微升氯仿混匀抽提,吸取下层有机层加入到新的离心管中,再添加100微升0.2N HCl,振荡混匀后,出现包含绿脓菌素的粉色溶液。该溶液在520nm处有最大吸收峰。绿脓菌素的含量和溶液OD520的吸收值正相关。该实验重复3次,结果以Mean±SD呈现。
实施例1化合物抑制铜绿假单胞菌群体感应相关基因转录。
在铜绿假单胞菌中,许多基因尤其是毒力因子相关基因的转录收到群体感应系统的调控。为了确定实施例化合物1对于铜绿假单胞菌群体感应系统的抑制作用,我们用RNA-seq方法对分析了A12处理组与DMSO处理组(对照组)转录差异基因。挑取生长在新鲜LB平板上的PAO1单菌落,接种到5mL LB培养基中,过夜培养,离心收集菌体,用LB洗涤重悬,测定OD600,然后转接到50mL LB培养基中,起始OD600为0.01。处理组:添加64μg/mL A12;对照组添加同样体积的DMSO,终浓度为0.25%(V/V)。每组3个平行。在37℃振荡培养8个小时(稳定生长期初期),4℃离心收集菌体,液氮速冻后保存于-80℃超低温冰箱。使用试剂按照说明书(Invitrogen)提取总RNA,使用DNase I(TaKara)去除基因组DNA。将RNA送到上海美吉生物医药科技有限公司进行测序。构建好文库后,使用Illumina HiSeq X Ten进行RNA-seq双端测序。RNA-seq的原始数据已经提交SRA数据库,序列号为PRJNA832877。
与对照组相比,A12处理后,一共有355个基因的转录出现显著差异而且变化倍数大于2。其中,147个基因的转录上调,而208个基因的转录下调(见附表1)。在转录的下调的基因中,我们发现大量受群体感应调控的基因,包括编码elastase的lasA和lasB,编码rhamnosyltransferase的rhlA和rlhB,合成PQS的基因簇pqsABCD,合成绿脓菌素的phzA1和phzB1,以及涉及到PQS合成的anthranilate synthase的编码基因phnA和phnB。
实施例1化合物细胞毒性较低
我们采用CCK8方法检测了实施化合物1的细胞毒性。哺乳细胞Vero经培养后,接种到96孔板中,100微升每孔,含有2.0×104细胞。细胞培养基为RPMI-1640,添加了20%FBS。在含有5%CO2的细胞培养箱中37℃培养24小时后,加入不同浓度的A12溶液。未处理的细胞作为对照。在37℃继续培养24小时后,向每孔加入10微升CCK8,37度孵育1小时后,用酶标仪测定450nm处的最大吸收值。如图6所示,A12的IC50为1224.62μg/ml,在250μg/ml时,细胞活性有93.91%。
实施例1化合物显著延长了铜绿假单胞菌急性感染的秀丽隐杆线虫的生命周期
秀丽隐杆线虫(Caenorhabditis elegans)是一种简单的模式动物,常常被用于测试病原细菌和宿主的相互作用。铜绿假单胞菌野生型菌株PA14可以快速杀死线虫,这依赖于细菌产生的毒力因子,而不是定殖的病原菌本身。而毒力因子的分泌受到群体感应系统的调控。因此,这种快速杀虫模型常被用来测试和筛选群体感应抑制化合物。
将PA14划线到新鲜的LB培养基上过夜培养,挑取单菌落接种LB液体培养基,在37℃过夜培养。离心收集菌体,用LB培养基洗涤重悬,测定OD600,再转接到5mL LB培养基中,起始OD600为0.01。PA14在37℃振荡培养18小时后,分别取50微升菌液涂布在60mm Peptone-Glucose-Sorbitol(PGS)琼脂平板上。PGS平板在37℃培养24小时后,在室温冷却2个小时。处理组在液体培养基里和PGS平板上都加入64μg/mL A12,而对照组为等体积的DMSO(0.25%,V/V)。作为线虫的常规食物,大肠杆菌OP50被用来作为无害对照。每组设立3个平行。
将经过“同步化”的野生型秀丽隐杆线虫(N2)L4期线虫转移到以上PGS平板上,每个平板放入25-30条线虫。将NGM平板放入25度培养箱里培养。在不同时间点进行观察计数死亡和存活的线虫。在图7所示,A12处理之后,抑制了铜绿假单胞菌的毒力因子分泌,减轻了对线虫的毒性。
Claims (7)
1.3-硝基苯酚酯类化合物或其药用盐,选自:
2-吗啉基乙酸(3-硝基)苯酯,
3-吗啉基丙酸(3-硝基)苯酯,
2-吗啉基乙酸(2-硝基)苯酯,
2-硫代吗啉基乙酸(3-硝基)苯酯,
2-(4H-吡喃-4-基)-乙酸(3-硝基)苯酯,
3-(4-三氟甲基苯基)丙酸(3-硝基)苯酯,
3-(吡啶-3-基)丙酸(3-硝基)苯酯,
6-马来酰亚胺基己酸(3-硝基)苯酯。
2.根据权利要求1所述的化合物或其药用盐,其特征在于,药用盐为所述化合物与无机酸或有机酸形成的盐。
3.根据权利要求1所述的化合物或其药用盐,其特征在于,药用盐为盐酸盐。
4.一种制备权利要求1所述化合物或其药用盐的方法,其特征在于,2-吗啉基乙酸(3-硝基)苯酯的制备,其包括如下步骤:
将化合物1.0mmol 2-吗啉基乙酸溶于10mL二氯甲烷中,然后依次加入3.0mmol三乙胺,1.0mmolEDCI和1mmolHOBt,室温反应0.5个小时后,加入1.0mmol3-硝基苯酚,室温继续反应5个小时,TLC监测反应结束,后处理:反应液浓缩并进行柱层析得淡黄色固体,其中柱层析,乙酸乙酯/石油醚=1/2。
5.权利要求1中所述的化合物或其药用盐在制备铜绿假单胞菌群体感应抑制剂中的应用。
6.含有权利要求1所述化合物的药物组合物在制备铜绿假单胞菌群体感应抑制剂中的应用。
7.以权利要求1中所述的化合物或其药用盐为活性成分的药物组合物。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002322054A (ja) * | 2001-04-26 | 2002-11-08 | Dai Ichi Seiyaku Co Ltd | 薬剤排出ポンプ阻害薬 |
CN101146782A (zh) * | 2004-12-15 | 2008-03-19 | 拜耳先灵医药股份有限公司 | 间位取代的噻唑烷酮化合物、其制备方法以及作为药物的应用 |
CN101481323A (zh) * | 2008-01-11 | 2009-07-15 | 中国人民解放军军事医学科学院毒物药物研究所 | 苯并环庚烯类衍生物、其制备方法及医药用途 |
KR20130053240A (ko) * | 2011-11-15 | 2013-05-23 | 중앙대학교 산학협력단 | 신경줄기세포 분화조절제용 신규 피리미딘-2,4-디아민 유도체 및 이의 의학적 용도 |
CN104230954A (zh) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-二氨基嘧啶类化合物及其医药用途 |
CN109563144A (zh) * | 2016-06-01 | 2019-04-02 | M3生物技术公司 | 化合物 |
-
2022
- 2022-05-13 CN CN202210517348.2A patent/CN114907288B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002322054A (ja) * | 2001-04-26 | 2002-11-08 | Dai Ichi Seiyaku Co Ltd | 薬剤排出ポンプ阻害薬 |
CN101146782A (zh) * | 2004-12-15 | 2008-03-19 | 拜耳先灵医药股份有限公司 | 间位取代的噻唑烷酮化合物、其制备方法以及作为药物的应用 |
CN101481323A (zh) * | 2008-01-11 | 2009-07-15 | 中国人民解放军军事医学科学院毒物药物研究所 | 苯并环庚烯类衍生物、其制备方法及医药用途 |
KR20130053240A (ko) * | 2011-11-15 | 2013-05-23 | 중앙대학교 산학협력단 | 신경줄기세포 분화조절제용 신규 피리미딘-2,4-디아민 유도체 및 이의 의학적 용도 |
CN104230954A (zh) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-二氨基嘧啶类化合物及其医药用途 |
CN109563144A (zh) * | 2016-06-01 | 2019-04-02 | M3生物技术公司 | 化合物 |
Non-Patent Citations (1)
Title |
---|
RN 2120356-87-6;STN REGISTRY;STN REGISTRY;1 * |
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