CN102675302A - 含1,4-苯并二噁烷的噻二唑衍生物及其制法与其抗菌活性 - Google Patents
含1,4-苯并二噁烷的噻二唑衍生物及其制法与其抗菌活性 Download PDFInfo
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- CN102675302A CN102675302A CN2011100637406A CN201110063740A CN102675302A CN 102675302 A CN102675302 A CN 102675302A CN 2011100637406 A CN2011100637406 A CN 2011100637406A CN 201110063740 A CN201110063740 A CN 201110063740A CN 102675302 A CN102675302 A CN 102675302A
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- benzodioxan
- acid
- thiadiazoles
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
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Abstract
一类含1,4-苯并二噁烷的噻二唑衍生物,它有如下通式:式中R为:
Description
技术领域
本发明涉及含1,4-苯并二噁烷的噻二唑衍生物及其制备方法与作为抗菌药物的用途。
背景技术。
在过去的几十年中,多药耐药微生物的问题在全球已经达到令人震惊的程度。因此,寻找高效、低副作用的抗微生物感染的新药物成为一个重要和迫切的任务。
噻二唑是生产头孢唑啉、头孢卡奈、头孢西酮、唑酮头孢菌素、头孢帕罗、头孢菌素BL-S339,呋苄唑头孢菌素等医药的重要中间体,由于该类药物具有抗菌广谱、吸收好、副作用小,尤其适于口服吸收等特点,因此在临床上被广泛使用。近期有人报道1,4-苯并二噁烷-6-羧酸也具有一定的抗菌抗炎活性。因此,本发明将1,4-苯并二噁烷引入1,3,4-噻二唑,制备含有1,4-苯并二噁烷的噻二唑衍生物。
此类衍生物对细菌生长有明显的抑制作用,因此,1,3,4-噻二唑衍生物作为很有潜力的抗细菌药物的前景十分值得关注。随着1,3,4-噻二唑类药物研究的不断深入,在对其抗菌作用机制不断了解的基础上进行有效的结构改造与修饰和分子设计,将会有越来越多的高效、低毒的1,3,4-噻二唑类抗菌药物用于临床,造福人类。
发明内容
本发明的目的在于提供一类含1,4-苯并二噁烷的噻二唑衍生物以及它们的制备方法与用途。
本发明的技术方案如下:
一类含1,4-苯并二噁烷的噻二唑衍生物,其特征是它有如下通式:
式中R为:
一种制备上述的含1,4-苯并二噁烷的噻二唑衍生物的方法,其特征是它由下列步骤组成:
步骤1.将0.1mol 1,4-苯并二噁烷-6-羧酸,0.1mol氨基硫脲,25mL三氯氧磷置于带有回流装置的圆底烧瓶中,油浴加热,在75℃下回流反应4h。冷却至室温。
步骤2.往冷却产物后的圆底烧瓶中缓缓加入110mL水,然后油浴加热。在110℃下回流反应6h,放置冷却。
步骤3.用50%氢氧化钾溶液调至pH 8,析出固体。趁热抽滤,黄色沉淀用乙醇重结晶,干燥后得产物。
步骤4.将步骤3中得到的黄色产物溶于二氯甲烷中,然后加入各种取代的芳香酸或者脂肪酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)、1-羟基-苯并- 三氮唑(HoBt),室温反应8个小时。其中反应物黄色固体与各种取代的芳香酸或者脂肪酸的摩尔比是1∶1,与1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)的摩尔比是1∶1.5,与1-羟基-苯并-三氮唑(HoBt)的摩尔比是1∶0.05。
步骤5.反应完全后,用乙酸乙酯萃取,有机层用饱和食盐水洗(饱和食盐水与反应物的摩尔比为100∶1),然后用无水Na2SO4干燥,溶剂减压蒸干,得到的粗产物用无水乙醇重结晶得到本发明的含1,4-苯并二噁烷的噻二唑衍生物。
实验结果表明,本发明的新型含1,4-苯并二噁烷的噻二唑衍生物对细菌具有明显的抑制作用。因此本发明的含1,4-苯并二噁烷的噻二唑衍生物可以应用于制备抗菌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例一:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-苯基乙酰胺(化合物1)的制备。
将0.1mol1,4-苯并二噁烷-6-羧酸,0.1mol氨基硫脲置于带有回流装置的圆底烧瓶中,缓慢加入25mL二氯氧磷,油浴加热,在75℃下回流反应4h,冷却至室温。然后缓缓加入110mL水,在110℃下回流反应6h,放置冷却。用50%氢氧化钾溶液调至pH 8,趁热抽滤,用乙醇重结晶,干燥后得黄色产物。将得到的黄色产物(10mmol)溶于30mL二氯甲烷中,然后加入苯乙酸(10mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)(15mmol)和1-羟基-苯并-三氮唑(HoBt)(0.5 mmol),室温反应8个小时,乙酸乙酯萃取,有机层用饱和食盐水洗(饱和食盐水与反应物的摩尔比为100∶1),然后用无水Na2SO4干燥,溶剂减压蒸干,无水乙醇重结晶得目标化合物。浅黄色粉末,产率60%.m.p.271-272℃;1H NMR(300MHz,CDCl3):4.01(s,2H);4.30(m,4H);6.91-6.95(d,J=4.2Hz,1H);7.32(s,1H);7.35-7.36(d,J=1.1Hz,1H);7.38-7.45(m,4H);7.47-7.48(d,J=1.1Hz,1H);11.13(s,1H).MS(ESI):354.0(C18H16N3O3S,[M+H]+).Anal.Calcd for C18H15N3O3S:C,61.18;H,4.28;N,11.89%.Found:C,61.45;H,4.03;N,12.06%.
实施例二:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-苯甲酰胺(化合物2)的制备。
制备方法同实施例一。以苯甲酸代替苯乙酸,得目标化合物。淡黄色粉末,产率65%,m.p.274-275℃;1H NMR(300MHz,CDCl3):4.33(m,4H);6.95-6.98(d,J=4.2Hz,1H);7.43-7.46(m,1H);7.51(s,1H);7.56-7.61(m,2H);7.65-7.67(d,J=3.6Hz,1H);8.23-8.26(d,J=3.6Hz,2H);11.85(s,1H).MS(ESI):340.07(C17H14N3O3S,[M+H]+).Anal.Calcd for C17H13N3O3S:C,60.17;H,3.86;N,12.38%.Found:C,60.41;H,4.03;N,12.62%.
实施例三:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-甲基苯甲酰胺(化合物3)的制备。
制备方法同实施例一。以邻甲苯甲酸代替苯乙酸,得目标化合物。白色粉末,产率60%,m.p.265-266℃;1H NMR(300MHz,CDCl3):2.58(s,3H);4.30-4.32(m,4H);6.94-6.97(d,J=4.2Hz,1H);7.33-7.38(m,2H);7.40-7.44(m,1H);7.46-7.51(m,2H);7.70-7.73(d,J=3.7Hz,1H);10.56(s,1H).MS(ESI):354.08(C18H16N3O3S,[M+H]+).Anal.Calcd for C18H15N3O3S:C,61.18;H,4.28;N,11.89%.Found:C,61.50;H,4.03;N,12.08%.
实施例四:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-(3-甲氧基苯基)-乙酰胺(化合物4)的制备。
制备方法同实施例一。以邻甲氧基苯乙酸代替苯乙酸,得目标化合物。白色粉末,产率65%,m.p.250-252℃;1H NMR(300MHz,CDCl3):3.78(s,3H);4.00(s,2H);4.32(m,4H);6.86-6.89(m,1H);6.93-6.99(m,1H);7.04-7.07(m,2H);7.30-7.33(m,1H);7.41-7.45(m,1H);7.51-7.52(m,1H);11.81(s,1H).MS(ESI);384.09(C19H18N3O4S,[M+H]+).Anal.Calcd for C19H17N3O4S:C,59.52;H,4.47;N,10.96%.Found:C,59.83;H,4.19;N,11.09%.
实施例五:2-(3-氯苯基)-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-乙酰胺(化合物5)的制备。
制备方法同实施例一。以邻氯苯乙酸代替苯乙酸,得目标化合物。白色粉末,产率62%,m.p.251-253℃;1H NMR(300MHz,CDCl3):4.08(s,2H);4.33-4.49(m,4H);6.93-6.97(m,1H);7.29-7.31(m,2H);7.39-7.47(m,2H);7.53-7.56(m,2H);12.68(s,1H).MS(ESI):388.04(C18H15ClN3O3S,[M+H]+).Anal.Calcd for C18H14ClN3O3S:C,55.74;H,3.64;N,10.83%.Found:C,55.96;H,3.43;N,10.65%.
实施例六:2-(4-氯苯基)-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-乙酰胺(化合物6)的制备。
制备方法同实施例一。以对氯苯乙酸代替苯乙酸,得目标化合物。白色粉末,产率61%,m.p.291-293℃;1H NMR(300MHz,CDCl3):4.06-4.16(m,4H);4.31-4.37(d,J=18Hz;4H);6.89-6.97(m,1H);7.01-7.07(m,2H);7.38-7.42(m,1H);7.44-7.49(m,2H);7.51-7.54(m,1H);12.47(s,1H).MS(ESI):388.04(C18H15ClN3O3S,[M+H]+).Anal.Calcd for C18H14ClN3O3S:C,55.74;H,3.64;N,10.83%.Found:C,55.89;H,3.91;N,10.60%.
实施例七:2-(3-溴苯基)-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-乙酰胺(化合物7)的制备。
制备方法同实施例一。以邻溴苯乙酸代替苯乙酸,得目标化合物。白色粉末,产率64%,m.p.240-242℃;1H NMR(300MHz,CDCl3):4.01(s,2H);4.31-4.37(m,4H);6.93-6.96(m,2H);7.02-7.04(d,J=6Hz;1H);7.40-7.47(m,1H);7.54-7.55(m,3H);13.15(s,1H).MS(ESI):431.99(C18H15BrN3O3S,[M+H]+).Anal.Calcd forC18H14BrN3O3S:C,50.01;H,3.26;N,9.72%.Found:C,50.33;H,3.51;N,9.49%.
实施例八:2-(4-溴苯基)-N-(5-(2,3-二氯苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-乙酰胺(化合物8)的制备。
制备方法同实施例一。以对溴苯乙酸代替苯乙酸,得目标化合物。白色粉末,产率60%,m.p.315-316℃;1H NMR(300MHz,CDCl3):3.71-3.73(m,2H);4.32-4.34(m,4H);6.95-6.98(d,J=9Hz;1H);7.00-7.03(d,J=9Hz;1H);7.35-7.43(m,2H);7.53-7.54(m,1H);7.68-7.71(d,J=9Hz;1H);7.75(s,1H);12.45(s,1H).MS(ESI):431.99(C18H15BrN3O3S,[M+H]+).Anal.Calcd for C18H14BrN3O3S:C,50.01;H,3.26;N,9.72%.Found;C,50.28;H,3.50;N,9.55%.
实施例九:2-(3,4-二乙氧苯基)-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-乙酰胺(化合物9)的制备。
制备方法同实施例一。以3,4-二乙氧基醋酸代替苯乙酸,得目标化合物。白色粉末,产率68%,m.p.249-252℃;1H NMR(300MHz,CDCl3):3.69-3.80(m,10H);3.94-3.99(m,2H);4.01-4.12(m,4H);7.00-7.02(d,J=6Hz;1H);7.39-7.55(m,3H);7.60-7.66(m,1H);7.75(s,1H);11.98(s,1H).MS(ESI):442.14(C22H24N3O5S,[M+H]+).Anal.Calcd for C22H23N3O5S:C,59.85;H,5.25;N,9.52%.Found:C,59.59;H,5.44;N,9.81%.
实施例十:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-3-苯基丙酰胺(化合物10)的制备。
制备方法同实施例一。以苯丙酸代替苯乙酸,得目标化合物。白色粉末,产率63%,m.p.288-290℃;1H NMR(300MHz,CDCl3):3.18-3.25(m,4H);4.31-4.33(m,4H);6.94-6.96(d,J=8.4Hz,1H);7.23(s,1H);7.31-7.34(m,3H);7.48-7.49(m,1H);7.52(s,2H).12.02(s,1H).MS(ESI):368.10(C19H18N3O3S,[M+H]+).Anal.Calcd forC19H17N3O3S:C,62.11;H,4.66;N,11.44%.Found:C,62.35;H,4.87;N,11.28%.
实施例十一:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-(萘-2-基)乙酰胺(化合物11)的制备。
制备方法同实施例一。以萘乙酸代替苯乙酸,得目标化合物。白色粉末,产率60%,m.p.316-317℃;1H NMR(300MHz,CDCl3):4.09-4.13(m,2H);4.34-4.35(m,4H);6.91-6.94(m,2H);7.00-7.02(d,J=6.0Hz,1H);7.43-7.47(m,2H);7.58-7.61(m,3H);7.63-7.66(d,J=9.0Hz,1H);7.75(s,1H);10.95(s,1H).MS(ESI):404.10(C22H18N3O3S,[M+H]+).Anal.Calcd for C22H17N3O3S:C,65.49;H,4.25;N,10.42%.Found;C,65.72;H,4.40;N,10.21%.
实施例十二:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-(4-氟苯基)乙酰胺(化合物12)的制备。
制备方法同实施例一。以对氟苯乙酸代替苯乙酸,得目标化合物。白色粉末,产率66%,m.p.312-313℃;1H NMR(300MHz,CDCl3):4.09-4.16(m,2H);4.32-4.35(m,4H);6.91-7.01(m,2H);7.03-7.06(d,J=9.0Hz,1H);7.42-7.46(m,1H);7.53-7.54(m,1H);7.66-7.69(m,1H);7.72-7.73(m,1H).11.35(s,1H).MS(ESI):372.07(C18H15FN3O3S,[M+H]+).Anal.Calcd for C18H14FN3O3S:C,58.21;H,3.80;N,11.31%.Found:C,58.51;H,3.50;N,11.08%.
实施例十三:4-乙酰-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)苯甲酰胺(化合物13)的制备。
制备方法同实施例一。以对甲氧基苯甲酸代替苯乙酸,得目标化合物。白色粉末,产率64%,m.p.315-317℃;1H NMR(300MHz,CDCl3):2.17(s,3H);4.36-4.37(m,4H);6.91-6.97(m,1H);7.00-7.03(m,1H);7.42-7.46(m,1H);7.58-7.70(m,3H);7.79-7.80(m,1H).12.18(s,1H).MS(ESI);382.08(C19H16N3O4S,[M+H]+).Anal.Calcd for C19H15N3O4S:C,59.83;H,3.96;N,11.02%.Found:C,59.63;H,4.13;N,11.33%.
实施例十四:4-氨基-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)苯甲酰胺(化合物14)的制备。
制备方法同实施例一。以对氨基苯甲酸代替苯乙酸,得目标化合物。白色粉末,产率58%,m.p.279-281℃;1H NMR(300MHz,CDCl3):4.33(m,4H);5.78-5.79(m,2H);6.95-6.97(d,J=4.2Hz,1H);7.43-7.46(m,1H);7.51(s,1H);7.56-7.61(m,2H);7.65-7.67(d,J=3.6Hz,1H);8.23-8.26(d,J=3.6Hz,1H);11.85(s,1H).MS(ESI):355.08(C17H15N4O3S,[M+H]+).Anal.Calcd for C17H14N4O3S:C,57.62;H,3.98;N,15.81%.Found:C,57.93;H,3.65;N,15.98%.
实施例十五:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)烟酰 胺(化合物15)的制备。
制备方法同实施例一。以烟酸代替苯乙酸,得目标化合物。白色粉末,产率64%,m.p.289-292℃;1H NMR(300MHz,CDCl3);4.32-4.36(m,4H);7.00-7.03(m,1H);7.46-7.50(m,1H);7.63-7.66(m,2H);8.39-8.43(m,1H);8.78(s,1H);9.34(s,1H).11.34(s,1H).MS(ESI):341.06(C16H13N4O3S,[M+H]+).Anal.Calcd for C16H12N4O3S:C,56.46;H,3.55;N,16.46%.Found:C,56.70;H,3.75;N,16.27%.
实施例十六:5-溴-N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)烟酰胺(化合物16)的制备。
制备方法同实施例一。以5-溴烟酸代替苯乙酸,得目标化合物。白色粉末,产率60%,m.p.297-298℃;1H NMR(300MHz,CDCl3):4.34(s,4H);7.07-7.10(d,J=9.0Hz,1H);7.65-7.67(m,2H);8.74(s,1H);8.93-8.94(d,J=2.01Hz,1H);9.25-9.26(d,J=1.47Hz,1H);11.56(s,1H).MS(ESI):418.97(C16H12BrN4O3S [M+H]+).Anal.Calcd for C16H14BrN4O3S:C,45.84;H,2.64;N,13.36%.Found:C,45.78;H,2.90;N,13.62%.
实施例十七:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)桂皮 酰胺(化合物17)的制备。
制备方法同实施例一。以肉桂酸代替苯乙酸,得目标化合物。白色粉末,产率60%,m.p.302-304℃;1H NMR(300MHz,CDCl3):4.33(s,4H);6.98-7.00(d,J=8.94Hz,1H);7.06-7.11(d,J=16.8Hz,1H);7.38-7.43(m,3H);7.57-7.64(m,5H).12.23(s,1H).MS(ESI):366.08(C19H16N3O3S[M+H]+).Anal.Calcd for C19H15N3O3S:C,62.45;H,4.14;N,11.50%.Found:C,62.71;H,4.32;N,11.26%.
实施例十八:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)三甲氧基酰胺(化合物18)的制备。
制备方法同实施例一。以3,4,5-三甲氧基苯甲酸代替苯乙酸,得目标化合物。白色粉末,产率63%.m.p.307-309℃;1H NMR(300MHz,CDCl3):3.93-3.97(m,9H);4.2l-4.34(m,4H);6.97-7.02(m,1H);7.26-7.35(m,2H);7.64-7.65(m,2H).12.12(s,1H).MS(ESI):430.10(C20H20N3O6S[M+H]+).Anal.Calcd for C20H19N3O6S:C,55.94;H,4.46;N,9.78%.Found:C,55.67;H,4.71;N,9.97%.
实施例十九:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-硝基苯甲酰胺(化合物19)的制备。
制备方法同实施例一。以邻硝基苯甲酸代替苯乙酸,得目标化合物。黄色粉末,产率53%.m.p.313-315℃;1H NMR(300MHz,CDCl3):4.29-4.35(m,4H);6.96-6.99(m,1H);7.54-7.57(m,2H);7.70-7.81(m,2H);8.00-8.09(m,2H).11.67(s,1H).MS(ESI):385.05(C17H13N4O5S[M+H]+).Anal.Calcd for C17H12N4O5S:C,53.12;H,3.15;N,14.58%.Found:C,53.37;H,2.96;N,14.81%.
实施例二十:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-3-硝基苯甲酰胺(化合物20)的制备。
制备方法同实施例一。以间硝基苯甲酸代替苯乙酸,得目标化合物。黄色粉末,产率54%.m.p.312-313℃;1H NMR(300MHz,CDCl3):4.33-4.36(m,4H);7.00-7.03(m,1H);7.65-7.68(m,2H);7.72-7.75(m,1H);8.39-8.41(d,J=5.7Hz,1H);8.47-8.50(d,J=7.9Hz,1H);8.92(s,1H).11.65(s,1H).MS(ESI):385.05(C17H13N4O5S[M+H]+).Anal.Calcd for C17H12N4O5S:C,53.12;H,3.15;N,14.58%.Found:C,53.37;H,2.96;N,14.81%.
实施例二十一:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-4-硝基苯甲酰胺(化合物21)的制备。
制备方法同实施例一。以对硝基苯甲酸代替苯乙酸, 得目标化合物。黄色粉末,产率60%.m.p.316-317℃;1H NMR(300MHz,CDCl3):3.48-3.50(m,4H);4.32-4.35(m,3H);6.9 1-7.04(m,1H);7.60-7.67(m,1H);8.30-8.43(m,2H).11.45(s,1H).MS(ESI):385.05(C17H13N4O5S[M+H]+).Anal.Calcd for C17H12N4O5S:C,53.12;H,3.15;N,14.58%.Found:C,53.37;H,2.96;N,14.81%.
实施例二十二:N-(5-(2,3-二氢苯并[b][1,4]二噁烷-6-基)-1,3,4-噻二唑-2-基)-2-苯氧基乙酰胺(化合物22)的制备。
制备方法同实施例一。以苯氧基醋酸代替苯乙酸,得目标化合物。白色粉末,产率65%.m.p.302-304℃;1H NMR(300MHz,CDCl3):4.27-4.32(m,4H);4.68(s,2H);6.91-6.93(d,J=8.2Hz,1H);6.96-6.99(m,2H);7.02-7.07(m,1H);7.31-7.37(m,3H);7.39-7.40(m,1H).12.23(s,1H).MS(ESI):370.08(C18H16N3O4S[M+H]+).Anal.Calcd for C18H15N3O4S;C.58.53;H,4.09;N,11.38%.Found:C,58.72;H,4.31;N,11.14%.
实施例二十三:含1,4-苯并二噁烷的噻二唑衍生物抗菌活性研究
1.实验材料和方法
1.1药品与试剂
Mueller-Hinton培养基(牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中)、卡那霉素、青霉素、DMSO、MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名为噻唑蓝)、异丙醇、盐酸、均为分析纯试剂、合成的化合物1-22、PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.12H2O 2.9g,KH2PO4 0.2g,NaCl 8.0g,KCl 0.2g,蒸馏水1000mL)。
1.2菌种
大肠杆菌(E.coli)、金黄色葡萄球菌(S.aureus)、枯草芽孢杆菌(B.subtilis)、铜绿假单胞菌(P.aeruginosa)
1.3实验方法
1.3.1培养基的配制
取牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中,加热煮沸溶解,分装,121℃高压火菌15分钟备用。
1.3.2试验菌的培养
在无菌室内,取大肠杆菌,金黄色葡萄球菌,枯草芽孢杆菌和铜绿假单胞菌四种试验菌株,于酒精灯下用接种针分别在四种试验菌株斜面上,刮取少量斜面菌苔,用一定量的无菌水制成菌恳液,然后取一定量加到已融化又冷却至50℃左右的MH培养基中,摇匀,即刻倒入无菌培养皿中,待充分冷凝后用胶塞密封后,于37℃培养18-24小时备用。吸取菌液1mL,用MH培养基按1∶1000稀释,使菌液浓度药为105cfu/mL。
1.3.3抗菌实验:
将待测药品溶于DMSO中配制成2mg/mL的溶液,然后用二倍稀释法将药品稀释成一定浓度梯度(50μg/mL,25μg/mL,12.5μg/mL,3.125μg/mL)与DMSO中。于灭菌微量滴定板第一条中分别加入100uL的培养基,第二条为阳性对照,加入100μL菌悬液。其余的孔中加入90μL的菌悬液和10μL的药物溶液。每个药物溶液浓度平行3次。在微量滴定板底部标明细菌名称。将处理完的培养皿于37℃培养24h,观察。
1.3.4 MIC的测定
在每个微量滴定板都可以直观的测定其MIC值之后,在板的每个孔中加入50μL PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH 7.4,Na2HPO4.2H2O 2.9g,KH2PO4 0.2g,NaCl 8.0g,KCl 0.2g,蒸馏水1000mL),其中包含2mgMTT/mL。在室温下继续孵育4-5h。将孔中的物质移出并加入100μL含有5%1mol/L HCl的异丙醇来萃取染料。继续在室温下赋育12h,于酶标仪测定各孔光吸收(OD值),测定波长550nm。根据各孔OD值计算药物对细菌生长的最小抑制浓度。
最小抑制浓度(minimum inhibitory concentration,MIC):在特定环境下孵育24小时,可抑制某种微生物出现明显增长的最低药物浓度即最小抑制浓度,根据测定的光密度(OD值),制作细菌生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的MIC见表1所示
2.实验结果
表1 本发明所列含1,4-苯并二噁烷的噻二唑衍生物对细菌的抑制MIC值(μg/mL)
Kanamycin;Penicillin:阳性对照
Claims (3)
2.一种制备权利要求1所述的含1,4-苯并二噁烷的噻二唑衍生物的方法,其特征是它由下列步骤组成:
步骤1.将0.1mol 1,4-苯并二噁烷-6-羧酸,0.1mol氨基硫脲,25mL三氯氧磷置于带有回流装置的圆底烧瓶中,油浴加热,在75℃下回流反应4h。冷却至室温。
步骤2.往冷却产物后的圆底烧瓶中缓缓加入110mL水,然后油浴加热。在110℃下回流反应6h,放置冷却。
步骤3.用50%氢氧化钾溶液调至pH 8,析出固体。趁热抽滤,黄色沉淀用乙醇重结晶,干燥后得产物。
步骤4.将步骤3中得到的黄色产物溶于二氯甲烷中,然后加入各种取代的芳香酸或者脂肪酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)、1-羟基-苯并-三氮唑(HoBt),室温反应8个小时。其中反应物黄色固体与各种取代的芳香酸或者脂肪酸的摩尔比是1∶1,与1-(3-二甲氨基丙基)-3-乙基碳二亚胺(EDC)的摩尔比是1∶1.5,与1-羟基-苯并-三氮唑(HoBt)的摩尔比是1∶0.05。
步骤5.反应完全后,用乙酸乙酯萃取,有机层用饱和食盐水洗(饱和食盐水与反应物的摩尔比为100∶1),然后用无水Na2SO4干燥,溶剂减压蒸干,得到的粗产物用无水乙醇重结晶得到本发明的含1,4-苯并二噁烷的噻二唑衍生物。
3.权利要求1所述的含1,4-苯并二噁烷的噻二唑衍生物在制备抗菌药物中的应用。
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CN114605352A (zh) * | 2022-04-22 | 2022-06-10 | 江苏海洋大学 | 含1,3,4-噻二唑酰胺的没食子酸类衍生物及制法与用途 |
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CN1085217A (zh) * | 1992-08-11 | 1994-04-13 | 默克专利股份有限公司 | 1,4-苯并二噁烷衍生物 |
CN1120041A (zh) * | 1994-02-25 | 1996-04-10 | 阿迪尔公司 | 新型苯并二噁烷,它们的制备方法以及含这些化合物的药物组合物 |
CN101879161A (zh) * | 2010-07-15 | 2010-11-10 | 张康 | N-(4-(1氢-吡唑-4-)苯基)-2,3-二氢-1,4-苯并二噁烷-2-酰胺衍生物在制备治疗青光眼的药物中的用途 |
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CN1085217A (zh) * | 1992-08-11 | 1994-04-13 | 默克专利股份有限公司 | 1,4-苯并二噁烷衍生物 |
CN1120041A (zh) * | 1994-02-25 | 1996-04-10 | 阿迪尔公司 | 新型苯并二噁烷,它们的制备方法以及含这些化合物的药物组合物 |
CN101879161A (zh) * | 2010-07-15 | 2010-11-10 | 张康 | N-(4-(1氢-吡唑-4-)苯基)-2,3-二氢-1,4-苯并二噁烷-2-酰胺衍生物在制备治疗青光眼的药物中的用途 |
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CN108395426A (zh) * | 2018-04-27 | 2018-08-14 | 铜仁学院 | 含噻二唑与喹啉结构Schiff碱类衍生物及制备应用 |
CN108395426B (zh) * | 2018-04-27 | 2020-03-24 | 铜仁学院 | 含噻二唑与喹啉结构Schiff碱类衍生物及制备应用 |
CN114605352A (zh) * | 2022-04-22 | 2022-06-10 | 江苏海洋大学 | 含1,3,4-噻二唑酰胺的没食子酸类衍生物及制法与用途 |
CN114605352B (zh) * | 2022-04-22 | 2023-04-25 | 江苏海洋大学 | 含1,3,4-噻二唑酰胺的没食子酸类衍生物及制法与用途 |
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