CN112645975A - 硅-邻菲罗琳衍生物及其制备和用途 - Google Patents
硅-邻菲罗琳衍生物及其制备和用途 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及药物化学和药理学研究成果,特别是一类硅-邻菲罗琳衍生物、制备该类化合物的方法与用途。
背景技术
微生物感染致病己成为威胁人类和动物健康的重要原因,因此研究各种新的高效、安全、稳定的抗菌药物成为国内外医药领域的热点。尽管已经发现并研发出了不少具有抗菌效果的药物。但是随着各类抗生素的滥用,部分细菌已出现明显的抗药特性。此外,市场也需要抗菌谱广的化合物,用于混合型感染(如手术后、免疫力降低患者)或者未明原因的动物感染。针对目前抗菌药的抗菌潜能几乎已经被开发殆尽,我们开发了新型结构的化合物,用于抑制细菌和真菌的生长繁殖。
配合物是由中心原子稳定、与配位体以配位键方式连接的一类化合物。常见的配合物为过渡金属配合物。但由于金属配合物在体内蓄积时,其金属毒性往往难以避免,因此我们开发了以硅原子为中心原子的配合物。硅原子具有明显优于过渡金属的优点,例如缺乏毒性和配位中的高稳定性。以邻菲啰啉和联苯吡啶为配位体的八面体硅配合物,具有广谱的抗菌活性,可用于体内外的细菌或真菌感染的治疗。
发明内容
有鉴于此,为了解决上述问题,本发明公开了一类新的硅-邻菲罗琳衍生物、制备该类化合物的方法和用途。该类配合物制备方法简单,易操作,适合扩大化生产。对金黄色葡萄球菌、大肠杆菌等细菌,隐球菌、白色念珠菌等真菌具有抑菌、杀菌作用。该类配合物可以用药学可接受的载体或赋形剂混合制备成抗细菌和/或抗真菌药物。
本发明的目的之一提供一类新的硅-邻菲罗琳衍生物。
本发明的目的之二是提供上述化合物的制备方法。
本发明的目的之二是提供上述化合物的用途。
本发明公开的一类硅-邻菲罗琳衍生物,具体包括:
以硅原子为中心,2分子1,10-邻菲啰啉及其衍生物和1分子4,4'-二壬基 -2,2'-联吡啶为结构的配合物。结构式如下所示:
其中R为氢、烷基(甲基、乙基)或芳香基(苯基、甲苯基或乙苯基)。该类化合物形成的盐为与药学上的无机酸或有机酸形成的盐,其中无机酸或有机酸包括硫酸、盐酸、硝酸、六氟磷酸、醋酸、草酸、柠檬酸、苹果酸等。
上述化合物的制备方法,包括以下步骤:
将2mol的邻菲啰啉或其衍生物和1mol的4,4'-二壬基-2,2'-联吡啶溶解到10mL二甲基甲酰胺(DMF)中,在低温下加入适量氯化锂,搅拌均匀后加入1mol的四氯化硅,反应6h后抽滤,烘干后得到目标产物。
上述化合物的用途,具体涉及:
推荐用于金黄色葡萄球菌、大肠杆菌等细菌,隐球菌、白色念珠菌等真菌的抑菌、杀菌作用。可以用药学可以接受的载体或赋形剂混合制备成抗细菌和/或抗真菌药物。
本发明的其它优点、目标和特征在某种程度上将在随后的说明书中进行阐述,并且在某种程度上,基于对下文的考察研究对本领域技术人员而言将是显而易见的,或者可以从本发明的实践中得到教导。本发明的目标和其他优点可以通过下面的说明书,权利要求书来实现和获得。
附图说明
为了使本发明的目的、技术方案和优点更加清楚,下面将结合附图对本发明作进一步的详细描述,其中:
图1口服邻菲啰啉联苯吡啶硅配合物对隐球菌所致肺部感染小鼠的抗菌作用。硅配合物可明显清除肺部感染的真菌,其中低剂量(2mg/kg)可达到临床用药氟康唑(8mg/kg)的效果。
具体实施方式
下面将结合实例对本发明的实施方案进行详细说明,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或者按照制造商建议的条件执行,所用试剂或仪器未注明生产厂商者,均为可通过市购获得的常规产品。
以下对采用本发明的方法用于对硅-邻菲罗琳衍生物的制备和用途研究为例进行详细的描述。
实施例1
硅-邻菲啰啉配合物(化合物1),结构如下:
将2mol的1,10-邻菲啰啉和1mol的4,4'-二壬基-2,2'-联吡啶溶解到10mL 的二甲基甲酰胺(DMF)中,在低温下加入适量氯化锂,搅拌均匀后加入1mol 的四氯化硅,反应6h后抽滤,烘干后得到硅-邻菲啰啉配合物。将硅-邻菲啰啉配合物经阴离子交换树脂处理后,可得到配合物盐。
实施例2
硅-四甲基邻菲啰啉配合物(化合物2),结构如下:
将2mol的3,4,7,8-四甲基-1,10-菲罗啉和1mol的4,4'-二壬基-2,2'-联吡啶溶解到10mL的二甲基甲酰胺(DMF)中,在低温下加入适量氯化锂,搅拌均匀后加入1mol的四氯化硅,反应6h后抽滤,烘干后得到硅-四甲基邻菲啰啉配合物。
实施例3
硅-二苯基邻菲啰啉配合物(化合物3),结构如下:
将2mol的4,7-二苯基-1,10-菲啰啉和1mol的4,4'-二壬基-2,2'-联吡啶溶解到10mL的二甲基甲酰胺(DMF)中,在低温下加入适量氯化锂,搅拌均匀后加入1mol的四氯化硅,反应6h后抽滤,烘干后得到硅-二苯基邻菲啰啉配合物。
该专利描述的化合物的制备方法总结:
该类配合物制备方法简单,易操作,适合扩大化生产。
实施例4
本发明中,陈述的部分化合物的抗菌活性测定。
选取本发明陈述的部分化合物,采用符合美国国家委员会制定的临床实验标准(Clinical and Laboratory Standards Institute,CLSI)的96孔微量稀释法,分别测定硅-邻菲啰啉(化合物1)、硅-四甲基邻菲啰啉配合物(化合物2)、硅-二苯基邻菲啰啉配合物(化合物3)对革兰氏阳性菌(金黄色葡萄球菌)、革兰氏阴性菌(大肠杆菌)和真菌(白色念珠菌、新型隐球菌)的最低抑菌浓度 (MIC)、最低杀菌浓度(MBC)和半数有效量(IC50)。
实验的具体步骤为:
·将待测配合物用少量DMSO溶解,再加水稀释制成浓度为1mg/mL的溶液,再用培养液稀释至不同浓度,37℃培养12-72h;
·将培养板至振荡器上充分摇匀后,在波长600nm处测定吸光度,测得配合物抑制微生物的MIC、MBC和IC50值。
测定化合物1、化合物2和化合物3对金黄色葡萄球菌、大肠杆菌、白色念珠菌、隐球菌等的MIC、MBC、IC50,综合判定各药物的体外抗菌活性。结果见表1至表3。
结果表明,化合物1、化合物2和化合物3对金黄色葡萄球菌、大肠杆菌、白色念珠菌、隐球菌均有抗菌效果,其中无取代基团的化合物1活性较弱,而化合物2与化合物3的抗菌作用相当。但化合物3对白色念珠菌的抑制作用 (MBC为8μg/ml)略强于化合物2(MBC为4μg/ml)。
此外,由表1,表2和表3可知,与阳性对照药头孢氨苄和氟康唑相比,本发明中硅-邻菲罗琳配合物的抗菌谱更为广泛,对体外对革兰氏阳性菌和革兰氏阴性菌、真菌都具有比较明显的杀灭作用。
表1各配合物的MIC值
表2各配合物的IC50值
表3各配合物的MBC值
实施例5
本发明中,陈述的部分化合物的体内抗隐球菌感染作用测定。实验具体步骤为:
·将小鼠分为4组,分别为正常对照组、模型组、阳性对照组(氟康唑组)、硅-邻菲啰啉衍生物按低剂量(2mg/kg/day)和高剂量(4mg/kg/day) 组。
·将数量为1×108的隐球菌静脉注射给小鼠制备隐球菌感染的小鼠模型。
·在隐球菌注射后8h,给予药物治疗:阳性对照组是将氟康唑(8 mg/kg/day)腹腔注射给予新型隐球菌感染的小鼠,而硅-邻菲啰啉衍生物是将硅-邻菲啰啉配合物灌胃给予隐球菌感染的小鼠,各组小鼠均连续给药5天。仅给予生理盐水的模型组小鼠作为模型组。
结果表明,将陈述的部分化合物的低、高剂量(SC 2mg/kg/day、SC 4 mg/kg/day)和阳性对照药氟康唑(8mg/kg/day)分别给予隐球菌感染的小鼠,连续给药5天。未经处理的感染小鼠逐渐出现精神萎靡、体重下降且毛色暗淡、偏瘫等症状,5天后死亡。硅-邻菲啰啉配合物(化合物1)给药后,高剂量组没有出现明显的上述感染症状,低剂量组症状好转,氟康唑给药组与硅-邻菲啰啉配合物低剂量组疗效相似。
HE染色显示(图1),硅-邻菲啰啉配合物(化合物1)高、低剂量组的小鼠肺组织的菌落数显著低于模型组,且肺组织病理损害明显改善。硅-邻菲啰啉配合物的抗菌效果优于氟康唑组,且随着配合物剂量的增加,肺组织病理损害的改善越显著。
该专利描述的化合物的活性及用途总结:
对金黄色葡萄球菌、大肠杆菌等细菌,隐球菌、白色念珠菌等真菌具有抑菌、杀菌作用。该类配合物可以用药学可以接受的载体或赋形剂混合制备成抗细菌和/或抗真菌药物。
以上所述仅为本发明的优选实施例,并不用于限制本发明,显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
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