CN113827592A - 一种噻二唑烷二酮基化合物在治疗致病性感染中的应用 - Google Patents
一种噻二唑烷二酮基化合物在治疗致病性感染中的应用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Oncology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种噻二唑烷二酮基化合物在治疗致病性感染中的应用。具体而言，本发明涉及一种噻二唑烷二酮基化合物或其药学上可接受的盐或水合物在抑菌和杀菌方面的用途。
Description
技术领域
本发明设计药物化学领域，具体地是涉及一种噻二唑烷二酮基化合物或其药学上可接受的盐，以及它的制备方法和用途。所述的一种噻二唑烷二酮基化合物可以用来治疗感染，如葡萄球菌、耐甲氧西林葡萄球菌的感染，因此可能在细菌感染的疾病的防止药物中有所运用。
背景技术
自1928年弗莱明发现青霉素以来，抗生素的发现以及临床使用将人均寿命延长了10-15年，是人类医学史上的伟大发明。目前临床常用的抗生素包括β-内酰胺类、氨基糖苷类、大环内酯类、林可霉素类、多肽类、喹诺酮类、磺胺类等。其作用机制主要包括抑制核酸的合成、抑制蛋白质的合成、抑制细胞壁的合成、改变细胞膜的通透性。然而传统的抗生素对致病菌和益生菌并没有选择性，因此会带来诸多的副作用：导致人体菌群失调，细菌的耐药性增加或者二重感染等不良反应；产生再生障碍性贫血；出现皮疹或血管神经性水肿等过敏反应；引发哮喘肥胖等。
然而自20世纪70年代末，新型抗生素的研发速度减慢，1984年以来几乎没有全新骨架结构的抗生素上市。伴随的是，由于抗生素杀菌导致的全球范围内细菌耐药的不断加剧，使得人类面临步入“后抗生素时代”(有抗生素，但都已失效)的健康风险。世界卫生组织预测，2050年，全球由抗生素造成的死亡人数将超1000万，抗生素对人类的危害或将超过癌症。实验科学表明，细菌的致病性与细菌的毒力因子有关，毒力因子可以帮助细菌的定植、粘附、细胞毒性、免疫逃避等，并成功感染宿主。由于细菌耐药的不断产生，抗细菌毒力的药物正在成为新型抗细菌感染药物研究所关注的热点。
细菌的生物膜也称为生物被膜，是指附着于生命或无生命体表面被细菌胞外大分子包裹的有组织的细菌群体。生物膜的产生会增强细菌对抗生素和宿主免疫防御机制的抗性。1978年，卡尔加里大学Bill Costerton在研究寄居在牛胃部的细菌时发现，细菌总是以粘附的形态出现在牛的粘膜表面，这和细菌以游离态在试管中培养时大不相同，他把这种和牙菌斑类似的粘附形态称作生物膜。随后，他首次提出了细菌生物膜可以极大的提高细菌对抗生素的耐受性的研究课题。据估计，人类65％的细菌性感染与生物膜有关。抗细菌毒力的药物可以在不影响细菌正常生长状态下，抑制细菌生物膜的形成，降低细菌的毒力，从而缓解细菌耐药的难题。
综上所述，本领域尚缺乏一种高效的细菌生物膜抑制剂。
发明内容
本发明的目的是提供一种高效的细菌生物膜抑制剂。
本发明的第一方面，提供了一种噻二唑烷二酮基化合物，或其药学上可接受的盐或水合物在制备治疗动物致病性感染的药物组合物中的用途，所述的化合物具有如下式I所示的结构：
式中，
X和Y各自独立选自O、S、NR、C(R)2；
Ra和Rb各自独立地选自：H、取代或未取代的C1-8烷基、取代或未取代的C1-4烯基、取代或未取代的C3-8环烷基、取代或未取代的C6-10芳基、取代或未取代的C7-12芳烷基和取代或未取代的(-C1-4亚烷基-COO-C1-8烷基)、取代或未取代的(-(Z)n-C6-10芳基)、取代或未取代的(-(Z)n-5-12元杂芳基)、取代或未取代的5-12元杂芳基，取代或未取代的5-12元杂环基，-OR3，-C(O)R3，-C(O)OR3，-(Z)nC(O)OR3、-(Z)nC(O)NR3、-C＝NR3-CN，-OC(O)R3和-S(O)t-R3；
n为0、1或2；
t是0、1或2；
R3和R4独立地选自氢，取代或未取代的C1-8烷基、取代或未取代的C6-10芳基、取代或未取代的C7-12芳烷基、取代或未取代的5-12元杂芳基，取代或未取代的5-12元杂环基；和
各个Z各自独立地选自-C(R3)(R4)-，-C(O)-，-O-，-C(＝NR3)-，-S(O)t-和-N(R3)；
R选自下组：氢，取代或未取代的C1-8烷基；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：C1-8烷基、C3-8环烷基、芳基和芳烷基任选地被1-3个选自C1-8烷基、C1-4烷氧基、卤代C1-8烷基、卤素，或位于相邻碳原子上的两个取代基与其连接的碳原子形成5-7元碳环或5-7元杂环。
在另一优选例中，所述X和Y都是O；或者所述X是O，Y是S。
在另一优选例中，所述的Ra选自下组：取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、或取代或未取代的C7-12芳烷基；优选地，所述的取代指基团上的1-3个H原子被选自下组的取代基取代：C1-8烷基、C1-4烷氧基、卤代C1-8烷基和卤素的取代基。
在另一优选例中，所述的Rb选自下组：取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C6-10芳基、取代或未取代的C7-12芳烷基、取代或未取代的(-(Z)n-5-12元杂芳基)。
在另一优选例中，所述式I化合物具有下式III所示的结构：
其中，各个R1各自独立选自下组：羟基、C1-8烷基、C1-4烷氧基、卤代C1-8烷基、羧基和卤素；和
n选自0、1、2和3。
在另一优选例中，所述的噻二唑烷二酮基化合物为CN 107151235 A、WO 2008/057933 A2、WO 2006/084934 Al、WO 2006/045581、及/或WO 2005/097117 Al中记载的噻二唑烷二酮基化合物中的任意一种以上的化合物。
在另一优选例中，所述的化合物具有选自下组的结构：
在另一优选例中，所述的病症为病原体感染。
在另一优选例中，所述的病原体感染是细菌感染。
在另一优选例中，所述细菌感染是革兰氏阳性菌感染。
在另一优选例中，所述的细菌为革兰氏阳性菌；优选地，所述细菌为葡萄球菌、耐甲氧西林葡萄球菌、耐青霉素肺炎链球菌、耐万古霉素金黄色葡萄球菌
在另一优选例中，所述的病原体感染可以由一种或多种细菌引发。
在另一优选例中，所述的动物是人类或家养动物。
在另一优选例中，所使用方法可以是单独使用或者与常用抗菌药物联用。
在另一优选例中，所述的药物组合物用于降低细菌的致病性和/或毒性。
在另一优选例中，所述的药物组合物是抑制细菌生物膜形成的药物组合物。
在另一优选例中，所述的药物组合物是细菌的生物膜形成过程中关键酶SrtA抑制剂。
在另一优选例中，所述的药物组合物是细菌的生物膜形成抑制剂类抗菌药物。
本发明的第二方面，提供了一种选自下组的化合物：
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为化合物1和32抑制Nweman生物膜形成结果图；
图2为化合物TD处理后的S.aureus USA300感染小鼠模型实验。
具体实施方式
本发明人通过药物筛选研究，发现一种噻二唑烷二酮基化合物可以抑制细菌生物膜的形成，降低细菌的致病力，可以用于制备抗菌药物，且所述的药物具有非常优异的抑菌活性。基于上述发现，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C1-C4烷氧基”是指具有1-4个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“C6-10元芳基”是指具有6-10个碳原子的芳基，例如，萘基、蒽基、菲基或类似基团。
如本文所用，术语“5-12元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别限定了“取代的或未取代的”及其定义，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
如本文所用，术语“药学上可接受的盐”包括式(I)化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、乳酸、草酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、苯甲酸、甲磺酸、对甲苯磺酸、水杨酸、苯基乙酸、杏仁酸，此外还包括无机碱的酸式盐。
噻二唑烷二酮基化合物的应用
本发明提供了一种噻二唑烷二酮基化合物的用途，其用作制备药物组合物，且所述的药物组合物可以作为：
a.细菌的生物膜形成抑制剂；和/或
b.细菌的生物膜形成过程中关键酶SrtA抑制剂；和/或
c.细菌的生物膜形成抑制剂类抗菌药物。
所述的药物组合物可以用于抑制葡萄球菌、耐甲氧西林葡萄球菌、耐青霉素肺炎链球菌、耐万古霉素金黄色葡萄球菌、铜绿假单胞菌和肠杆菌的生物膜形成。
含有噻二唑烷二酮基化合物的药物组合物
由于本发明的噻二唑烷二酮基化合物可以用作细菌抑制剂，用于抑制细菌生物膜的形成，因此该化合物及其药学上可接受的盐或水合物可以用于制备相应的药物组合物，所述药物组合物包括：
(1)如本发明第一方面所述的化合物、或其药学上可接受的盐。
(2)本发明第二方面提供的药物组合物；和/或
选自下组的药物：
β-内酰胺酶抑制剂、氨基糖苷类、大环内酯类、林可霉素类、磺胺类、青霉素类、头孢菌素类、氨基糖苷类、糖肽类、酰胺类、四环素类、硝咪唑类、喹诺酮类、或其组合。
在另一优选例中，所述β-内酰胺酶抑制剂选自下组：阿莫西林克拉维酸、替卡西林克拉维酸、氨苄西林舒巴坦、舒拉西林舒巴坦、头孢哌酮舒巴坦、哌拉西林三唑巴坦、或其组合。
在另一优选例中，氨基糖苷类选自下组：链霉素、卡那霉素、妥布霉素、新霉素、大观霉素、庆大霉素、西索米星、小诺米星、阿米卡星、奈替米星、或其组合。
在另一优选例中，所述大环内酯类选自下组：红霉素、乙酰螺旋霉素、琥乙红霉素、依托红霉素、阿奇霉素、罗红霉素、吉他霉素、麦白霉素、克拉霉素、泰利霉素、或其组合。
在另一优选例中，所述林可霉素类选自下组：林可霉素和克林霉素、或其组合。
在另一优选例中，所述磺胺类选自下组：异烟肼、利福平、盐酸乙胺丁醇、吡嗪酰胺、磺胺甲恶唑、甲氧苄啶、或其组合。
在另一优选例中，所述青霉素类选自下组：青霉素V、甲氧西林、苯唑西林、氯唑西林、双氯西林、氨苄西林、阿莫西林、羧苄西林、哌拉西林、美西林、替莫西林、长效西林、或其组合。
在另一优选例中，所述头孢菌素类选自下组：头孢唑林，头孢拉定、头孢羟氨苄、头孢克洛、头孢氨苄、头孢孟多、头孢呋辛、头孢西丁、头孢噻肟钠、头孢唑肟、头孢他啶、头孢曲松、头孢咪唑、头孢匹罗、头孢唑喃、或其组合。
在另一优选例中，所述氨基糖苷类选自下组：链霉素、卡那霉素、新霉素、妥布霉素、庆大霉素、阿米卡星、依替米星、或其组合。
在另一优选例中，所述糖肽类选自下组：万古霉素、去甲万古霉素、替考拉宁、欧利万星、达巴万星、泰拉万星、雷莫拉宁、或其组合。
在另一优选例中，所述酰胺类选自下组：氯霉素。
在另一优选例中，所述四环素类选自下组：米诺环素、多西环素、美他环素、金霉素、四环素、土霉素、或其组合。
在另一优选例中，所述硝咪唑类选自下组：甲硝唑、替硝唑、奥硝唑、或其组合。
在另一优选例中，所述喹诺酮类选自下组：诺氟沙星、氧氟沙星、环丙沙星、氟罗沙星、或其组合。
在本发明范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以相互结合，从而构成新的或优选的技术方案。
与现有技术相比，本发明的主要优点包括：
(1)提供了一种噻二唑烷二酮基化合物、或其药学上可接受的盐；
(2)提供了一种细菌生物膜形成的小分子抑制剂，所述的抑制剂可以抑制细菌中的转肽酶SrtA，从而降低细菌的毒力因子；
(3)提供了一类治疗致病菌感染相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
本发明的化合物的合成参考专利WO 2006/045581中的合成方法，选用对应的底物片段进行，依据专利中的合成方法，本发明获得的化合物数据如下：
实施例1 4-(2-羟基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色色固体，收率是14.6％，1H NMR(400MHz,DMSO)δ9.78(s,1H),8.10(t,J＝7.2Hz,2H),7.93(d,J＝7.6Hz,1H),7.80(d,J＝7.3Hz,1H),7.77–7.55(m,3H),7.13(d,J＝7.3Hz,2H),6.85(dd,J＝15.4,7.6Hz,2H),4.86(s,2H).
实施例2 4-(3-羟基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率是5.0％，1H NMR(400MHz,DMSO)δ9.54(s,1H),8.10(t,J＝8.2Hz,2H),7.98–7.84(m,1H),7.79(d,J＝7.1Hz,1H),7.74–7.51(m,3H),7.19(t,J＝8.0Hz,1H),6.82(d,J＝6.5Hz,2H),6.73(d,J＝8.8Hz,1H),4.81(s,2H).
实施例3 4-(4-羟基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率是18.4％，1H NMR(400MHz,DMSO)δ9.51(s,1H),8.09(dd,J＝10.0,5.9Hz,2H),7.85(dd,J＝6.1,3.5Hz,1H),7.77(d,J＝7.0Hz,1H),7.69–7.57(m,3H),7.23(d,J＝8.5Hz,2H),6.78(d,J＝8.5Hz,2H),4.77(s,2H).
实施例4 4-(4-氟苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率67％，1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.1Hz,1H),7.80(d,J＝8.2Hz,1H),7.75–7.59(m,3H),7.58–7.48(m,3H),7.38(d,J＝8.3Hz,2H),4.96(s,2H).
实施例5 4-(4-氯苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率67％，1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.1Hz,1H),7.80(d,J＝8.2Hz,1H),7.75–7.59(m,3H),7.58–7.48(m,3H),7.38(d,J＝8.3Hz,2H),4.96(s,2H).
实施例6 4-(3,4-二氯苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率75％，1H NMR(400MHz,DMSO-d6)δ8.30(d,J＝8.3Hz,1H),8.09(d,J＝7.8Hz,1H),7.85(s,2H),7.83–7.75(m,2H),7.73–7.62(m,3H),7.43(d,J＝8.2Hz,1H),4.90(s,2H).
实施例7 4-(4-甲基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率70％，1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ8.41–8.34(m,1H),7.85–7.81(m,1H),7.72–7.66(m,2H),7.64(d,J＝7.9Hz,1H),7.59(s,1H),7.53(d,J＝8.0Hz,1H),7.46(d,J＝8.0Hz,2H),7.22(d,J＝7.8Hz,2H),4.97(d,J＝3.3Hz,2H),2.39(s,3H).
实施例8 4-甲基-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率是56％，1H NMR(400MHz,CDCl3)δ7.97(t,J＝7.6Hz,2H),7.87(d,J＝8.1Hz,1H),7.68–7.50(m,4H),3.40(s,3H).
实施例9 4-乙基-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率47％，1H NMR(400MHz,DMSO)δ8.09(dd,J＝10.5,5.2Hz,2H),7.95–7.88(m,1H),7.78(d,J＝7.3Hz,1H),7.64(dq,J＝15.1,7.5Hz,3H),3.76(q,J＝7.1Hz,2H),1.27(t,J＝7.1Hz,3H).
实施例10 4-正丁基-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率60％，1H NMR(400MHz,DMSO)δ8.09(t,J＝7.2Hz,2H),7.89(d,J＝7.8Hz,1H),7.77(d,J＝7.3Hz,1H),7.70–7.58(m,3H),3.72(t,J＝7.1Hz,2H),1.77–1.55(m,2H),1.38(dd,J＝14.8,7.4Hz,2H),0.94(t,J＝7.3Hz,3H).
实施例11 2-(1-萘基)-4-苯乙基-1,2,4-噻二唑-3,5-二酮
白色固体，收率80％，1H NMR(400MHz,CDCl3)δ7.95(m,J＝6.3,5.5,2.3Hz,2H),7.67–7.51(m,5H),7.44–7.30(m,5H),4.15–4.08(m,2H),3.22–3.11(m,2H).
实施例12 2-苄基-4-甲基-1,2,4-噻二唑-3,5-二酮
白色固体，收率52％，1H NMR(400MHz,DMSO)δ7.37(dt,J＝15.3,7.2Hz,5H),4.80(s,2H),3.08(s,3H).
实施例13 2-苄基-4-正丁基-1,2,4-噻二唑-3,5-二酮
白色固体，收率55％，1H NMR(400MHz,CDCl3)δ7.39(dd,J＝13.0,7.5Hz,3H),7.32(d,J＝7.7Hz,2H),4.80(s,2H),3.73(t,J＝7.4Hz,2H),1.75–1.65(m,2H),1.39(dd,J＝15.1,7.5Hz,2H),0.98(t,J＝7.3Hz,3H).
实施例14 2-苄基-4-(2-氯乙基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率66％，1H NMR(400MHz,CDCl3)δ7.45–7.37(m,3H),7.36–7.30(m,2H),4.81(s,2H),4.07(t,J＝6.3Hz,2H),3.80(t,J＝6.3Hz,2H)..
实施例15 2-苄基-4-异丙基-1,2,4-噻二唑-3,5-二酮
白色固体，收率67％，1H NMR(400MHz,CDCl3)δ7.44–7.36(m,3H),7.35–7.30(m,2H),4.78(s,2H),4.59(dt,J＝13.9,6.9Hz,1H),1.52(s,3H),1.50(s,3H).
实施例16 2-苄基-4-(2-氟苄基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率64％，1H NMR(400MHz,DMSO)δ7.41–7.30(m,7H),7.20(t,J＝8.3Hz,2H),4.82(s,2H),4.77(s,2H).
实施例17 2-苄基-4-苄基-1,2,4-噻二唑-3,5-二酮
白色固体，收率23％，1H NMR(400MHz,CDCl3)δ7.49(dd,J＝7.8,1.5Hz,2H),7.45–7.35(m,6H),7.34–7.29(m,2H),4.88(s,2H),4.80(s,2H).
实施例18 2-苄基-4-(2-甲基苄基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率55％，1H NMR(400MHz,DMSO)δ7.43–7.27(m,5H),7.19(dd,J＝18.3,7.8Hz,4H),4.82(s,2H),4.73(s,2H),2.28(s,3H).
实施例19 2-苄基-4-(2-氯苄基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率65％，1H NMR(400MHz,DMSO)δ7.51(dd,J＝8.5,4.6Hz,1H),7.39(dt,J＝12.2,8.2Hz,7H),7.24–7.16(m,1H),4.87(s,2H),4.85(s,2H).
实施例20 2-苄基-4-(3,4-二氯苄基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率62％，1H NMR(400MHz,DMSO)δ7.64(d,J＝8.3Hz,1H),7.59(s,1H),7.44–7.23(m,6H),4.82(s,2H),4.79(s,2H).
实施例21 4-(4-氯苄基)-2-乙基-1,2,4-噻二唑-3,5-二酮
白色固体，收率37％，1H NMR(400MHz,CDCl3)δ7.41(d,J＝8.4Hz,2H),7.35–7.30(m,2H),4.80(s,2H),3.71(q,J＝7.2Hz,2H),1.29(t,J＝7.2Hz,3H).
实施例22 4-(4-甲基苄基)-2-乙基-1,2,4-噻二唑-3,5-二酮
白色固体，收率72％，1H NMR(400MHz,CDCl3)δ7.37(d,J＝7.9Hz,2H),7.17(d,J＝7.8Hz,2H),4.80(s,2H),3.70(q,J＝7.2Hz,2H),2.35(s,3H),1.28(t,J＝7.2Hz,3H).
实施例23 4-苯乙基-2-乙基-1,2,4-噻二唑-3,5-二酮
白色固体，收率49％，1H NMR(400MHz,CDCl3)δ7.36–7.29(m,2H),7.28–7.22(m,3H),3.99–3.88(m,2H),3.73–3.66(m,2H),3.00(dd,J＝8.7,6.8Hz,2H),1.30–1.21(m,3H).
实施例24 2,4-二丁基-1,2,4-噻二唑-3,5-二酮
无色液体，收率58％，1H NMR(400MHz,CDCl3)δ3.66(d,J＝18.5,7.3,1.1Hz,4H),1.71–1.57(m,4H),1.44–1.30(m,4H),0.95(d,J＝7.3,4.4,1.1Hz,6H).
实施例25 4-环己基-2-环戊基-1,2,4-噻二唑-3,5-二酮
无色液体，收率39％，1H NMR(400MHz,CDCl3)δ4.79(dd,J＝15.0,7.6Hz,1H),4.14(tt,J＝12.3,3.9Hz,1H),3.50–3.41(m,1H),2.23(qd,J＝12.4,3.3Hz,2H),2.13–2.01(m,2H),1.86(d,J＝13.7Hz,2H),1.78(ddd,J＝20.3,12.3,9.6Hz,4H),1.71(m,2H),1.58(m,2H),1.43–1.17(m,3H).
实施例26 4-苄基-2-苯乙基-1,2,4-噻二唑-3,5-二酮
无色液体，收率21％，1H NMR(400MHz,CDCl3)δ7.48–7.14(m,10H),4.81(s,2H),3.90(t,J＝7.2Hz,2H),2.96(t,J＝7.2Hz,2H).
实施例27 4-环己基-2-苯乙基-1,2,4-噻二唑-3,5-二酮
无色液体，收率28％，1H NMR(400MHz,CDCl3)δ7.34(t,J＝7.1Hz,2H),7.28(q,J＝2.9Hz,1H),7.24(dd,J＝7.7,6.3Hz,2H),4.18–4.03(m,1H),3.87(t,J＝7.3Hz,2H),2.96(t,J＝7.3Hz,2H),2.20(qd,J＝12.4,3.2Hz,2H),1.86(d,J＝13.5Hz,2H),1.68(t,J＝11.6Hz,3H),1.41–1.16(m,3H).
实施例28 4-异丙基-2-苯乙基-1,2,4-噻二唑-3,5-二酮
无色液体，收率26％，1H NMR(400MHz,CDCl3)δ7.37–7.30(m,2H),7.30–7.26(m,1H),7.24(dd,J＝6.9,5.5Hz,2H),4.51(dt,J＝13.9,6.9Hz,1H),3.87(t,J＝7.3Hz,2H),2.96(t,J＝7.2Hz,2H),1.46(s,3H),1.44(s,3H).
实施例29 2-(4-苯基[d][1,3]-二氧戊烷)-4-苄基-1,2,4-噻二唑-3,5-二酮
白色固体，收率42％，1H NMR(400MHz,CDCl3)δ7.52(dd,J＝7.7,1.7Hz,2H),7.42–7.33(m,3H),6.98–6.82(m,3H),6.07(s,2H),4.94(s,2H).
实施例30 4-苄基-4-(2,3-二氢茚)-1,2,4-噻二唑-3,5-二酮
白色固体，收率24％，1H NMR(400MHz,CDCl3)δ7.53(dd,J＝7.7,1.5Hz,2H),7.43–7.32(m,3H),7.27(s,1H),7.22(t,J＝7.5Hz,1H),7.16(d,J＝7.5Hz,1H),4.94(s,2H),2.99(t,J＝7.5Hz,2H),2.90(t,J＝7.4Hz,2H),2.22–2.06(m,2H).
实施例31 4-苄基-4-(5,6,7,8-四氢萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率21％，1H NMR(400MHz,CDCl3)δ7.52(dd,J＝7.7,1.6Hz,2H),7.38(d,J＝7.7Hz,3H),7.17(t,J＝4.7Hz,3H),4.94(s,2H),2.82(s,2H),2.64(s,2H),1.81(d,J＝2.8Hz,4H).
实施例32 4-苄基-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率57％，1H NMR(400MHz,DMSO)δ7.59–7.13(m,5H),4.83(s,2H),2.39(s,3H),2.16(s,3H).
实施例33 4-乙基-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
无色液体，收率41％，1H NMR(400MHz,CDCl3)δ3.86(q,J＝7.2Hz,2H),2.42(s,3H),2.25(s,3H),1.35(t,J＝7.2Hz,3H).
实施例34 4-正丁基-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
无色液体，收率41％，1H NMR(400MHz,CDCl3)δ3.85–3.74(m,2H),2.42(s,3H),2.26(s,3H),1.78–1.69(m,2H),1.42(dd,J＝15.2,7.5Hz,2H),1.00(t,J＝7.4Hz,3H).
实施例35 4-异丙基-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
无色液体，收率41％，1H NMR(400MHz,CDCl3)δ4.63(dt,J＝13.8,6.9Hz,1H),2.41(s,3H),2.24(s,3H),1.55(d,J＝6.9Hz,6H).
实施例36 4-(4-甲基苯基)-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率81％，1H NMR(400MHz,CDCl3)δ7.39(d,J＝8.0Hz,2H),7.20(d,J＝7.8Hz,2H),4.89(s,2H),2.40(s,3H),2.37(s,3H),2.23(s,3H).
实施例37 4-(4-甲氧基苯基)-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率83％，1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.6Hz,2H),6.90(d,J＝8.7Hz,2H),4.87(s,2H),3.83(s,3H),2.39(s,3H),2.22(s,3H).
实施例38 4-(3,4-二氯苄基)-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率71％，1H NMR(400MHz,CDCl3)δ7.60(d,J＝2.0Hz,1H),7.47(d,J＝8.2Hz,1H),7.34(dd,J＝8.2,2.0Hz,1H),4.87(s,2H),2.41(s,3H),2.24(s,3H).
实施例39 4-(2-氯苄基)-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率67％，1H NMR(400MHz,CDCl3)δ7.47–7.40(m,1H),7.31(t,J＝3.4Hz,3H),5.09(s,2H),2.43(s,3H),2.27(s,3H).
实施例40 4-(4-氯苄基)-2-(4-3,5-二甲基异噁唑基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率69％，1H NMR(400MHz,CDCl3)δ7.49(dd,J＝8.4,5.4Hz,2H),7.07(t,J＝8.6Hz,2H),4.89(s,2H),2.40(s,3H),2.22(s,3H).
实施例41 4-(2-羧基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率是2.4％，1H NMR(400MHz,DMSO)δ13.29(s,1H),8.09(dd,J＝12.9,5.1Hz,2H),8.03(d,J＝7.6Hz,1H),7.98(d,J＝6.7Hz,1H),7.86(d,J＝6.6Hz,1H),7.75–7.59(m,4H),7.46(t,J＝7.4Hz,1H),7.40(d,J＝7.8Hz,1H),5.30(s,2H).
实施例42 4-(3-羧基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率是5.7％，1H NMR(400MHz,CDCl3)δ8.26(s,1H),8.11(d,J＝7.6Hz,1H),7.94(t,J＝8.3Hz,2H),7.79(d,J＝7.7Hz,2H),7.58(dt,J＝13.5,6.8Hz,3H),7.52(t,J＝7.8Hz,2H),5.06(s,2H).
实施例43 4-(4-羧基苄基)-2-(1-萘基)-1,2,4-噻二唑-3,5-二酮
白色固体，收率是8.3％，1H NMR(400MHz,DMSO)δ13.01(s,1H),8.17–8.04(m,2H),7.99(d,J＝8.2Hz,2H),7.96–7.90(m,1H),7.86–7.77(m,1H),7.72–7.58(m,3H),7.54(d,J＝8.2Hz,2H),4.98(s,2H).
实施例44SDS-PAGE转肽活性实验
使用的转肽反应缓冲液为50mM Tris-HCl、150mM NaCl、5mM CaCl2、pH为7.5。反应体系为50μL，在体系中加入终浓度为200μg/mL的转肽酶SaSrtA，化合物的终浓度为6.25μM-100μM，室温孵育20min，随后加入终浓度为300μg/ml的表面蛋白IsdA和终浓度为3mM的反应底物(Gly)3，37℃水浴条件下反应1.5h，再加入12.5uL5×SDS凝胶上样缓冲液(含有200mMDTT)，于100℃煮沸10min，使反应终止并使蛋白充分变性。样品于12％SDS-PAGE电泳，上样量为10μl，电泳电压150V,电泳时间80min，考马斯亮蓝染色，拍照。
表1.化合物1-40的SDS-PAGE对转肽酶SrtA的抑制活性数据
由表1可以看出，本发明的化合物具有对转肽酶SrtA的抑制活性，说明本发明的化合物可以发展为靶向抑制SrtA转肽酶活性的小分子抑制剂。尤其的，化合物2、3、4、8、9、29、32、33、34、36、37、38、39、40表现出较强的抑制活性，其IC50均小于10μM。
实施例45生物膜形成实验
挑取S.aureus Newman以及S.aureus NewmanΔSrtA单克隆于TSB培养基中过夜培养。次日用新鲜的TSB培养基稀释100倍。将含有不同浓度化合物的培养基200μL加入96孔板中，在37℃培养箱培养18h后，移除培养基，用PBS小心清洗3次，静置使生物膜干燥、固定。然后用0.1％的结晶紫(w/v)染色15min。吸除过量的结晶紫染液，用去离子水清洗3次后拍照。然后用30％(v/v)醋酸溶解结晶紫，在Spectra Max Flex Station 3酶标仪中测定595nm处的吸光度，用于定量。每个样品做3个平行孔。
由图1可知，化合物1和32可以抑制Newman生物膜的形成，结晶紫染色后，从左往右，颜色深度递减，表明生物膜的形成受到化合物1和32的抑制。说明本发明的化合物可以发展成为抑制细菌毒力因子的抗菌药物。
实施例46最小抑菌浓度(MIC)的测定
挑取S.aureus Newman单克隆于TSB培养基中过夜培养。次日用新鲜的TSB培养基稀释1000倍，37℃摇床中培养至A600至0.6-0.8时，用新鲜的TSB培养基稀释400倍。然后取50μL菌液加入到含50μL用TSB培养基稀释的化合物的96孔板中，化合物浓度为0.2-100μg/mL。将96孔板置于37℃培养箱中静置培养16h。次日肉眼观察每个孔的细菌生长情况，每个化合物以不抑制细菌生长的最低浓度为该化合物的MIC值，每个样品做3个平行孔。
由表2可知，部分化合物6、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28表现出抑制细菌生长的能力；而化合物1、2、3、4、5、7、8、9、10、11、29、30、31、32、33、34、35、36、37、38、39、40对细菌的生长不抑制，表明这部分化合物可以应用于抑制细菌的毒力因子。说明本发明的化合物可以发展成为抗细菌致病力的药物。
表2.化合物1-40的对S.aureus Newman的MIC活性数据
实施例47 S.aureus USA300感染小鼠模型实验
挑取S.aureus USA300单克隆于TSB培养基中过夜培养。次日用新鲜的TSB培养基稀释1000倍至30mL，37℃摇床中培养中继续培养3h。菌液3000g离心，用PBS洗涤3次之后，重悬于PBS中，使A600至0.8-1.6。BCLA/c小鼠(6周大雌鼠)随机分为两组。化合物用ddH2O溶解后，每隔24h以40mg/kg的剂量腹腔注射(i.p.)给药。以生理盐水作为对照。第一次给药/生理盐水4h后，对麻醉小鼠眶周注射S.aureus USA300，使之成功感染S.aureus USA300。接种物涂板培养，计数克隆形成单位(CFU)。在10天内观察并记录实验组和对照组小鼠的存活情况，采用对数秩检验对存活率进行分析，绘制生存曲线。
由图2可知，在化合物TD处理之后，感染耐药菌S.aureus USA300的小鼠相对于DMSO组，生存周期明显延长。说明本发明的化合物具有一定的药效，可发展成为抗细菌感染的药物。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种噻二唑烷二酮基化合物，或其药学上可接受的盐或水合物在制备治疗动物致病性感染的药物组合物中的用途，其特征在于，所述的化合物具有如下式I所示的结构：
式中，
X和Y各自独立选自O、S、NR、C(R)2；
Ra和Rb各自独立地选自：H、取代或未取代的C1-8烷基、取代或未取代的C1-4烯基、取代或未取代的C3-8环烷基、取代或未取代的C6-10芳基、取代或未取代的C7-12芳烷基和取代或未取代的(-C1-4亚烷基-COO-C1-8烷基)、取代或未取代的(-(Z)n-C6-10芳基)、取代或未取代的(-(Z)n-5-12元杂芳基)、取代或未取代的5-12元杂芳基，取代或未取代的5-12元杂环基，-OR3，-C(O)R3，-C(O)OR3，-(Z)nC(O)OR3、-(Z)nC(O)NR3、-C＝NR3-CN，-OC(O)R3和-S(O)t-R3；
n为0、1或2；
t是0、1或2；
R3和R4独立地选自氢，取代或未取代的C1-8烷基、取代或未取代的C6-10芳基、取代或未取代的C7-12芳烷基、取代或未取代的5-12元杂芳基，取代或未取代的5-12元杂环基；和
各个Z各自独立地选自-C(R3)(R4)-，-C(O)-，-O-，-C(＝NR3)-，-S(O)t-和-N(R3)；
R选自下组：氢，取代或未取代的C1-8烷基；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：C1-8烷基、C3-8环烷基、芳基和芳烷基任选地被1-3个选自C1-8烷基、C1-4烷氧基、卤代C1-8烷基、卤素，或位于相邻碳原子上的两个取代基与其连接的碳原子形成5-7元碳环或5-7元杂环。
2.如权利要求1所述的用途，其特征在于，所述X和Y都是O；或者所述X是O，Y是S。
3.如权利要求1所述的用途，其特征在于，所述的Ra选自下组：取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、或取代或未取代的C7-12芳烷基；优选地，所述的取代指基团上的1-3个H原子被选自下组的取代基取代：C1-8烷基、C1-4烷氧基、卤代C1-8烷基和卤素的取代基。
4.如权利要求1所述的用途，其特征在于，所述的Rb选自下组：取代或未取代的C1-8烷基、取代或未取代的C3-8环烷基、取代或未取代的5-12元杂芳基、取代或未取代的C6-10芳基、取代或未取代的C7-12芳烷基、取代或未取代的(-(Z)n-5-12元杂芳基)。
5.如权利要求1所述的用途，其特征在于，所述式I化合物具有下式III所示的结构：
其中，各个R1各自独立选自下组：羟基、C1-8烷基、C1-4烷氧基、卤代C1-8烷基、羧基和卤素；和
n选自0、1、2和3。
6.如权利要求1所述的用途，其特征在于，所述的化合物具有选自下组的结构：
7.如权利要求1-6任一所述的用途，其特征在于，所述的病症为病原体感染。
8.如权利要求7所述的方法，其特征在于，所述的病原体感染是细菌感染。
9.如权利要求8所述的用途，其特征在于，所述的细菌为革兰氏阳性菌；优选地，所述细菌为葡萄球菌、耐甲氧西林葡萄球菌、耐青霉素肺炎链球菌、耐万古霉素金黄色葡萄球菌
10.一种选自下组的化合物：
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