CN106573007A - 小分子外排泵抑制剂 - Google Patents
小分子外排泵抑制剂 Download PDFInfo
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- CN106573007A CN106573007A CN201580030544.5A CN201580030544A CN106573007A CN 106573007 A CN106573007 A CN 106573007A CN 201580030544 A CN201580030544 A CN 201580030544A CN 106573007 A CN106573007 A CN 106573007A
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Abstract
提供了小分子外排泵抑制剂以及其用于治疗感染的方法。本文还提供了使用小分子外排泵抑制剂恢复微生物的抗生素易感性的方法。
Description
优先权申请的交叉引用
本申请要求2014年6月13日提交的美国临时申请号62/011,613的优先权,所述临时申请以引用的方式整体并入本文。
背景技术
鲍氏不动杆菌已出现为可引起呼吸机相关性肺炎(VAP)和菌血症的主要医院病原体,其相关死亡率在易感患者群体中高达60%。鲍氏不动杆菌相关的高发病率和死亡率主要是由于阻碍目前可用抗生素的有效性的抗生素抗性的出现。疾病控制和预防中心最近报道了所有美国的鲍氏不动杆菌感染中的63%由对三种或更多种类别的抗生素有抗性的多药抗性菌株引起,并且最近在美国和其他地方鉴别了对所有目前类别的抗生素有抗性的菌株。
鲍氏不动杆菌抗生素抗性通过酶促决定簇(诸如β-内酰胺酶)广泛的列表和从细胞内挤出毒性剂(包括抗生素)的外排泵来介导。关于后者,已显示生物体容纳五种细菌药物外排泵家族各自的代表物。例如,CraA和AmvA为提出分别外排氯霉素和红霉素的主要易化物超家族(MFS)泵;AbeM为外排氨基糖苷类、喹诺酮类和氯霉素的多药物和毒性化合物排出(MATE)家族蛋白;AbeS为赋予对红霉素和新生霉素的抗性以及对氨基糖苷类、喹诺酮类、四环素和甲氧苄啶的低水平耐受性的小多药抗性(SMR)家族泵;AdeABC、AdeFGH和AdeIJK为与对氨基糖苷类、β-内酰胺类、氟喹诺酮类、四环素类、替加环素、大环内酯类、氯霉素,以及甲氧苄啶的抗性相关的抗性结节***(RND)家族泵。另外,还已知鲍氏不动杆菌具有若干ABC家族转运体并且水平获得属于赋予四环素抗性的MFS的Tet外排泵。
除上述良好鉴定的外排泵之外,据报道鲍氏不动杆菌具有可赋予抗生素抗性的一系列另外推定的外排泵。例如,常见实验室菌株AYE和ATCC17978分别含有46个和73个基因,它们注释为推定的药物外排泵。这些因素是否确实调节抗生素耐受性或哪些内源性或外源性线索调节其活性尚有待研究。尽管如此,最新研究表明它们可能具有临床意义。已发现在生理学相关盐条件中在鲍氏不动杆菌生长期间18种先前禾鉴定的推定药物外排相关因子显著上调并且赋予对左氧氟沙星和阿米卡星的抗性。同样地,已发现鲍氏不动杆菌在人类血浆中的生长诱导约22种药物外排相关基因表达并且对应于外排介导的对临床相关水平的米诺环素的耐受性。此类调节改变外排泵表达,并且因此认为响应于宿主相关环境线索的活性暂时增加细菌存活于抗生素攻击的能力并且假设允许临床上另外定义的抗生素易感菌株抵抗抗生素攻击;这一现象最近被称为适应性外排介导的抗性。
概述
本文描述了小分子外排泵抑制剂。本文还描述了使用小分子外排泵抑制剂恢复微生物抗微生物易感性的方法。
本文所述的药物组合物包含具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中L为直接键或者取代或未取代的连接单元;R2、R3、R4、R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或禾取代的磺酰基;并且X选自由以下组成的组:取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的磺酰基、或者取代或未取代的羧基;以及抗微生物剂。
任选地,所述外排泵抑制剂为
其中R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
任选地,所述外排泵抑制剂为
其中R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或未取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或禾取代的磺酰基;并且R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或禾取代的杂芳基。
任选地,所述外排泵抑制剂为
其中R1选自由氢和取代或禾取代的烷基组成的组。
任选地,所述外排泵抑制剂为
其中
其中R1选自由氢和取代或禾取代的烷基组成的组;并且R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
任选地,所述外排泵抑制剂为
其中R1选自由氢和取代或未取代的烷基组成的组;R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或未取代的磺酰基;并且R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或禾取代的烷基、取代或禾取代的芳基,以及取代或未取代的杂芳基。
任选地,所述外排泵抑制剂为
本文所述的药物组合物包含具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中R1、R2和R3各自独立地选自氢、取代的烷基、取代的烯基、取代的炔基、取代或未取代的芳基、或者取代或未取代的杂芳基;以及抗微生物剂。任选地,所述外排泵抑制剂为
任选地,所述外排泵抑制剂选自由以下组成的组:
任选地,抗微生物剂选自由以下组成的组:米诺环素、环丙沙星、左氧氟沙星、萘啶酸、阿米卡星、庆大霉素、卡那霉素、美罗培南、头孢曲松、红霉素、粘杆菌素多粘菌素B、磺胺甲噁唑、替加环素、妥布霉素,以及甲氧苄啶。任选地,所述组合物还包含药学上可接受的载体。
本文还描述了用于治疗受试者的微生物感染的方法。一种用于治疗受试者的微生物感染的方法包括向所述受试者施用有效量的如本文所述的外排泵抑制剂和抗微生物剂。任选地,抗微生物剂选自由以下组成的组:米诺环素、环丙沙星、左氧氟沙星、萘啶酸、阿米卡星、庆大霉素、卡那霉素、美罗培南、头孢曲松、红霉素、粘杆菌素多粘菌素B、磺胺甲噁唑、替加环素、妥布霉素,以及甲氧苄啶。
任选地,所述方法还可包括选择被对所述抗微生物剂有抗性的微生物感染的受试者。任选地,所述方法还可包括选择被能够产生对所述抗微生物剂的抗性的微生物感染的受试者。所述抗性可由外排泵介导。外排泵抑制剂和抗微生物剂可依次(以任一顺序)或同时施用。
任选地,所述微生物感染为细菌感染。细菌感染可任选地为革兰氏阴性细菌感染,诸如不动杆菌属细菌感染(例如,鲍氏不动杆菌感染)或假单胞菌属细菌感染(例如,绿脓假单胞菌感染)。细菌感染可任选地为***感染。
本文还描述了用于抑制细胞内的外排泵的方法。用于抑制细胞内的外排泵的方法包括使所述细胞与有效量的如本文所述的外排泵抑制剂接触。任选地,所述细胞为微生物细胞(例如,细菌细胞)。任选地,所述细菌细胞为革兰氏阴性细菌细胞。任选地,所述革兰氏阴性细菌细胞为不动杆菌属细菌细胞(例如,鲍氏不动杆菌细菌细胞)或假单胞菌属细菌细胞(例如,绿脓假单胞菌细菌细胞)。任选地,所述细菌细胞为***细胞。
一个或多个实施方案的详情在附图和以下说明书中陈述。其他特征、目标和优点通过阅读说明书和附图,以及权利要求书将是显而易见的。
附图描述
图1包含比较鲍氏不动杆菌菌株98-37-09在Luria-Bertani(LB)肉汤中、在人类血清中,以及在具有外排泵抑制剂利血平且补充有增加浓度的环丙沙星(图A)、四环素(图B)或替加环素(图C)的血清中的生长的图。星号指示LB生长与血清生长之间的统计学显著差异,如通过学生t检验所测定(*P<0.05,**P<0.01,***P<0.001)。
图2为示出在补充有0.5μg ml-1米诺环素和50μg ml-1维拉帕米或1X MEC本文所述的化合物的人类血清中生长的鲍氏不动杆菌菌株98-37-09每个细胞内累积的米诺环素浓度的图。虚线表示在补充有米诺环素和50μg ml-1维拉帕米的人类血清中生长的细胞内的米诺环素的浓度。
图3的图A为显示在补充有0.125μg ml-1环丙沙星、ST009675、ST058165或ST060273的人类血清中生长的鲍氏不动杆菌菌株98-37-09的图。图3的图B为在补充有增加浓度的环丙沙星的LB肉汤和人类血清中生长的绿脓假单胞菌菌株PA01的图。使用已知的外排泵抑制剂利血平(灰色三角形)、ABEPI1(灰色X)和ABEPI2(黑色圆圈)抑制外排。星号指示LB生长与血清生长之间的统计学显著差异,如通过学生t检验测定的(*P<0.05,**P<0.01)。图3的图C含有ABEPI1和ABEPI2的结构。
图4示出溴化乙锭(EtBr)外排测定的结果,其表明已知EPI苯丙氨酸-精氨酸β萘酰胺(PAβN,白色方块)、ABEPI1(灰色三角形)和ABEPI2(灰色x)抑制了鲍氏不动杆菌菌株98-37-09中的外排。
图5包含来自真核细胞钙通道抑制测定的结果。将人类胚胎肾细胞(HEK 293T)接种到96孔黑壁板中并且用Fluo-4钙结合荧光团装载。在荧光监控15秒(黑色箭头)后用单独的卡巴胆碱(图A)、维拉帕米(图B)、ABEPI1(图C)或ABEPI2(图D)处理细胞。在60秒后,用卡巴胆碱刺激所有的孔(灰色箭头)。
详细描述
本文描述了小分子外排泵抑制剂。任选地,外排泵抑制剂为微生物外排泵抑制剂(例如,抗生素外排泵抑制剂)。任选地,所述外排泵抑制剂为哺乳动物外排泵抑制剂。本文还描述了使用所述小分子外排抑制剂恢复微生物的抗生素易感性的方法,所述微生物诸如革兰氏阴性细菌病原体(例如,鲍氏不动杆菌或绿脓假单胞菌)。本文所述的化合物不存在通常与其他类别的外排泵抑制剂相关的问题,即显著哺乳动物细胞毒性和钙通道抑制。这些化合物可用作辅助治疗,以加强用于治疗性干预细菌感染(例如,葛兰阴性细菌感染和***感染)的当前和未来抗生素的活性。
I.化合物
适用于本文所述的方法中的一类外排泵抑制剂包括由式I表示的化合物:
或其药学上可接受的盐或前药。
在式I中,L为直接键或者取代或未取代的连接单元。如本文所用,术语直接键表示在六元环结构上显示与L附接的碳与X或X的原子之间的共价键。当L为取代或未取代的连接单元时,它是具有1至4个碳原子和多至2个杂原子(例如,氧、氮或硫)的连接单元。L作为取代或未取代的连接单元的实例包括取代或未取代的烷基(例如,甲基;乙基;丙基;丁基;-C(O)-;-CH2(O)-;或-C(O)CH2-)、取代或未取代的烯基(例如,=CH-;=CHCH2-;=CHCH2CH2-;或=CHCH2CH2CH2-)、取代或禾取代的炔基、取代或禾取代的具有多至2个杂原子的杂烷基(例如,-NH-;-CH2NH-;-NHCH2-;-NHC(O)-;-C(O)NH-;-CH2NHC(O)-;-CH2C(O)NH-;-NHC(O)CH2-;或-C(O)NHCH2-)、取代或禾取代的具有多至2个杂原子的杂烯基(例如,=N-或-N=),以及取代或禾取代的具有多至2个杂原子的杂炔基。
任选地,L可被R1基取代。在式I中,R1选自由氢和取代或禾取代的烷基组成的组。任选地,R1为氢或甲基。
任选地,在式I中,R2、R3、R4、R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。任选地,R2、R3、R4、R5和R6中的一个或多个为氢、卤素(例如,溴、氯或氟)、羟基、甲氧基、乙氧基、甲基、乙基、硝基、氨基、或二甲基氨基。
同样,在式I中,X选自由以下组成的组:取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的磺酰基、或者取代或未取代的羧基。任选地,X为取代或未取代的芳基或者取代或未取代的杂芳基。例如,X可任选地为五元环、六元环或七元环。任选地,X为取代或未取代的苯基。任选地,X为取代或未取代的噻唑。任选地,X包括取代或未取代的磺酰基。例如,X可包括磺酰胺基。
任选地,在式I中,相邻R基团组合以形成取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基,和/或取代或未取代的杂芳基。例如,在式I中,R2和R3、R3和R4、R4和R5、或R5和R6可组合以形成取代或未取代的环烷基、取代或禾取代的杂环烷基、取代或禾取代的芳基,和/或取代或禾取代的杂芳基。
在式I的一些实例中,X为取代或禾取代的芳基。任选地,X为取代或禾取代的苯基以提供结构I-A:
在结构I-A中,R1、R2、R3、R4、R5和R6如式I中所定义。同样在结构I-A中,R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或禾取代的磺酰基。任选地,R9选自氢、磺酰胺或甲基。
任选地,在结构I-A中,相邻R基团组合以形成取代或禾取代的环烷基、取代或禾取代的杂环烷基、取代或禾取代的芳基,和/或取代或未取代的杂芳基。例如,在结构I-A中,R2和R3、R3和R4、R4和R5、R5和R6、R7和R8、R8和R9、R9和R10,和/或R10和R11可组合以形成取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、或者取代或未取代的杂芳基。
在结构I-A中,R9可为根据结构I-B的取代或禾取代的磺酰胺:
在结构I-B中,R1、R2、R3、R4、R5、R6、R7、R8、R10和R11如式I中所定义。同样在结构I-B中,R12和R13各自独立地选自由以下组成的组:氢、取代或禾取代的脒、取代或未取代的烷基、取代或禾取代的芳基,以及取代或禾取代的杂芳基。
在式I的一些实例中,X为取代或禾取代的杂芳基。任选地,X为根据结构I-C的取代或禾取代的噻唑:
在结构I-C中,R1、R2、R3、R4、R5和R6如式I中所定义。同样在结构I-C中,R14和R15各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或未取代的磺酰基。任选地,R14和R15为氢。
在式I的一些实例中,L为取代或未取代的含有氮原子的杂烯基。任选地,L为-C(R1)=N-以提供结构I-D:
在结构I-D中,R1、R2、R3、R4、R5、R6,以及X如式I中所定义。
在结构I-D的一些实例中,X为取代或未取代的芳基。任选地,X为取代或未取代的苯基以提供结构I-E:
在结构I-E中,R1、R2、R3、R4、R5和R6如式I中所定义。同样在结构I-E中,R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。任选地,R9选自氢、磺酰胺或甲基。
任选地,在结构I-E中,相邻R基团组合以形成取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基,和/或取代或未取代的杂芳基。例如,在结构I-E中,R2和R3、R3和R4、R4和R5、R5和R6、R7和R8、R8和R9、R9和R10,和/或R10和R11可组合以形成取代或未取代的环烷基、取代或未取代的杂环烷基、取代或未取代的芳基、或者取代或未取代的杂芳基。
在结构I-E中,R9可为根据结构I-F的取代或未取代的磺酰胺:
在结构I-F中,R1、R2、R3、R4、R5、R6、R7、R8、R10和R11如式I中所定义。同样在结构I-F中,R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
在结构I-D的一些实例中,X为取代或未取代的杂芳基。任选地,X为根据结构I-G的取代或未取代的噻唑:
在结构I-G中,R1、R2、R3、R4、R5和R6如式I中所定义。同样在结构I-G中,R14和R15各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。任选地,R14和R15为氢。
适用于本文所述的方法中的一类外排泵抑制剂包括由式II表示的化合物:
或其药学上可接受的盐或前药。
在式II中,R1、R2和R3各自独立地选自氢、取代的烷基、取代的烯基、取代的炔基、取代或未取代的芳基、或者取代或未取代的杂芳基。任选地,R1为叔丁基。任选地,R2为氢。任选地,R3为叔丁基。在式II的一些实例中,R2和R3不能同时为氢。任选地,R1和R2为相同的。
在式II的一些实例中,R3为氢以提供结构II-A:
适用于本文所述的方法中的外排泵抑制剂的实例包括以下化合物:
任选地,所述外排泵抑制剂为ST009675(ABEPI1)或ST060273(ABEPI2)。任选地,所述外排泵抑制剂不是ST009655、ST009694、ST009699、ST009696、ST009698、ST010277、ST010344、ST012901、ST012902、ST012929、ST012934、ST012941、ST012955、ST012961、ST012963、ST016436、ST016442、ST016443、ST016444、ST009531、
ST006953、ST007013、ST007852、ST007924、ST008277、ST009495、ST009847、ST060355、ST009850、ST009896、ST010260、ST011123、ST020959、ST020992、ST024775、ST025773、ST026450、ST026465、ST029434、ST031144、ST033061、ST033063、ST033065、ST033231、ST033232、ST033235、ST033341、ST033346、ST033447、ST034012、ST034014、ST036291、ST036365、ST040282、ST040289、ST040724、ST048001、ST058165、ST058478、ST058672、ST058811、ST058899、ST059010、ST059421、ST059447、ST059581、ST059822、ST060053、ST060056、或ST060272。
如本文所述,术语烷基、烯基和炔基包括直链和支链单价取代基。实例包括甲基、乙基、异丁基、3-丁炔基等。适用于本文所述的化合物和方法的这些基团的范围包括C1-C20烷基、C2-C20烯基,以及C2-C20炔基。适用于本文所述的化合物和方法的这些基团另外的范围包括C1-C12烷基C2-C12烯基、C2-C12炔基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C4烷基、C2-C4烯基,以及C2-C4炔基。
杂烷基、杂烯基和杂炔基与烷基、烯基和炔基类似地定义,但可在主链内含有O、S或N杂原子或其组合。适用于本文所述的化合物和方法的这些基团的范围包括C1-C20杂烷基、C2-C20杂烯基和C2-C20杂炔基。适用于本文所述的化合物和方法的这些基团另外的范围包括C1-C12杂烷基C2-C12杂烯基、C2-C12杂炔基、C1-C6杂烷基、C2-C6杂烯基、C2-C6杂炔基、C1-C4杂烷基、C2-C4杂烯基,以及C2-C4杂炔基。
术语环烷基、环烯基和环炔基包括具有单环或多缩合环的环烷基。实例包括环己基、环戊基乙基和金刚烷基。适用于本文所述的化合物和方法的这些基团的范围包括C3-C20环烷基、C3-C20环烯基和C3-C20环炔基。适用于本文所述的化合物和方法的这些基团的范围包括C5-C12环烷基、C5-C12环烯基、C5-C12环炔基、C5-C6环烷基、C5-C6环烯基,以及C5-C6环炔基。
术语杂环烷基、杂环烯基和杂环炔基与环烷基、环烯基和环炔基类似地定义,但可在环主链内含有O、S或N杂原子或其组合。适用于本文所述的化合物和方法的这些基团的范围包括C3-C20杂环烷基、C3-C20杂环烯基和C3-C20杂环炔基。适用于本文所述的化合物和方法的这些基团的范围包括C5-C12杂环烷基、C5-C12杂环烯基、C5-C12杂环炔基、C5-C6杂环烷基、C5-C6杂环烯基,以及C5-C6杂环炔基。
芳基分子包括例如结合具有通常六个碳原子的一个或多个平面集合的环烃,所述碳原子通过离域电子连接,这些电子就像它们由交替单共价键和双共价键组成一样地来编号。芳基分子的一个实例为苯。杂芳基分子包含沿着其主要环链原子诸如O、N或S的取代基。当引入杂原子时,一组五个原子,例如四个碳和一个杂原子可形成芳族***。杂芳基分子的实例包括呋喃、吡咯、噻吩、咪唑、噁唑、吡啶,以及吡嗪。芳基和杂芳基分子还可包括另外的稠合环,例如苯并呋喃、吲哚、苯并噻吩、萘、蒽,以及喹啉。芳基和杂芳基分子可附接在环上的任何位置处,除非另外说明。
本文所用的烷基、烯基、炔基、芳基、杂烷基、杂烯基、杂炔基、杂芳基、环烷基、环烯基、环炔基、杂环烷基、杂环烯基、或杂环炔基可为取代或未取代的。如本文所用,术语取代的包括将烷基、烯基、炔基、芳基、杂烷基、杂烯基、杂炔基、杂芳基、环烷基、环烯基、环炔基、杂环烷基、杂环烯基、或杂环炔基添加到附接至烷基、烯基、炔基、芳基、杂烷基、杂烯基、杂炔基、杂芳基、环烷基、环烯基、环炔基、杂环烷基、杂环烯基、或杂环炔基的主链的位置,例如,由这些分子之一替换氢。取代基的实例包括但不限于羟基、卤素(例如,F、Br、Cl或I),以及羧基。相反地,如本文所用,术语未取代的意指烷基、烯基、炔基、芳基、杂烷基、杂烯基、杂炔基、杂芳基、环烷基、环烯基、环炔基、杂环烷基、杂环烯基、或杂环炔基具有完全补充的氢,即与其饱和水平一致,不具有取代基,即线性癸烷(-(CH2)9-CH3)。
II.药物制剂
本文所述的化合物或其衍生物可以药物组合物提供。根据预期的施用模式,药物组合物可为固体、半固体或液体剂型的形式,例如像片剂、栓剂、丸剂、胶囊、散剂、液体、混悬剂、软膏、凝胶剂、乳剂、或溶液剂,优选地为适用于单次施用精确剂量的单位剂型。所述组合物将包含治疗有效量的如本文所述的化合物或其衍生物与药学上可接受的载体的组合并且另外可包含其他医学试剂、药剂、载体或稀释剂。药学上可接受的意指并非生物学上或其他方面不理想的物质,所述物质可连同选定化合物一起施用给个体而不引起不可接受的生物效应或者不以有害方式与其中含有所述物质的药物组合物的其他组分相互作用。
如本文所用,术语载体包括赋形剂、稀释剂、填充剂、盐、缓冲剂、稳定剂、增溶剂、脂质、稳定剂、或其他本领域已知用于药物制剂中的其他物质。用于组合物中的载体的选择将取决于施用所述组合物的路径。药学上可接受的载体和含有这些物质的制剂的制备描述于例如Remington′s Pharmaceutical Sciences,第21版,编著University of theSciences in Philadelphia,Lippincott,Williams&Wilkins,Philadelphia Pa.,2005。生理上可接受的载体的实例包括缓冲剂,诸如磷酸缓冲液、柠檬酸盐缓冲液,以及具有其他有机酸的缓冲液;抗氧化剂,包括抗坏血酸;低分子量(小于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖、多糖和其他碳水化合物,包括葡萄糖、甘露糖、或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨醇;成盐抗衡离子,诸如钠;和/或非离子型表面活性剂,诸如(ICI,Inc.;Bridgewater,New Jersey)、聚乙二醇(PEG)和PLURONICSTM(BASF;Florham Park,NJ)。
含有一种或多种本文所述的化合物或其衍生物的适用于胃肠外注射的组合物可包括生理上可接受的无菌水性或非水性溶液、分散液、混悬液或乳液,以及用于重构成无菌可注射溶液或分散液的无菌粉末。适合的水性和非水性载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(例如丙二醇、聚乙二醇、甘油等)、其适合的混合物、植物油(诸如橄榄油)以及可注射有机酯诸如油酸乙酯。可例如通过使用包衣(诸如卵磷脂)、通过在分散液的情况下维持所要求的粒度,以及通过使用表面活性剂来维持适当流动性。
这些组合物还可含有佐剂,诸如防腐剂、润湿剂、乳化剂以及分散剂。可通过各种抗细菌剂和抗真菌剂,例如对羟苯甲酸酯、三氯叔丁醇、苯酚、山梨酸等来促进预防微生物的作用。还可包含等渗剂,例如糖、氯化钠等。可通过使用延迟吸收的试剂(例如单硬脂酸铝和明胶)来实现可注射药物形式的吸收延长。
用于口服施用本文所述的化合物或其衍生物的固体剂型包括胶囊、片剂、丸剂、散剂,以及颗粒剂。在此类固体剂型中,本文所述的化合物或其衍生物与以下混合:至少一种惰性常规赋形剂(或载体)诸如柠檬酸钠或磷酸二钙,或者(a)填充剂或增量剂,例如像淀粉、乳糖、蔗糖、葡萄糖、甘露醇,以及硅酸;(b)粘合剂,例如像羧甲基纤维素、海藻酸盐(alignate)、明胶、聚乙烯吡咯烷酮、蔗糖,以及***树胶;(c)润湿剂,例如像甘油;(d)崩解剂,例如像琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些络合硅酸盐,以及碳酸钠;(e)溶液阻滞剂,例如像石蜡;(f)吸收促进剂,例如季铵化合物;(g)润湿剂,例如像鲸蜡醇,以及单硬脂酸甘油酯;(h)吸附剂,例如像高岭土和膨润土;以及(i)润滑剂,例如像滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇类、十二烷基硫酸钠、或其混合物。在胶囊、片剂和丸剂的情况下,所述剂型还可包含缓冲剂。
类似类型的固体组合物还可用作使用诸如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等的赋形剂的软填充和硬填充明胶胶囊中的填充剂。
固体剂型诸如片剂、糖衣丸、胶囊、丸剂,以及颗粒剂可使用包衣和衣壳诸如肠溶包衣和本领域已知的其他物质来制备。它们可包含乳浊剂并且还可作为一类组合物以使得它们以一种延迟方式在胃肠道某一部分中释放一种或多种活性化合物。可使用的包埋组合物的实例为聚合物质和蜡类。活性化合物在适当时也可为具有一种或多种上述赋形剂的微包囊形式。
用于口服施用一种或多种本文所述的化合物或其衍生物的液体剂型包括药学上可接受的乳剂、溶液、悬浮液、糖浆剂,以及酏剂。除所述活性化合物之外,液体剂型还可含有本领域常用的惰性稀释剂(诸如水或其他溶剂)、增溶剂和乳化剂,例如像乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体地是棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇,以及脱水山梨醇脂肪酸酯、或这些物质的混合物等等。
除这些惰性稀释剂之外,所述组合物还可包含另外的试剂,诸如润湿剂、乳化剂、助悬剂、甜味剂、调味剂、或芳香剂。
除活性化合物之外,混悬剂还可含有一种或多种另外的试剂,例如像乙氧基化异十八烷醇、聚氧乙烯山梨醇和失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶、或这些物质的混合物等等。
一种或多种本文所述的化合物或其衍生物用于直肠施用的组合物任选地为栓剂,其可通过将所述化合物与适合的无刺激性赋形剂或载体诸如可可脂、聚乙二醇或栓剂蜡混合来制备,所述栓剂在常温下为固体但是在体温下为液体,并且因此在直肠或***内融化并释放活性组分。
用于局部施用一种或多种本文所述的化合物或其衍生物的剂型包括软膏、散剂、喷雾剂、吸入剂、凝胶剂、乳膏剂,以及溶液。本文所述的化合物或其衍生物在无菌条件下可根据需要与生理上可接受的载体和任何防腐剂、缓冲剂或推进剂混合。眼用制剂、软膏、散剂,以及溶液也涵盖在所述组合物的范围内。
所述组合物可包含一种或多种本文所述的化合物和一种药学上可接受的载体。如本文所用,术语药学上可接受的盐是指本文所述的化合物或其衍生物的那些盐,它们在合理医学判断范围内适用于与受试者的组织接触而无明显的毒性、刺激性、过敏反应等,与合理的益处/风险比率一致,并且有效用于其预期用途,以及在可能时为本文所述化合物的两性离子形式。术语盐是指本文所述的化合物相对无毒的无机酸和有机酸加成盐。这些盐可在所述化合物的分离和纯化期间原位制备或者通过单独地将游离碱形式的纯化化合物与适合的有机酸或无机酸反应并且分离因此形成的盐来制备。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐甲磺酸盐、葡庚糖酸盐、乳糖醛酸盐、甲磺酸铜,以及月桂基磺酸盐等。这些盐可包含基于碱金属和碱土金属诸如钠、锂、钾、钙、镁等的阳离子,以及无毒性铵、季铵和胺离子,包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。(参见S.M.Barge等,J.Pharm.Sci.(1977)66,1,所述文献以引用的方式整体、至少将关于其中教授的组合物并入本文。)
本文所述的化合物和组合物或其药学上可接受的盐的施用可使用有效量的本文所述的化合物和组合物或如本文所述的其药学上可接受的盐来进行,持续有效于治疗病症的时间段。本文所述的化合物和组合物或如本文所述的其药学上可接受的盐的有效量可通过本领域技术人员测定并且包括用于哺乳动物的示例性剂量每天每千克体重约0.5至约200mg的活性化合物,其可以单一剂量或以单独分开的剂量(诸如每天1至4次)来施用。或者,所述剂量为每天每千克体重约0.5至约150mg活性化合物、每天每千克体重约0.5至100mg活性化合物、每天每千克体重约0.5至约75mg活性化合物、每天每千克体重约0.5至约50mg活性化合物、每天每千克体重约0.5至约25mg活性化合物、每天每千克体重约1至约20mg活性化合物、每天每千克体重约1至约10mg活性化合物、每天每千克体重约20mg活性化合物、每天每千克体重约10mg活性化合物、或每天每千克体重约5mg活性化合物。本领域技术人员将理解的是,用于任何特定受试者的特定剂量水平和给药频率可以改变并且将根据许多因素,包括所采用的一种或多种特定化合物的活性、所述化合物的代谢稳定性和作用时间长度、一般健康、受试者的性别和膳食;施用模式和时间;***路径;药物组合;以及特定病状的严重性。
III.制备所述化合物的方法
本文所述的化合物可以有机化学领域已知的许多方式或根据其上的变化来制备,如本领域技术人员所了解。本文所述的化合物可由容易获得的起始物质制备。最佳反应条件可随着所使用的特定反应物或溶剂的不同而改变,但是此类条件可由本领域技术人员确定。
在式I、式II和本文所述的化合物上的变化包括各种成分的添加、去除或移动,如对于每种化合物所述。类似地,当分子中存在一个或多个手性中心时,分子的手性可发生改变。另外,化合物合成可涉及各种化学基团的保护和脱保护。保护和脱保护的使用和适当保护基团的选择可由本领域技术人员确定。保护基团的化学方面可见于例如Wuts和Greene,Protective Groups in Organic Synthesis,第4版,Wiley&Sons,2006,所述文献以引用的方式整体并入本文。考虑如本文所述的各种化合物的测定功效的合成和随后的测试。
产生本文所述的化合物的反应可在溶剂中进行,所述溶剂可由有机合成领域的技术人员选择。溶剂在进行反应的条件即温度和压力下可基本上不与起始物质(反应物)、中间体或产物反应。反应可在一种溶剂或超过一种溶剂的混合物中进行。产物或中间体形成可根据本领域已知的任何适合的方法来监控。例如,产物形成可通过光谱手段诸如核磁共振光谱法(例如,1H或13C)、红外光谱法、分光光度法(例如,UV-可见光)或质谱分析法或者通过色谱法诸如高效液相色谱法(HPLC)或薄层色谱法来监控。
任选地,本文所述的化合物可由商业来源获得,所述商业来源包括例如TimTec(Newark,DE)。
IV.使用方法
本文提供了治疗、预防或减轻受试者中的微生物感染的方法。所述方法包括向所述受试者施用有效量的如本文所述的外排泵抑制剂和抗微生物剂。本文所述的化合物和组合物或其药学上可接受的盐适用于治疗人类(例如幼儿和老人群体)和动物(例如兽医应用)中的微生物感染。微生物感染包括例如细菌感染和真菌感染。在一些实例中,所述微生物感染为细菌感染。任选地,所述细菌感染为革兰氏阴性细菌感染,诸如不动杆菌属感染(例如,鲍氏不动杆菌感染)、假单胞菌属感染(例如,绿脓假单胞菌感染)、克雷伯氏菌属感染、埃希氏菌属感染、沙门菌属感染、耶尔森氏菌属感染、志贺氏杆菌属感染、变形杆菌属感染、肠杆菌属感染、沙雷氏菌属感染、或柠檬杆菌属感染在一些实例中,微生物感染为***感染,诸如芽胞杆菌属感染、利斯特杆菌属感染、葡萄球菌属感染、链球菌属感染、肠道球菌属感染、或梭菌属感染。
治疗、预防或减轻受试者中的微生物感染的方法还可包括选择被对抗微生物剂有抗性的微生物感染的受试者或者选择被能够形成对抗微生物剂的抗性的微生物感染的受试者。任选地,所述抗性通过外排泵介导。本文所述的外排泵抑制剂增加微生物对抗微生物剂的易感性。任选地,本文所述的外排泵抑制剂可增加抗微生物剂对所述微生物的抗微生物活性。
这些方法还可包括使用一种或多种另外的治疗剂(例如,抗生素)进行治疗。所述一种或多种另外的药剂和如本文所述的化合物和组合物或其药学上可接受的盐可以任何顺序施用,包括同时施用,以及依次施用(例如,短暂间隔多至若干天的顺序)。所述方法还可包括超过一次单独施用一种或多种另外的药剂和/或如本文所述的化合物和组合物或其药学上可接受的盐。一种或多种另外的药剂和如本文所述的化合物和组合物或其药学上可接受的盐的施用可通过相同或不同的路径来进行。当用一种或多种另外的药剂治疗时,如本文所述的化合物和组合物或其药学上可接受的盐可组合成一种药物组合物,其包含一种或多种另外的药剂。例如,如本文所述的化合物和组合物或其药学上可接受的盐可组合成具有抗生素的一种药物组合物。适合的抗生素可包括有效于治疗细菌感染的任何抗生素并且包括例如四环素类(例如,米诺环素)、喹诺酮类(例如,环丙沙星、左氧氟沙星和萘啶酸)、氨基糖苷类(例如,阿米卡星、庆大霉素、卡那霉素和妥布霉素)、碳青霉烯类(例如,美罗培南)、头孢菌素类(例如,头孢曲松)、大环内酯类(例如,红霉素)、多肽类(例如,粘杆菌素和多粘菌素B)、磺酰胺类(例如,磺胺甲噁唑)、甘氨酰环素(例如,替加环素)、β内酰胺类(例如,青霉烷类)、脂肽(例如,达托霉素)、噁唑烷酮(例如,利奈唑胺),以及甲氧苄啶。
如本文所述的方法和化合物适用于预防性治疗和治疗性治疗。如本文所用,术语治疗(treating或treatment)包括预防;延迟发作;减少、根除或延迟在发作之后的体征或症状加重;以及预防复发。出于预防性用途,在发作之前(例如,在微生物感染的明显体征之前)、在早期发作期间(例如,在微生物感染的初始特征和症状时)、在形成微生物感染之后、或甚至在出现对抗生素的抗性之后,向受试者施用治疗有效量的如本文所述的化合物和组合物或其药学上可接受的盐。预防性施用可在感染症状出现之前进行数天至数年。治疗性治疗涉及在诊断微生物感染之后向受试者施用治疗有效量的如本文所述的化合物和组合物或其药学上可接受的盐。
本文还提供了抑制细胞(包括真核细胞和原核细胞)内的外排泵的方法。适合类别的原核细胞外排泵包括主要易化物超家族、ATP结合盒(ABC)超家族、小多药抗性(SMR)家族、抗性成节细胞***(RND)超家族、多抗微生物扩展(MATE),以及药物代谢物转运体(DMT)超家族。适合类别的真核细胞外排泵包括单羧酸盐转运体(MCT)、多药抗性蛋白、多药抗性相关蛋白、肽转运体(PEPT),以及Na+磷酸盐转运体(NPT)。
抑制细胞内的外排泵的方法包括使所述细胞与有效量的如本文所述的外排泵抑制剂接触。外排泵抑制剂的有效量可为抑制细胞内的外排泵的量。任选地,所述细胞可为微生物细胞。任选地,所述微生物细胞可为细菌细胞。任选地,所述细菌细胞为革兰氏阴性细菌细胞。任选地,革兰氏阴性细菌细胞为不动杆菌属细菌细胞(例如,鲍氏不动杆菌细菌细胞)、假单胞菌属细菌细胞(例如,绿脓假单胞菌细菌细胞)、克雷伯氏菌属细菌细胞、埃希氏菌属细菌细胞、沙门氏菌属细菌细胞、耶尔森氏菌属细菌细胞、志贺氏杆菌属细菌细胞、变形杆菌属细菌细胞、肠杆菌属细菌细胞、沙雷氏菌属细菌细胞、或柠檬杆菌属细菌细胞。任选地,所述细菌细胞为***细胞。任选地,***细胞为芽胞杆菌属细菌细胞、利斯特杆菌细菌细胞、葡萄球菌属细菌细胞、链球菌属细菌细胞、肠道球菌属细菌细胞、或梭菌属细菌细胞。接触可在体内(例如,在人类受试者中)或在体外进行。
V.试剂盒
本文还提供了用于治疗或预防受试者中的微生物感染(例如,细菌感染)的试剂盒。试剂盒可包含如本文所述的化合物(单独或组合的)或一种或多种组合物中的任一种和一种或多种另外的药剂诸如抗生素。例如,试剂盒可包含如本文所述的化合物和抗生素诸如四环素类(例如,米诺环素)、喹诺酮类(例如,环丙沙星、左氧氟沙星和萘啶酸)、氨基糖苷类(例如,阿米卡星、庆大霉素、卡那霉素,以及妥布霉素)、碳青霉烯类(例如,美罗培南)、头孢菌素类(例如,头孢曲松)、大环内酯类(例如,红霉素)、多肽类(例如,粘杆菌素和多粘菌素B)、磺酰胺类(例如,磺胺甲噁唑)、甘氨酰环素(例如,替加环素),以及甲氧苄啶。试剂盒还可包含本文所述的化合物或组合物中任一种的口服制剂。试剂盒可另外包含试剂盒的使用说明(例如,用于治疗受试者的说明书)、一个或多个容器(用于化合物、组合物或另外的药剂)、用于施用所述化合物或组合物的装置,和/或载体。
如本文所用,术语治疗(treatment、treat或treating)是指减少感染、疾病或病状的一种或多种症状。因此在公开的方法中,治疗可以是指感染、疾病或病状的一种或多种症状的严重性减小10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、或在10%与100%之间的任何减小百分比。例如,如果与对照相比受试者感染的一种或多种症状或体征减小10%,则一种用于治疗感染的方法被视为治疗。如本文所用,对照是指未治疗的感染。因此,与天然或对照水平相比减小可为10%、20%、30%、40%、50%、60%、70%、80%、90%、100%、或在10%与100%之间的任何减小百分比。应当理解,治疗并不一定是指感染、疾病、病状、或者所述感染、疾病或病状的症状的治愈或完全消除。
如本文所用,术语感染、疾病或病症的预防(prevent、preventing和prevention)是指例如在受试者开始显示所述疾病或病症的一种或多种症状之前或同时施用组合物或治疗剂的作用,所述施用抑制或延迟所述疾病或病症的一种或多种症状的发作或严重性。
如本文所用,关于降低、减少或抑制包括与对照水平相比10%、20%、30%、40%、50%、60%、70%、80%、90%或更大的变化、或在10%与大于约90%或更大之间的任何变化百分比。此类术语可包括但不限于完全消除。
如本文所用,受试者意指哺乳动物和非哺乳动物。哺乳动物包括例如人类;非人灵长类,例如猿和猴;牛;马;绵羊;大鼠;小鼠;猪;以及山羊。非哺乳动物包括例如鱼和鸟。
以下实施例意图进一步说明本文所述的方法和组合物的某些方面并且不意图限制本发明的范围。
实施例
细菌菌株和生长条件:
鲍氏不动杆菌菌株98-37-02、98-37-05、98-37-09,以及07-09-54为从疾病控制与预防中心获得的临床分离株。绿脓假单胞菌菌株PA01和克雷伯氏肺炎菌菌株CKP4为常见实验室菌株。所有菌株均在Luria-Bertani(LB)培养基(Becton Dickinson,Franklin Lakes,NJ)或100%人类血清(MP Biomedicals,Solon,OH)中生长。在指示的地方,LB或血清补充有卡那霉素(50μg ml-1,Thermo Fisher,Waltham,MA)和/或指示浓度的米诺霉素(Sigma-Aldrich,Saint Louis,MO)、环丙沙星(Sigma Aldrich)、美罗培南(LKT实验室,Minneapolis-St.Paul,MO)、或替加环素(Pfizer,Groton,CT)。
实施例1:抗生素易感性测定
已发现抗生素外排泵导致细菌对实际上每种目前可获得的抗生素产生抗性。截至目前为止已鉴定十种鲍氏不动杆菌抗生素外排泵***。已显示在生物学相关培养基人类血清中生长的鲍氏不动杆菌诱导二十二种先前未鉴定的药物外排泵相关基因的表达并且其表达对应于外排泵介导的对抗生素米诺霉素的耐受性,其水平在治疗期间与患者血清水平相关。作为进一步评估此现象的手段,在本文中评定在血清中生长的鲍氏不动杆菌是否引起对其他四环素类、喹诺酮类(环丙沙星、左氧氟沙星和萘啶酸)、氨基糖苷类(阿米卡星、庆大霉素和卡那霉素)、碳青霉烯类(美罗培南)、头孢菌素类(头孢曲松)、大环内酯类(红霉素)、多肽类(粘杆菌素和多粘菌素B)、磺酰胺类(磺胺甲噁唑)、甘氨酰环素(替加环素),以及甲氧苄啶的药物外排介导的耐受性。
根据以下所述方法测量在LB培养基或100%人类血清中生长的鲍氏不动杆菌和绿脓假单胞菌的抗生素易感性。简言之,将所指定细菌物种/菌株在LB培养基中生长过夜,稀释成新鲜培养基(1∶100稀释)并且使其在37℃下通风生长至对数生长中期(OD600nm=0.4至0.5)。将总计1x105个菌落形成单位(CFU)转移到96孔圆底板含有100μL LB或100%人类血清的单个孔中,所述培养基或血清补充有2倍增加浓度(0至2μg mL-1)的米诺环素、阿米卡星、庆大霉素、卡那霉素、美罗培南、头孢曲松、红霉素、粘杆菌素、多粘菌素B、环丙沙星、左氧氟沙星、萘啶酸、磺胺甲噁唑、甲氧苄啶、替加环素或0至16μg mL-1四环素,并将板在37℃下培育48小时。为了量化每种抗生素针对在LB或血清中生长的细菌的抗微生物效应,将孔构成物以PBS连续稀释并置于LB琼脂上以计算CFU mL-1。在指示的地方,还在50μg mL-1外排泵抑制剂维拉帕米、利血平、苯丙氨酸精氨酸β萘酰胺(PAβN)或推定的外排泵抑制剂ABEPI1和ABEPI2存在下进行抗微生物易感性测定,以分别测量抗生素外排泵对抗生素耐受性的贡献或推定的外排泵抑制剂加强指定抗生素的抗微生物活性的能力。
如图1A所示,与LB中的生长相比,在人类血清中生长的鲍氏不动杆菌菌株98-37-09显著(P<0.001)更不易感于浓度≤1μg ml-1的环丙沙星。在补充有已知外排泵抑制剂利血平的血清中生长的细胞可恢复环丙沙星易感性,这显示与抗生素封存和/或由血清组分进行的灭活相反,生物体血清相关环丙沙星耐受性为外排泵介导的。同样地,在人类血清中生长的鲍氏不动杆菌显示对抗生素浓度≥2μg ml-1的四环素的外排泵介导的耐受性(图1B)。更具体的说,用4-16μg ml-1四环素处理LB生长的鲍氏不动杆菌使细胞生存力减小至不可检测的水平(<1x 101个菌落形成单位;cfu),而在血清中生长的细胞显示适当的抗生素耐受性,等于1x 106与1x 104cfu之间。在药物外排泵抑制剂PAβN存在下血清中生长的鲍氏不动杆菌四环素易感性得到部分恢复,这表明外排泵在血清生长期间部分调节生物体四环素耐受性。对于十一种先前鉴定的评定的鲍氏不动杆菌品系中的三种代表物观察到类似的表型,这表明血清相关外排泵介导的米诺环素和环丙沙星耐受性为半保守性鲍氏不动杆菌响应,这可能依赖于所评价生物体的一般组成。另外,虽然在血清与LB生长的98-37-09细胞对其他类别测试的抗生素的易感性之间未观察到显著差异,但是在研究过程期间,表示测试的十一种其他品系中的七种的菌株显示虽然有不同但都在血清生长期间显著增加对抗生素替加环素的外排泵介导的耐受性(在图1C中示出的代表性结果)。作为一个实例,替加环素在浓度≥1μg ml-1下在LB培养基中生长期间显示针对鲍氏不动杆菌菌株01-12-05的清晰抗微生物活性,但是所述菌株似乎在血清中生长期间对抗生素具有高抗性。通过加入外排泵抑制剂利血平可部分恢复易感性,这显示血浆相关外排泵活性至少部分促成菌株在血清中生长期间对替加环素耐受的能力。
所观察到的血浆依赖性外排泵介导的抗生素耐受性可部分解释抗生素针对临床上定义的易感性鲍氏不动杆菌菌株的临床失败;在适应宿主相关环境条件诸如血清期间,生物体诱导外排泵,从而允许临床上定义的抗生素易感性生物体在体内耐受抗生素攻击。因此,使用相应外排泵抑制剂的辅助治疗提供一种限制宿主内的抗生素耐受性的有价值策略,并且因此充当当前抗生素和未来抗生素的有吸引力的治疗方法。
实施例2:对于鲍氏不动杆菌血清依赖性抗生素外排泵抑制剂的高通量筛选
最初通过识别增强亚抑制浓度的米诺环素针对人类血清中生长的鲍氏不动杆菌的抗微生物活性的化合物来针对推定的外排泵抑制剂筛选TimTec ActiProbe-25K多样性集合和天然产品化合物库(总计29,900种化合物;TimTec,Newark,DE)。为此,将鲍氏不动杆菌菌株98-37-09在LB培养基中在37℃下在225rpm旋转振荡器上生长16小时。然后将约1x105CFU转移到96孔圆底板(Corning Costar,Tewksbury,MA)含有100μL人类血清的单个孔中,所述血清补充有米诺环素(0.5μg mL-1;0.5x血清中的最小抑制浓度)和TimtecActiProbe或天然产品库(50μM)的个别成员。然后将板在37℃下培育48小时。测量作为浊度的函数的生长。将推定的外排泵抑制剂识别为抑制在含有米诺环素的人类血清中生长的鲍氏不动杆菌的化合物并且随后重新测试,重复三次,如以上所指示。在补充有米诺环素+/-PAβN的血清中生长的未处理鲍氏不动杆菌分别用作阳性对照和阴性对照。大部分化合物(99.6%;29,806种化合物)并不影响生物体生长,而94种化合物(0.4%)抑制菌株在补充有米诺环素的血清中生长的能力。重复测试,其中将孔组成物连续稀释并置于LB琼脂板上,证实85种化合物确实限制鲍氏不动杆菌在补充有米诺环素的血清中的生长,这与仅米诺环素处理的细胞相比减少活菌落形成单位数目为2-6log cfu之间。
为了区分具有固有抗微生物特征的化合物与推定的外排泵抑制剂,评价每种化合物针对在血清或LB中在米诺环素不存在下的鲍氏不动杆菌的抗微生物活性。为此,将1x105CFU鲍氏不动杆菌菌株98-37-09加入到微量滴定板含有补充有增加浓度的测试化合物(0至128μg mL-1)的100μL 100%人类血清的单个孔中并且在37℃下培育48小时。所测试的85种化合物中的十二种(12.7%)展示针对在血清和/或LB中在米诺环素不存在下生长的鲍氏不动杆菌的抗微生物活性并且可代表新颖抗微生物剂。其余73种化合物在米诺环素不存在下并禾显示抗微生物活性,表明这些化合物的子集可代表增强米诺环素针对血清生长的鲍氏不动杆菌的抗微生物活性的外排泵抑制剂。将显示抗微生物活性的化合物归类,而并不显示直接抗微生物活性的那些化合物被视为推定的外排泵抑制剂并且测定它们增强米诺环素针对血清生长的鲍氏不动杆菌的抗微生物活性的最低有效浓度(MEC)。
对于MEC测定,用约1x105CFU鲍氏不动杆菌菌株98-37-09接种96孔圆底板含有补充有0.5X MIC米诺环素(0.5μg mL-1)和增加浓度的测试化合物(0至128μg mL-1)的100%人类血清的单个孔中并且在37℃下培育48小时。MEC被定义为在0.5μg ml-1米诺环素存在下在血清中抑制鲍氏不动杆菌的生长所需要的测试化合物的最低浓度。平板培养证实加入1XMEC的每种化合物引起在仅补充有米诺环素的血清中生长的鲍氏不动杆菌细胞的≥1.9-log减少(参见表1)。
表1:
实施例3:米诺环素的细胞积累
使用高压液相色谱法和三重四极质谱法测量米诺环素在人类血清中在每种推定的外排泵抑制剂不存在和存在下生长期间的鲍氏不动杆菌细胞内水平。为此,将鲍氏不动杆菌菌株98-37-09在补充有0.5μg mL-1米诺环素的5mL 100%人类血清中在0.5X MEC每种推定的外排泵抑制剂(测试化合物)或已知外排泵抑制剂维拉帕米不存在和存在下生长。将培养物在振摇下培育48小时,此时取出等分部分,连续稀释并且平板培养,以测定每种混合物的活CFU数目。通过在4℃下在900x g下离心来沉淀其余细胞,以PBS洗涤两次,用FastPrep细胞破碎仪(MP Biomedicals,Santa Ana,CA)以5m s-1机械裂解20秒并且经由在900xg和4℃下离心来沉淀细胞碎片。测量存在于破裂细胞上清液内的米诺环素的量。简言之,首先将多西环素(0.5μg mL-1)加入各上清液中以用作内部对照,从而说明样品至样品制备可变性。然后以1∶10比率将所述上清液与乙腈(ACN)组合并且在16,000xg、4℃下离心,以收集米诺环素和多西环素。丢弃上清液并且将残余液体在速度真空中在8,000x g下蒸发2小时。为了量化保留的抗生素的量,将样品物质悬浮在50%乙腈中,通过0.2μm低蛋白质结合亲水性膜(Millipore,Billerica,MA)过滤,然后在Shimadzu高效液相色谱仪(FisherScientific)上使用BetaBasic C18反相柱(Thermo Scientific)进行分离。使用两种流动相溶液进行分离,所述流动相溶液由溶液(A)具有0.1%甲酸的水和溶液(B)100%ACN组成。色谱运行的梯度特征如下:从0至0.1min,8%溶液B,从0.1至6.5min逐步升高(37%至60%溶液B),然后保持一分钟,之后从7.5至8min从60%逐步降低至10%。随后在10%溶液B下保持一分钟。从10至13min,梯度升高至100%溶液B并且保持直到11.5分钟并且然后降低至8%溶液B并且在这些条件下再持续四分钟。在40℃下以8%溶液B平衡柱并且将流速设定为0.2mL min-1。使用Thermo TSQ Quantum Ultra三重四极杆质谱仪(Fisher Scientific)进行级分的质谱分析。使用Xcalibur软件(Thermo Scientific)分析数据;使用以下参数检测米诺环素和内部对照多西环素:对于米诺环素为458.208m/z→282.971m/z(碰撞能量=43,镜筒透镜=119)并且对于多西环素为445.144m/z→266.900m/z(碰撞能量=39,镜筒透镜=127)。通过使用利用Genesis算法的曲线下面积计算确定每种样品中的浓度来进行原始数据分析。将预先建立的米诺环素的峰强度和y截距与多西环素标准曲线之间的差值除以标准曲线的斜率,以量化每种样品内的米诺环素的量。通过将每个相应培养物内的细胞数目归一化来计算每个孔内的米诺环素的总浓度。
在血清中生长(外排泵活性条件)期间,细胞米诺环素浓度被测定为1.58x 10-10飞摩尔/细菌细胞,而加入已知外排泵抑制剂维拉帕米使细胞浓度增加了将近1,000倍(3.56x10-7飞摩尔细胞-1),这表明所述方法适于测量外排泵依赖性细胞抗生素累积。如图2所示,虽然几乎所有评价的化合物与假处理的细胞相比似乎诱导米诺环素累积,但是有41种化合物刺激血清生长的鲍氏不动杆菌细胞内的米诺环素累积至等于或超过已知抗生素外排泵抑制剂维拉帕米水平的水平,并且被视为可能包括外排泵抑制剂的最高优先级药剂以及经由未理解方式导致抗生素累积的化合物。这41种化合物被视为假定临床上有价值的试剂,它们增强抗微生物活性和米诺环素在血清中的鲍氏不动杆菌内的细胞内累积,并且接着进行进一步鉴定。
实施例4:细胞毒性测定
为了区分假定无毒的化合物与人类细胞毒性化合物,对每种化合物以其1X和4XMEC进行常规3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化鎓(MTT)细胞活力测定(American Type Culture Collection,Manassas,VA)。简言之,使人类HepG2细胞在补充有10%胎牛血清(Invitrogen,Carlsbad,CA)的达尔伯克改良伊格尔培养基中生长至约1x106个细胞/孔,然后用1X或4X MEC的单独指定化合物或所述化合物与0.5μg ml-1米诺环素的组合处理24小时。根据制造商建议在加入四唑鎓盐(MTT)后测量细胞活力;用50ug ml-1丝裂霉素C(Sigma Aldrich)挑战的细胞和假处理的细胞分别用作阳性对照和阴性对照。
如表1所示,19种(46.3%)测试的化合物引起针对HepG2细胞的显著毒性,所定义的毒性在4X MEC处理48小时期间具有<75%细胞存活。相反,22种(53.6%)化合物显示≥75%存活(75.1%至100%)并且被认为显示无人类细胞毒性或低水平人类细胞毒性。应注意,将75%人类细胞存活用作筛选标准是因为它近似于抗生素米诺环素当在这些测定条件中单独测试时的毒性量度(在2μg ml-1下的77.9%HepG2存活)。
实施例5:活性谱
作为基于其治疗前景进一步对感兴趣的无毒化合物划分优先级的方式,认为广谱抗微生物外排泵抑制剂在临床上比仅增强有限数目的抗生素的活性或者显示针对单一细菌种类的活性的窄谱药剂更有价值。如上所述,除米诺环素之外,人类血清中的鲍氏不动杆菌生长促成外排泵和生物体的环丙沙星耐受性(图1A)。因此,评价每种化合物是否增强环丙沙星针对血清生长的细胞的活性。为此,将1x 105个鲍氏不动杆菌菌株98-37-09接种到含有补充有0.125μg ml-1环丙沙星和0、1X或2X化合物MEC(如通过增强米诺环素抗微生物作用所需要的最低浓度所定义)的100%人类血清的微量滴定板的单个孔中(以上)。将板培育48小时,此时将每种化合物增强环丙沙星的能力测量为生长抑制。所评价的十九种化合物在这些条件期间并不影响生物体对环丙沙星的耐受性,这显示它们均是限制米诺环素而非环丙沙星外排泵的窄谱药剂。相反,3种化合物增强环丙沙星抗微生物活性,这显示它们可代表光谱抗生素药物外排泵抑制剂。平板培养证实,当与环丙沙星组合施用时,与用单独的环丙沙星处理的细胞相比,每种化合物在1X化合物MEC下使鲍氏不动杆菌活力减小至少1.5log(图3A;表1)。
还研究革兰氏阴性病原体克雷伯氏肺炎菌和绿脓假单胞菌是否在人类血清中生长期间显示对米诺环素和/或环丙沙星的抗生素耐受性。虽然克雷伯氏肺炎菌菌株CKP4并未显示耐受性,但是发现血清生长的绿脓假单胞菌PA01细胞展示出外排泵介导的对环丙沙星的耐受性,如以下所述。因此,作为评价活性谱并且同时识别增强抗生素对细菌种类的活性的最高优先级的感兴趣化合物的另一种方式,评价上述三种假定的光谱鲍氏不动杆菌外排泵抑制剂是否也显示绿脓假单胞菌血清依赖性环丙沙星耐受性。为此,将PA01接种到含有补充有1X MEC测试化合物和增加浓度的环丙沙星(0至2μg ml-1)的100%人类血清的微量滴定板的单个孔中,并且测量细胞活力。结果显示三种假定光谱外排泵抑制剂中的两种也增强环丙沙星针对血清生长的绿脓假单胞菌的活性(图3B),这显示这些化合物ABEPI1和ABEPI1(图3C)代表可增强抗生素针对至少两种直接健康问题的细菌种类鲍氏不动杆菌和绿脓假单胞菌的抗微生物特征的广谱药剂。
为了区分ABEPI1和ABEPI2的抗微生物增强是否与鲍氏不动杆菌外排泵特征的抑制相关,在每种化合物存在和不存在下进行常规溴化乙锭外排泵测定。在***细胞核酸期间预测针对溴化乙锭荧光特征的测定,由此外排活性细胞显示有限的细胞内溴化乙锭累积并且因此显示低荧光。相反,外排抑制导致细胞溴化乙锭水平增加并且相应地相对于精通外排的细胞具有高荧光。使用细胞溴化乙锭外排活性测定来测量感兴趣化合物的外排抑制特征。对于测定,将鲍氏不动杆菌菌株98-37-09的过夜培养物稀释(1∶100)到100%人类血清或新鲜LB中并且生长至指数生长中期。经由900xg离心20分钟来收集细胞沉淀,用20mM磷酸钠缓冲液洗涤3x并且将其在磷酸钠缓冲液中重悬至OD600nm=0.2。将约1X 106CFU装载到96孔白底板的单个孔中,与10μg ml-1溴化乙锭混合,并且在Spectramax5荧光计(MolecularDevices,Sunnyvale,CA)上测量乙锭荧光(激发530nm;发射600nm),每5分钟一次,持续90分钟。为了确定假定外排泵抑制剂是否影响溴化乙锭外排,用指定量的感兴趣的化合物或外排泵抑制剂PaβN处理细胞,两分钟后开始荧光监测。将假处理的细胞用作阴性对照;平板培养证实所使用的测试条件并不影响细胞活力。
如图4所示,假处理的细胞显示低水平溴化乙锭荧光信号,所述信号在实验过程期间缓慢增加,可能反映了随着时间的缓慢染料累积(尽管有外排泵活动)。相反,与假处理细胞相比,外排缺陷型PAβN处理的细胞显示显著增加的细胞溴化乙锭累积,这证实测定条件适于测量鲍氏不动杆菌细胞的外排特征。同样地,与假处理的细胞相比,ABEPI1和ABEPI2二者在所有测量的时间点均显示显著增加的信号,这表明它们用作鲍氏不动杆菌外排泵抑制剂。更具体地说,在处理的前20分钟内APEPI1显著增加细胞荧光至超过PABN水平的水平,此时所述化合物的效能似乎稳定。APEPI2处理测量值基本上与PAβN的测量值相同,直到处理后约35分钟后,此时外排抑制似乎降低至低于PAβN水平,尽管所观察到的差异并不认为是显著不同的。因此,ABEPI1和ABEPI2代表新颖细菌药物外排泵抑制剂。
实施例6:哺乳动物钙通道测定
许多实验室细菌外排泵抑制剂工具化合物不能用于临床环境,因为它们限制了哺乳动物离子通道活性。维拉帕米就是一种这样的药剂,它不仅有效限制了细菌抗生素外排泵,而且由于宿主Ca2+通道而引起人类神经毒性。因此,使用Fluo-4直接钙通道测定试剂盒(Life Technologies,Carlsbad,CA)测量ABEPI1和ABEPI2对哺乳动物钙通道功能的作用,其中染料Fluo-4用于测量哺乳动物细胞质Ca2+水平在测试化合物不存在和存在下响应于钙通道刺激剂卡巴胆碱的变化。简言之,使5x 104人类HEK 293T胚胎肾细胞在96孔黑壁板(Corning Incorporated,Corning,NY)的每个孔中生长。接着,将补充有丙磺舒(5mM)的2X Fluo-4染料加入到每个孔中并且允许在37℃下平衡1小时。为了确定ABEPI1或ABEPI2是否影响Ca2+通道活性,每秒采集Fluo-4荧光测量值(激发495nm;发射516nm),持续15秒。此时,用DMSO(假处理)、50μg mL-1Ca2+通道抑制剂维拉帕米(阳性对照)或1X MECABEPI1或ABEPI2处理细胞,接着在60秒后用钙通道刺激剂甲氨酰基胆碱氯(50μg ml-1;ThermoFisher Scientific,Waltham,MA)处理并且在FlexStation 3台式多模式微量板读数计(Molecular Devices,Sunnyvale,CA)再持续120秒来测量荧光。
图5A示出在加入卡巴胆碱之前和之后的人类胚胎肾(HEK 293T)细胞内Ca2+水平的曲线,所述卡巴胆碱刺激内质钙-通道活性并因此使Ca2+释放到细胞质。卡巴胆碱处理诱导了细胞质Ca2+水平的约2.3倍增加。相反,用已知钙通道抑制剂维拉帕米处理HEK 293T细胞基本上消除了Ca2+通道活性和细胞质累积,这表明所述***适于测量哺乳动物细胞质通道活性和抑制(图5B)。如图5C和图5D所示,用1X MEC ABEPI1或ABEPI2进行HEK 293T处理似乎并不显著影响哺乳动物细胞Ca2+通道响应于卡巴胆碱的刺激。
总之,ABEPI1和ABEPI2代表新颖的、结构不同的分子,所述分子通过抑制生物体药物外排特征来增强抗生素针对血清生长的细菌细胞的活性,从而引起细胞抗生素累积并因此引起抗微生物效应。这些化合物作为与目前用于改进细菌感染的治疗的抗生素结合使用的辅助外排泵抑制剂为有效的。
随附权利要求书的化合物和方法的范围不限于本文中描述的特定化合物和方法,所述化合物和方法意图作为权利要求书的几个方面的说明,并且功能等效的任何化合物和方法都在本公开的范围内。除了本文中示出和描述的化合物和方法之外,预期所述化合物和方法的各种修改属于随附权利要求书的范畴。此外,虽然仅特定描述了某些代表性化合物、方法以及这些化合物和方法的方面,但是预期其他化合物和方法以及所述化合物和方法的各种特征的组合也属于随附权利要求书的范畴,即使不特定地叙述也是如此。因此,本文中可明确地提到步骤、要素、组分或组成的组合;然而,即使不明确说明,也包括步骤、要素、组分和组成的所有其它组合。本文引用的所有出版物、专利和专利申请均出于所有目的以引用的方式整体并入本文。
Claims (56)
1.一种用于治疗受试者的微生物感染的方法,其包括:
向所述受试者施用有效量的具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中
L为直接键或者取代或未取代的连接单元;
R2、R3、R4、R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或未取代的杂芳基、取代或禾取代的烷氧基、取代或未取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或禾取代的磺酰基;并且
X选自由以下组成的组:取代或禾取代的烷基、取代或禾取代的杂烷基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的磺酰基、或者取代或禾取代的羧基;以及
抗微生物剂。
2.如权利要求1所述的方法,其中所述外排泵抑制剂为
其中
R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或禾取代的烯基、取代或未取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
3.如权利要求1所述的方法,其中所述外排泵抑制剂为
其中
R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基;并且
R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
4.如权利要求1所述的方法,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组。
5.如权利要求1所述的方法,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组;并且
R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
6.如权利要求1所述的方法,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组;
R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基;并且
R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
7.如权利要求1所述的方法,其中所述外排泵抑制剂其中所述外排泵抑制剂为
8.一种用于治疗受试者的微生物感染的方法,其包括:
向所述受试者施用有效量的具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中R1、R2和R3各自独立地选自氢、取代的烷基、取代的烯基、取代的炔基、取代或未取代的芳基、或者取代或未取代的杂芳基;以及
抗微生物剂。
9.如权利要求8所述的方法,其中所述外排泵抑制剂为
10.如权利要求8或9所述的方法,其中所述外排泵抑制剂为
11.一种用于治疗受试者的微生物感染的方法,其包括:
向所述受试者施用有效量的外排泵抑制剂和抗微生物剂,其中所述外排泵抑制剂选自由以下组成的组:
12.如权利要求1-11中任一项所述的方法,其还包括选择被对所述抗微生物剂有抗性的微生物感染的受试者。
13.如权利要求1-12中任一项所述的方法,其还包括选择被能够形成对所述抗微生物剂的抗性的微生物感染的受试者。
14.如权利要求12或13所述的方法,其中所述抗性由外排泵介导。
15.如权利要求1-14中任一项所述的方法,其中所述微生物感染为细菌感染。
16.如权利要求15所述的方法,其中所述微生物感染为革兰氏阴性细菌感染。
17.如权利要求16所述的方法,其中所述革兰氏阴性细菌感染为不动杆菌属细菌感染。
18.如权利要求17所述的方法,其中所述不动杆菌属细菌感染为鲍氏不动杆菌感染。
19.如权利要求16所述的方法,其中所述革兰氏阴性细菌感染为假单胞菌属细菌感染。
20.如权利要求19所述的方法,其中所述假单胞菌属细菌感染为绿脓假单胞菌感染。
21.如权利要求15所述的方法,其中所述细菌感染为***感染。
22.如权利要求1-21中任一项所述的方法,其中所述抗微生物剂选自由以下组成的组:米诺环素、环丙沙星、左氧氟沙星、萘啶酸、阿米卡星、庆大霉素、卡那霉素、美罗培南、头孢曲松、红霉素、粘杆菌素多粘菌素B、磺胺甲噁唑、替加环素、妥布霉素,以及甲氧苄啶。
23.如权利要求1-22中任一项所述的方法,其中所述外排泵抑制剂和所述抗微生物剂依次施用。
24.如权利要求1-22中任一项所述的方法,其中所述外排泵抑制剂和所述抗微生物剂同时施用。
25.一种用于抑制细胞内的外排泵的方法,其包括:
使所述细胞接触有效量的具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中
L为直接键或者取代或禾取代的连接单元;
R2、R3、R4、R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或禾取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或禾取代的磺酰基;并且
X选自由以下组成的组:取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的磺酰基、或者取代或未取代的羧基。
26.如权利要求25所述的方法,其中所述外排泵抑制剂为
其中
R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或禾取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的羰基、取代或禾取代的羧基、或者取代或未取代的磺酰基。
27.如权利要求25所述的方法,其中所述外排泵抑制剂为
其中
R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基;并且
R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
28.如权利要求25所述的方法,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组。
29.如权利要求25所述的方法,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组;并且
R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或禾取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
30.如权利要求25所述的方法,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组;
R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基;并且
R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
31.如权利要求25所述的方法,其中所述外排泵抑制剂为
32.一种用于抑制细胞内的外排泵的方法,其包括:
使所述细胞接触有效量的具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中R1、R2和R3各自独立地选自氢、取代的烷基、取代的烯基、取代的炔基、取代或未取代的芳基、或者取代或未取代的杂芳基;以及
抗微生物剂。
33.如权利要求32所述的方法,其中所述外排泵抑制剂为
34.如权利要求32所述的方法,其中所述外排泵抑制剂为
35.一种用于抑制细胞内的外排泵的方法,其包括
使所述细胞接触有效量的外排泵抑制剂和抗微生物剂,其中所述外排泵抑制剂选自由以下组成的组:
36.如权利要求25-35中任一项所述的方法,其中所述细胞为微生物细胞。
37.如权利要求36所述的方法,其中所述微生物细胞为细菌细胞。
38.如权利要求37所述的方法,其中所述细菌细胞为革兰氏阴性细菌细胞。
39.如权利要求38所述的方法,其中所述革兰氏阴性细菌细胞为不动杆菌属细菌细胞。
40.如权利要求39所述的方法,其中所述不动杆菌属细菌细胞为鲍氏不动杆菌细菌细胞。
41.如权利要求38所述的方法,其中所述革兰氏阴性细菌细胞为假单胞菌属细菌细胞。
42.如权利要求41所述的方法,其中所述假单胞菌属细菌细胞为绿脓假单胞菌细菌细胞。
43.如权利要求37所述的方法,其中所述细菌细胞为***细胞。
44.一种药物组合物,其包含:
具有下式的外排泵抑制剂
或其药学上可接受的盐或前药,其中
L为直接键或者取代或禾取代的连接单元;
R2、R3、R4、R5和R6各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基;并且
X选自由以下组成的组:取代或未取代的烷基、取代或未取代的杂烷基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或禾取代的磺酰基、或者取代或禾取代的羧基;以及
抗微生物剂。
45.如权利要求44所述的组合物,其中所述外排泵抑制剂为
其中
R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或禾取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
46.如权利要求44所述的组合物,其中所述外排泵抑制剂为
其中
R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或禾取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或禾取代的芳基、取代或禾取代的杂芳基、取代或禾取代的烷氧基、取代或禾取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基;并且
R12和R13各自独立地选自由以下组成的组:氢、取代或未取代的脒、取代或未取代的烷基、取代或未取代的芳基,以及取代或未取代的杂芳基。
47.如权利要求44所述的组合物,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组。
48.如权利要求44所述的组合物,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组;并且
R7、R8、R9、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或未取代的烯基、取代或未取代的炔基、取代或未取代的杂烷基、取代或未取代的杂烯基、取代或未取代的杂炔基、取代或未取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或未取代的磺酰基。
49.如权利要求44所述的组合物,其中所述外排泵抑制剂为
其中
R1选自由氢和取代或未取代的烷基组成的组;
R7、R8、R10和R11各自独立地选自由以下组成的组:氢、卤素、羟基、氰基、硝基、三氟甲基、取代或未取代的烷基、取代或禾取代的烯基、取代或禾取代的炔基、取代或禾取代的杂烷基、取代或禾取代的杂烯基、取代或禾取代的杂炔基、取代或禾取代的氨基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的烷氧基、取代或未取代的芳基氧基、取代或未取代的羰基、取代或未取代的羧基、或者取代或禾取代的磺酰基;并且
R12和R13各自独立地选自由以下组成的组:氢、取代或禾取代的脒、取代或禾取代的烷基、取代或未取代的芳基,以及取代或禾取代的杂芳基。
50.如权利要求44所述的组合物,其中所述外排泵抑制剂为
51.一种药物组合物,其包含:
具有下式的外排泵抑制剂:
或其药学上可接受的盐或前药,其中R1、R2和R3各自独立地选自氢、取代的烷基、取代的烯基、取代的炔基、取代或禾取代的芳基、或者取代或禾取代的杂芳基;以及
抗微生物剂。
52.如权利要求51所述的组合物,其中所述外排泵抑制剂为
53.如权利要求51所述的组合物,其中所述外排泵抑制剂为
54.一种药物组合物,其包含外排泵抑制剂和抗微生物剂,其中所述外排泵抑制剂选自由以下组成的组:
55.如权利要求44-54中任一项所述的组合物,其中所述抗微生物剂选自由以下组成的组:米诺环素、环丙沙星、左氧氟沙星、萘啶酸、阿米卡星、庆大霉素、卡那霉素、美罗培南、头孢曲松、红霉素、粘杆菌素多粘菌素B、磺胺甲噁唑、替加环素、妥布霉素,以及甲氧苄啶。
56.如权利要求44-55中任一项所述的组合物,其还包含药学上可接受的载体。
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CN108822089A (zh) * | 2018-08-22 | 2018-11-16 | 大连理工大学 | 2-芳基咪唑烷类化合物、制备方法及其作为Hsp90抑制剂在抗肿瘤上的应用 |
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US9834514B2 (en) * | 2015-04-20 | 2017-12-05 | New Mexico Tech Research Foundation | Antibiotic sensitivity-restoring and photosensitive agents |
US11110080B2 (en) | 2017-03-27 | 2021-09-07 | The Regents Of The University Of Colorado, A Body Corporate | Small molecule inhibitors of bacterial efflux pumps and methods of using same |
CN107216305B (zh) * | 2017-05-03 | 2020-05-08 | 中国人民解放军第四军医大学 | 一类苯并吡喃类化合物及其应用 |
EP3737664B1 (en) * | 2018-01-09 | 2024-04-10 | The Hong Kong Polytechnic University | Antimicrobial 2-[[(phenyl)imino]methyl]-4-nitro-phenol derivatives and related compounds as inhibitors of the nusb-nuse interaction of microorganisms for the treatment of bacterial infections |
MX2020008404A (es) | 2018-02-13 | 2020-09-25 | Gilead Sciences Inc | Inhibidores de molecula de muerte programada 1 (pd-1)/ligando de molecula de muerte programada 1 (pd-l1). |
CA3093130C (en) | 2018-04-19 | 2023-10-17 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
AU2019301811B2 (en) | 2018-07-13 | 2022-05-26 | Gilead Sciences, Inc. | PD-1/PD-L1 inhibitors |
TWI811428B (zh) | 2018-08-21 | 2023-08-11 | 日商杏林製藥股份有限公司 | 雙環雜芳香環衍生物 |
JP7158577B2 (ja) | 2018-10-24 | 2022-10-21 | ギリアード サイエンシーズ, インコーポレイテッド | Pd-1/pd-l1阻害剤 |
WO2023044364A1 (en) | 2021-09-15 | 2023-03-23 | Enko Chem, Inc. | Protoporphyrinogen oxidase inhibitors |
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JP6678599B2 (ja) | 2020-04-08 |
EP3154534B1 (en) | 2020-02-12 |
AU2015274427A1 (en) | 2016-12-01 |
US10471028B2 (en) | 2019-11-12 |
WO2015191988A1 (en) | 2015-12-17 |
CA2952111A1 (en) | 2015-12-17 |
US20170100414A1 (en) | 2017-04-13 |
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