CN116554124A - 一种2-(2-苯并[d]噻唑氨基)乙酰胺类化合物及其制备方法和应用 - Google Patents
一种2-(2-苯并[d]噻唑氨基)乙酰胺类化合物及其制备方法和应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明涉及医药领域,发明了一类式I所示的2‑(2‑苯并[d]噻唑氨基)乙酰胺类化合物及其在抗细菌生物膜形成的应用。本发明所涉及的2‑(2‑苯并[d]噻唑氨基)乙酰胺类化合物经体内外药效验证,所得化合物大都具有优秀的细菌生物膜及群体感应抑制活性,可用于制备广谱抗生素增效剂,能增强现有抗生素的抗菌效果。
Description
技术领域
本发明属于医药领域,特别涉及一类2-(2-苯并[d]噻唑氨基)乙酰胺类化合物及其制备方法和其在制备抗菌药物中的应用。
背景技术
抗生素的发现,改变了医学的发展轨迹,使得人类极大程度降低了微生物感染带来的危害。但近几十年来,抗生素的过度使用以及社会和经济因素加速了耐药细菌的传播,并导致多重耐药耐药的“超级细菌”出现,使目前的抗微生物药物治疗无效。目前,全世界每年至少有70万人死于抗菌素耐药性(AMR)。世界卫生组织预测,如果没有新的更好的治疗方法,到2050年,这一数字可能上升到1000万。细胞耐药的频繁发生迫使人类不断开发新结构和新靶点的抗生素,然而新抗生素的开发是需要耗费大量的时间和人力物力,这对人类健康和财产构成了重大威胁。
细菌的进化衍生了多种耐药机制用于抵抗抗生素的作用,包括药物摄取减少、药物靶点改变、药物灭活、药物外排泵激活,这使得传统抗生素失去原有的抗菌效率,导致治疗失败。其中,通过形成生物膜是细菌抵抗抗生素作用的主要机制之一。近三十年来的研究表明,细菌利用生物膜和群体感应来增强菌落的防御能力。生物膜由细菌分泌胞外聚合物组成,利用其结构的特性,为细菌形成一道天然的屏障,可以逃避免疫系统的作用,并降低对抗生素的摄取,这导致生物膜内的细菌不能被轻易杀死。另一方面,细菌通过群体感应对生物膜的形成和细菌的生长进行调控,进一步增强细菌对恶劣环境的应对能力。目前临床上没有针对该类耐药机制的有效药物,与传统抗生素相比,生物膜及群体感应抑制剂能有效削弱细菌的抵抗能力,能较为广泛的增强现有抗生素对耐药菌的杀伤能力,并且因其不威胁细菌的生存而不易产生耐药,因此研究新型抗生物膜及群体感应药物对于克服抗生素耐药具有重要意义。
苯并噻唑骨架具有良好的生物膜抑制活性,因此本发明从苯并噻唑结构出发,发明了一类新型高效稳定的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物,该类化合物或其药学上可接受的盐,可作为潜在抗生物膜药物和抗生素增效剂的应用,提升临床抗菌治疗效果。
发明内容
为了克服上述现有技术的缺点与不足,本发明找到了一类2-(2-苯并[d]噻唑氨基)乙酰胺类化合物,该类化合物化学结构稳定,经过活性实验证明,其具有抗生物膜和群体感应的作用,具有新型抗生素增效剂的潜力。
本发明另一目的在于提供上述2-(2-苯并[d]噻唑氨基)乙酰胺类化合物的制备方法。
本发明再一目的在于提供上述2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐作为抗生物膜药物和抗生素增效剂的应用。
本发明的目的通过下述方案实现:
在一个方面,本发明提供一类2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物,具有如式I所示的化学结构:
其中,R1为-H,-Cl,-OCH3,-NO2中的一种;
当R1为-H时,R2为C5~C8直链的烷基:
当R1为-Cl,-OCH3,-NO2中的一种时,R2为C4~C8直链的烷基:
优选的,本发明所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物,具有如表1所示的化学结构:
表1.化合物的结构与命名
在另一个方面,本发明提供一种上述2-(2-苯并[d]噻唑氨基)乙酰胺类化合物的制备方法,具体包括以下步骤:
(1.1)将不同基团取代的2-氨基苯并噻唑、二碳酸二叔丁酯和三乙胺在溶剂中进行反应,反应结束后得到的反应液经纯化即得化合物2;
(1.2)将化合物2、溴乙酸甲酯和氢化钠置于溶剂中0℃反应,得到的反应液经纯化所得到化合物3;
(1.3)将化合物3和氢氧化钠水溶液置于溶剂中50℃反应,得到的反应液经纯化所得到化合物4a-4d;
(1.4)化合物4a-4d、脂肪胺、HOBt和EDCI在溶剂中反应,得到的反应液经纯化得到化合物5a-5q;
(1.5)将化合物5a-5q于盐酸的甲醇溶液中反应,得到的反应液经纯化后得到化合物SN1-SN17;
此合成路线为:
优选的,反应条件为:(a)(Boc)2O,Et3N,DMAP,DCM,rt,4h;(b)ethylbromoacetate,NaH,dry DMF,rt,3h;(c)NaOH,H20,MeOH,40℃,6h;(d)Ethylamine~n-octylamine,HOBT,EDC,Et3N,dry DCM,40℃,4h;(e)HCl,MeOH,40℃,6h。
在又一个方面,本发明提供上述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备抗生物膜药物和抗生素增效剂中的应用。
优选的,所述生物膜为细菌生物膜。更优选的,所述细菌为铜绿假单胞菌。
优选的,所述抗生素用于抑制铜绿假单胞菌。
在又一个方面,本发明提供上述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备抗菌药物中的应用。
优选的,所述菌为细菌,更优选为铜绿假单胞菌。
在又一个方面,本发明提供了一种药物组合物,其包含2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物中的至少一种。
优选的,所述的药物还包含一种或多种药学上可接受的载体或赋形剂。
在又一个方面,本发明提供了一种联用药物,包括2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物中的至少一种,以及环丙沙星。
优选的,其中2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物与环丙沙星的质量比为50:0.5~20,优选50:1~10。
本发明相对于现有技术,具有如下的优点及有益效果:
(1)本发明从具有一定生物活性的苯并噻唑结构出发,经结构改造,发明了一种化学性质稳定的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物,经结晶紫染色法检测化合物对抗铜绿假单胞菌的抗生物膜抑制活性,荧光报告菌株实验检测化合物的群体感应抑制活性,利用动物模型测定最优化合物的抗生素增效作用,测定本发明所述的一种2-(2-苯并[d]噻唑氨基)乙酰胺类化合物对细菌的抗生物膜效果和抗生素增效作用,结果显示大部分化合物对铜绿假单胞菌具有优秀的生物膜抑制效果,并增强了环丙沙星的抗菌作用。
附图说明
图1为化合物SN11对环丙沙星的增效作用。(A)Control组、单独CIP给药组和SN11-CIP联合给药组小鼠伤口感染区域的细菌涂板结果。每组实验重复3次;(B)小鼠伤口感染区域的细菌存活率。*P<0.05,**P<0.01,***P<0.001,****P<0.0001;(C)对小鼠伤口感染区域的拍照监测;(D)小鼠伤口面积的监测,使用Image J计算伤口面积;(E)Control组、CIP组和SN11-CIP组小鼠心、肝、脾、肺、肾的代表性组织免疫图像。
具体实施方式
以下结合具体实施方式对本发明作进一步说明。
实施例中所用试剂如无特殊说明均可从市场常规购得。
实施例1:N-(苯并[d]噻唑-2-基)-N-(叔丁氧羰基)甘氨酸(中间体4a-4d)的制备
步骤一:苯并[d]噻唑-2-基氨基甲酸叔丁酯(中间体2)的制备
把2-氨基苯并噻唑(0.01mol)溶入于二氯甲烷中,加入三乙胺和DMAP(0.0002mol)后在室温下保持搅拌,然后滴加(Boc)2O(0.012mol),待溶剂滴加完成后,以继续反应约4h,终止反应。去除反应体系中残余的有机溶剂,然后用石油醚/乙酸乙酯(48:2)重结晶,减压抽滤,获得灰色的固体为中间体2,产率85%。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),7.92(d,J=7.9Hz,1H),7.70–7.63(m,1H),7.39(t,J=7.7Hz,1H),7.28–7.22(m,1H),1.51(d,J=2.1Hz,9H).13C NMR(101MHz,DMSO)δ160.05,153.41,149.53,132.56,126.46,123.61,121.89,120.61,82.28,28.31.
步骤二:N-(苯并[d]噻唑-2-基)-N-(叔丁氧基羰基)甘氨酸甲酯(中间体3)的制备
将中间体2(0.01mol)置于50mL的两口烧瓶中,用适量的无水DMF进行溶解,并置于0溶下加入氢化钠(0.012mol)搅拌30min,后滴加溴乙酸甲酯(0.011mol),继续反应约2h后加少量冰水淬灭反应。用100mL×3乙酸乙酯萃取后合并有机相,接着用100mL×3饱和的NH4Cl液洗和100mL×3饱和的NaCl液洗,直至流出水层为中性。用MgSO4充分干燥后抽滤,除去溶剂,残留物用快速色谱法(石油醚-乙酸乙酯=80/20v/v)纯化,得到白色固体为中间体3,产率70%。1H NMR(400MHz,Chloroform-d)δ7.87–7.72
(m,2H),7.40(ddd,J=8.4,7.3,1.3Hz,1H),7.30–7.26(m,1H),5.01(s,2H),3.79(s,3H),
1.60(s,9H).13C NMR(101MHz,CDCl3)δ169.12,160.52,148.80,133.67,133.41,125.78,123.51,121.20,120.82,77.24,52.31,48.10,28.08.
步骤三:N-(苯并[d]噻唑-2-基)-N-(叔丁氧羰基)甘氨酸(中间体4a)的制备
将中间体3(0.01mol)用甲醇溶解,加入2N氢氧化钠水溶液(含氢氧化钠0.02mol),于50℃下搅拌6h,终止反应。去除甲醇,用1mol/L的HCl调节其pH至5,固体析出,减压抽滤后真空干燥,得到白色的固体为中间体4a,产率:90%。4b-4d制备方法同4a。1HNMR(400MHz,DMSO-d6)δ12.88(s,1H),7.95(d,J=7.9Hz,1H),7.73(d,J=8.2Hz,1H),7.42(t,J=7.8Hz,1H),7.30(t,J=7.7Hz,1H),4.83(s,2H),1.52(s,9H).13C NMR(101MHz,DMSO)δ169.95,169.09,160.79,148.80,133.32,126.59,124.18,121.91,121.23,52.75,48.33,28.03.
实施例2:2-(2-苯并[d]噻唑氨基)乙酰胺类化合物(化合物SN1)
以中间体4a(0.60mmol)溶于二氯甲烷中,加入1-羟基苯并三唑(HOBT,0.72mmol)和三乙胺(1.20mmol),室温搅拌反应30min,后加入EDCI(0.72mmol)和戊胺(0.72mmol)反应6h,终止反应。用30mL×3乙酸乙酯萃取,分别用30mL×3饱和的NaHCO3液洗、30mL×3饱和的NH4Cl液洗和100mL×3饱和的NaCl液洗,直至流出水层为中性。合并有机相用MgSO4充分干燥后抽滤,除去溶剂,残留物用快速色谱法(石油醚-乙酸乙酯=60/40v/v)纯化,得到白色固体为中间体5a。将5a置于6N盐酸甲醇溶液中,室温搅拌反应12h,终止反应。用1mol/L的NaOH调节其pH至7,去除溶剂,用石油醚-乙酸乙酯重结晶,获得白色固体为化合物SN1,产率:53%。1H NMR(400MHz,DMSO-d6)δ8.23(t,J=5.6Hz,1H),7.97(t,J=5.6Hz,1H),7.67(dd,J=7.8,1.3Hz,1H),7.37(d,J=8.2Hz,1H),7.21(td,J=7.7,1.4Hz,1H),7.02(td,J=7.6,1.3Hz,1H),3.98(d,J=5.6Hz,2H),3.08(q,J=6.6Hz,2H),1.40(p,J=6.9Hz,2H),1.33–1.18(m,4H),0.83(t,J=6.7Hz,3H).13C NMR(101MHz,DMSO)δ168.95,166.72,152.63,131.09,125.96,121.57,121.39,118.57,47.12,38.98,29.20,28.97,22.29,14.32.
实施例3:2-(2-苯并[d]噻唑氨基)-N-己基乙酰胺(化合物SN2)
以中间体4a(0.60mmol)和己胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN2,产率:47%。1H NMR(400MHz,DMSO-d6)δ8.23(t,J=5.6Hz,1H),7.96(t,J=5.5Hz,1H),7.67(d,J=7.8Hz,1H),7.37(d,J=7.8Hz,1H),7.21(t,J=7.6Hz,1H),7.02(t,J=7.4Hz,1H),3.98(d,J=5.7Hz,2H),3.08(q,J=6.5Hz,2H),1.39(t,J=6.9Hz,2H),1.31–1.15(m,6H),0.83(t,J=6.2Hz,3H).13C NMR(101MHz,DMSO)δ168.88,166.67,152.67,131.13,125.91,121.50,121.39,118.55,47.08,39.00,31.46,29.52,26.48,22.51,14.37.
实施例4:2-(2-苯并[d]噻唑氨基)-N-庚基乙酰胺(化合物SN3)
以中间体4a(0.60mmol)和庚胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN3,产率:49%。1H NMR(400MHz,DMSO-d6)δ8.24(t,J=5.8Hz,1H),7.96(t,J=5.7Hz,1H),7.67(dd,J=7.9,1.2Hz,1H),7.37(dd,J=8.1,1.1Hz,1H),7.22(td,J=7.7,1.3Hz,1H),7.03(td,J=7.5,1.2Hz,1H),3.98(d,J=5.6Hz,2H),3.08(q,J=6.6Hz,2H),1.40(t,J=6.9Hz,2H),1.23(q,J=6.5,5.3Hz,8H),0.90–0.79(m,3H).13C NMR(101MHz,DMSO)δ168.89,166.67,152.68,131.14,125.91,121.50,121.39,118.55,47.10,38.98,31.71,29.56,28.91,26.76,22.52,14.41.
实施例5:2-(2-苯并[d]噻唑氨基)-N-辛基乙酰胺(化合物SN4)
以中间体4a(0.60mmol)和辛胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN4,产率:51%。1H NMR(400MHz,Methanol-d4)δ7.61(d,J=8.0Hz,1H),7.46(d,J=8.2Hz,1H),7.27(t,J=7.8Hz,1H),7.09(t,J=7.6Hz,1H),4.08(d,J=6.0Hz,2H),3.28–3.09(m,2H),1.50(q,J=7.0Hz,2H),1.26(d,J=12.7Hz,11H),0.89(t,J=6.7Hz,3H).13C NMR(101MHz,MeOD)δ170.19,166.61,151.66,130.38,125.48,121.62,120.47,118.12,46.72,39.04,31.56,29.02,29.00,28.96,26.54,22.29,13.00.
实施例6:2-[(6-氯-2-苯并[d]噻唑基)氨基]-N-丁基乙酰胺(化合物SN5)
以中间体4c(0.60mmol)和丁胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN5,产率:47%。1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.89(d,J=73.9Hz,2H),7.28(d,J=41.1Hz,2H),3.98(s,2H),3.08(s,2H),1.33(d,J=44.1Hz,4H),0.85(s,3H).13C NMR(101MHz,DMSO)δ168.68,167.30,151.62,132.86,126.06,125.22,121.10,119.40,47.05,38.67,31.66,19.93,14.12.
实施例7:2-[(6-氯-2-苯并[d]噻唑基)氨基]-N-戊基乙酰胺(化合物SN6)
以中间体4c(0.60mmol)和戊胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN6,产率:49%。1H NMR(400MHz,DMSO-d6)δ8.36(t,J=5.7Hz,1H),7.98(t,J=5.7Hz,1H),7.80(d,J=2.2Hz,1H),7.34(d,J=8.5Hz,1H),7.23(dd,J=8.6,2.3Hz,1H),3.98(d,J=5.7Hz,2H),3.07(q,J=6.6Hz,2H),1.40(p,J=7.0Hz,2H),1.29–1.19(m,4H),0.83(t,J=6.8Hz,3H).13C NMR(101MHz,DMSO)δ168.68,167.30,151.61,132.86,126.06,125.23,121.09,119.40,47.05,38.96,29.22,28.99,22.30,14.36.
实施例8:2-[(6-氯-2-苯并[d]噻唑基)氨基]-N-己基乙酰胺(化合物SN7)
以中间体4c(0.60mmol)和己胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN7,产率:48%。1H NMR(400MHz,DMSO-d6)δ8.36(t,J=5.7Hz,1H),7.98(t,J=5.7Hz,1H),7.80(d,J=2.2Hz,1H),7.33(d,J=8.5Hz,1H),7.23(dd,J=8.5,2.2Hz,1H),3.98(d,J=5.6Hz,2H),3.07(q,J=6.6Hz,2H),1.38(q,J=6.9Hz,2H),1.28–1.18(m,6H),0.87–0.79(m,3H).13C NMR(101MHz,DMSO)δ168.68,167.28,151.59,126.06,125.22,121.10,119.40,47.04,39.00,31.45,29.50,26.47,22.51,14.37.
实施例9:2-[(6-氯-2-苯并[d]噻唑基)氨基]-N-庚基乙酰胺(化合物SN8)
以中间体4c(0.60mmol)和庚胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN8,产率:48%。1H NMR(400MHz,Methanol-d4)δ7.67(d,J=2.2Hz,1H),7.40(d,J=8.5Hz,1H),7.26(dd,J=8.6,2.2Hz,1H),4.08(s,2H),3.21(q,J=5.7,4.4Hz,2H),1.49(q,J=7.1Hz,2H),1.27(qd,J=7.6,3.5Hz,8H),0.88(t,J=6.9Hz,3H).13C NMR(101MHz,DMSO)δ169.11,166.86,149.96,131.37,125.64,125.06,119.54,118.26,45.97,38.26,30.77,28.27,27.96,25.72,21.48,12.39.
实施例10:2-[(6-氯-2-苯并[d]噻唑基)氨基]-N-辛基乙酰胺(化合物SN9)
以中间体4c(0.60mmol)和辛胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN9,产率:50%。1H NMR(400MHz,DMSO-d6)δ8.36(d,J=6.4Hz,1H),7.97(d,J=6.1Hz,1H),7.79(s,1H),7.34(dd,J=8.7,2.6Hz,1H),7.22(d,J=8.6Hz,1H),3.98(d,J=5.7Hz,2H),3.07(t,J=7.0Hz,2H),1.38(q,J=14.1,10.5Hz,2H),1.21(s,10H),0.83(d,J=7.5Hz,3H).13C NMR(101MHz,DMSO)δ168.69,167.29,151.62,132.86,126.04,125.23,121.09,119.39,47.07,38.98,31.70,29.53,29.21,29.14,26.81,22.56,14.39.
实施例11:2-[(6-甲氧基-2-苯并[d]噻唑基)氨基]-N-戊基乙酰胺(化合物SN10)
以中间体4b(0.60mmol)和戊胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN10,产率:52%。1H NMR(400MHz,DMSO-d6)δ7.97(dt,J=26.8,6.0Hz,2H),7.36–7.21(m,2H),6.87–6.78(m,1H),3.94(d,J=5.6Hz,2H),3.73(s,J=2.4Hz,3H),3.07(q,J=6.8Hz,2H),1.40(p,J=7.2Hz,2H),1.31–1.18(m,4H),0.90–0.78(m,3H).13C NMR(101MHz,DMSO)δ169.03,165.09,154.88,146.75,132.15,118.90,113.38,106.00,55.99,47.10,38.94,29.24,28.99,22.31,14.36.
实施例12:2-[(6-甲氧基-2-苯并[d]噻唑基)氨基]-N-己基乙酰胺(化合物SN11)
以中间体4b(0.60mmol)和己胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN11,产率:51%。1H NMR(400MHz,DMSO-d6)δ7.98(dt,J=29.1,5.9Hz,2H),7.28(d,J=9.5Hz,2H),6.87–6.74(m,1H),3.96(d,J=5.5Hz,2H),3.73(s,3H),3.08(q,J=6.7Hz,2H),1.39(t,J=7.1Hz,2H),1.22(d,J=8.2Hz,6H),0.88–0.76(m,3H).13C NMR(101MHz,DMSO)δ169.08,165.11,154.90,146.76,132.17,118.91,113.35,105.94,55.95,47.14,39.01,31.48,29.53,26.50,22.53,14.33.
实施例13:2-[(6-甲氧基-2-苯并[d]噻唑基)氨基]-N-庚基乙酰胺(化合物SN12)
以中间体4b(0.60mmol)和庚胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN12,产率:55%。1H NMR(400MHz,DMSO-d6)δ7.97(dt,J=30.9,5.6Hz,2H),7.44–7.10(m,2H),6.82(dd,J=8.7,2.9Hz,1H),3.93(d,J=5.6Hz,2H),3.73(d,J=3.6Hz,3H),3.07(q,J=6.5Hz,2H),1.38(q,J=6.6Hz,2H),1.30–1.09(m,8H),0.83(t,J=6.8Hz,3H).13C NMR(101MHz,DMSO)δ169.03,165.08,154.88,146.75,132.16,118.90,113.37,105.98,55.98,47.12,38.96,31.71,29.56,28.91,26.76,22.52,14.40.
实施例14:2-[(6-甲氧基-2-苯并[d]噻唑基)氨基]-N-辛基乙酰胺(化合物SN12)
以中间体4b(0.60mmol)和辛胺(0.72mmol)原料,制备方法参考化合物SN1,得白色固体为化合物SN12,产率:51%。1H NMR(400MHz,DMSO-d6)δ7.97(dd,J=34.9,6.0Hz,2H),7.35–7.21(m,2H),6.86–6.75(m,1H),3.94(s,2H),3.74(d,J=1.9Hz,3H),3.07(q,J=6.7Hz,2H),1.38(q,J=7.1Hz,2H),1.23(d,J=12.2Hz,10H),0.90–0.78(m,3H).13C NMR(101MHz,DMSO)δ169.01,165.10,154.89,145.83,132.12,118.88,113.38,106.00,55.99,47.12,38.96,31.71,29.56,29.21,29.13,26.81,22.56,14.40.
实施例15:2-[(6-硝基-2-苯并[d]噻唑基)氨基]-N-戊基乙酰胺(化合物SN14)
以中间体4d(0.60mmol)和戊胺(0.72mmol)原料,制备方法参考化合物SN1,得黄色固体为化合物SN14,产率:43%。1H NMR(400MHz,DMSO-d6)δ9.12–8.92(m,1H),8.70(d,J=13.8Hz,1H),8.10(q,J=11.0,9.7Hz,2H),7.45(dd,J=15.9,8.5Hz,1H),4.06(d,J=13.8Hz,2H),3.08(dd,J=14.1,7.6Hz,2H),1.46–1.33(m,2H),1.32–1.15(m,4H),0.83(dd,J=14.4,7.2Hz,3H).13C NMR(101MHz,DMSO)δ171.50168.20,158.31,141.34,131.93,122.48,118.28,117.75,47.12,39.01,29.18,28.98,22.28,14.36.
实施例16:2-[(6-硝基-2-苯并[d]噻唑基)氨基]-N-己基乙酰胺(化合物SN15)
以中间体4d(0.60mmol)和己胺(0.72mmol)原料,制备方法参考化合物SN1,得黄色固体为化合物SN15,产率:41%。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.71(d,J=2.5Hz,1H),8.15–8.01(m,2H),7.45(d,J=8.9Hz,1H),4.07(s,2H),3.08(q,J=6.6Hz,2H),1.40(p,J=7.1,6.4Hz,2H),1.23(s,6H),0.83(d,J=6.8Hz,3H).13C NMR(101MHz,DMSO)δ171.45,168.17,158.32,141.33,131.95,122.44,118.28,117.73,47.14,39.01,31.29,29.31,26.60,22.35,14.38.
实施例17:2-[(6-硝基-2-苯并[d]噻唑基)氨基]-N-庚基乙酰胺(化合物SN16)
以中间体4d(0.60mmol)和庚胺(0.72mmol)原料,制备方法参考化合物SN1,得黄色固体为化合物SN16,产率:43%。1H NMR(400MHz,DMSO-d6)δ8.96(d,J=6.5Hz,1H),8.70(d,J=13.5Hz,1H),8.14–7.96(m,2H),7.49–7.36(m,1H),4.07(d,J=5.6Hz,2H),3.08(q,J=6.9Hz,2H),1.39(q,J=7.2Hz,2H),1.21(d,J=10.5Hz,8H),0.83(t,J=7.0Hz,3H).13CNMR(101MHz,DMSO)δ168.17,158.32,154.14,141.33,131.95,122.44,118.28,117.73,47.16,39.02,31.71,29.52,28.89,26.75,22.51,14.40.
实施例18:2-[(6-硝基-2-苯并[d]噻唑基)氨基]-N-辛基乙酰胺(化合物SN17)
以中间体4d(0.60mmol)和辛胺(0.72mmol)原料,制备方法参考化合物SN1,得黄色固体为化合物SN17,产率:41%。1H NMR(400MHz,DMSO-d6)δ8.95(t,J=5.7Hz,1H),8.70(d,J=2.5Hz,1H),8.13–8.01(m,2H),7.45(d,J=8.9Hz,1H),4.06(d,J=5.5Hz,2H),3.07(q,J=6.5Hz,2H),1.38(q,J=7.0Hz,2H),1.25–1.16(m,10H),0.82(t,J=6.7Hz,3H).13CNMR(101MHz,DMSO)δ171.45,168.17,158.32,141.33,131.95,122.44,118.28,117.73,47.15,39.02,31.69,29.51,29.19,29.13,26.80,22.55,14.39.
实施例19:化合物对铜绿假单胞菌生物膜抑制活性
实验方法:本实验采用结晶紫染色法定量测定生物膜含量:化合物最大筛选浓度为10μM,设空白对照组和阴性对照组,以阿奇霉素为阳性对照药,采用二倍稀释法将化合物稀释成一系列浓度梯度。向96孔板中分别加入75μL含药培养基,然后接种75μL菌液。置于37℃恒温培养箱中培养24h后,用PBS缓冲溶液洗去浮游细菌,加入160μL甲醇室温固定20min后,加入150μL浓度为0.1%结晶紫染色,室温放置15min,用蒸馏水洗去多余染料后,加入150μL 33%的冰乙酸,振荡均匀后,利用酶标仪在570nm波长处测定吸光值,实验重复三次,筛选出具有生物膜抑制活性的化合物,生物膜抑制活性实验结果见表1。生物膜的抑制率计算方法:
生物膜抑制率=[(ControlOD值-BlankOD值)-(药敏组OD值-BlankOD值)]/(ControlOD值-BlankOD值)
×100%。
表1所有化合物对铜绿假单胞菌生物膜的抑制作用
aIC50=抑制50%生物膜形成所需的抑制剂浓度。b大多数化合物的IC50筛选浓度为0.001~10μM。
实验结果:本发明所述2-(2-苯并[d]噻唑氨基)乙酰胺类化合物大部分均能以较低浓度抑制生物膜的形成,大部分化合物的IC50低于1μM,优于阳性对照药阿奇霉素AZM的IC50值(7.14±2.3μM)。其中,化合物SN11活性最佳的,抑制生物膜IC50为0.04±0.02μM。
实施例20:化合物SN11在小鼠伤口感染模型中对环丙沙星(CIP)的增效研究
实验方法:本动物实验按照国家有关动物实验的规定进行。铜绿假单胞菌PAO1菌株用于本动物实验,雌性5周龄Babl/c小鼠购自SPF(Beijing)Biotechnology.co.Ltd.整个实验过程中小鼠生活环境保持恒温25℃,12h的光/夜循环,提供充足的食物和水。首先将20只小鼠随机分为4组,5只/组。用4%水合氯醛进行麻醉处理后,将小鼠背部毛发剃掉,在每只小鼠背部建立4-5mm的圆形伤口,并在创面接种5×108CFU的PAO1,建立伤口感染模型24h。然后分别对不同组小鼠给以不同药物进行治疗(生理盐水,1mg/ml CIP,0.01mg/mlCIP+10μM SN11,0.001mg/ml CIP+10μM SN11)。连续给药3天后,取小鼠伤口处皮肤做CFU计数,同时每天对小鼠伤口拍照监测,以计算伤口面积。
实验结果:如图1所示,小鼠连续给药3天后,联合给药治疗组小鼠伤口处的细菌明显比生理盐水组(Control)治疗的细菌减少很多。通过对伤口处细菌存活率的计算,生理盐水组细菌存活率计为100%,用1mg/ml CIP治疗3天后,细菌基本全部清除,存活率为0%。0.01mg/ml CIP+10μM SN11联合用药治疗后,存活的细菌极少,存活率趋近于0%,说明SN11对CIP的增效效果达到了100倍。0.001mg/ml CIP+50μM SN11联合用药组,细菌存活率相对Control组来说也相对较低,仅为5%左右。随后,对小鼠伤口面积的监测也得到了一致的实验结果。SN11与稀释后的CIP联合给药3天后,伤口面积与单独CIP给药组基本相同,且都比Control组的伤口面积小很多,在第9天,伤口愈合程度达到80%左右。此外,根据小鼠器官组织学H&E染色结果来看,化合物SN11对小鼠心、肝、脾、肺、肾均未造成损害。以上结果均表明,SN11作为生物膜抑制剂,对CIP具有较好的增效效果,其增效效果为100-1000倍。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于所述技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (9)
1.一类2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物,其特征在于具有如式I所示的化学结构:
其中,R1为-H,-Cl,-OCH3,-NO2中的一种;
当R1为-H时,R2为C5~C8直链的烷基:
当R1为-Cl,-OCH3,-NO2中的一种时,R2为C4~C8直链的烷基:
2.根据权利要求1所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物,其特征在于优选具有如下化合物的一种或至少两种的组合:
3.一种根据权利要求1中所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物的制备方法,其特征在于,包括以下步骤:
(1.1)将不同基团取代的2-氨基苯并噻唑、二碳酸二叔丁酯和三乙胺在溶剂中进行反应,反应结束后得到的反应液经纯化即得化合物2;
(1.2)将化合物2、溴乙酸甲酯和氢化钠置于溶剂中0℃反应,得到的反应液经纯化所得到化合物3;
(1.3)将化合物3和氢氧化钠水溶液置于溶剂中50℃反应,得到的反应液经纯化所得到化合物4a-4d;
(1.4)化合物4a-4d、脂肪胺、HOBt和EDCI在溶剂中反应,得到的反应液经纯化得到化合物5a-5q;
(1.5)将化合物5a-5q于盐酸的甲醇溶液中反应,得到的反应液经纯化后得到化合物SN1-SN17;
此合成路线为:
4.根据权利要求1~2任一项所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备抗生物膜药物和抗生素增效剂中的应用。
5.根据权利要求1~2任一项所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物在制备抗菌药物中的应用。
6.要据权利要求5所述的应用,所述菌为铜绿假单胞菌。
7.一种药物组合物,其包含根据权利要求1~2任一项所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐中的至少一种,还包含一种或多种药学上可接受的载体或赋形剂。
8.一种联用药物,包括根据权利要求1~2任一项所述的2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物中的至少一种,以及环丙沙星。
9.根据权利要求8所述的联用药物,其中2-(2-苯并[d]噻唑氨基)乙酰胺类化合物或其药学上可接受的盐、医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物与环丙沙星的质量比为50:0.5~20,优选50:1~10。
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