CN101400684B - 噻唑类化合物 - Google Patents
噻唑类化合物 Download PDFInfo
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- CN101400684B CN101400684B CN2005800478205A CN200580047820A CN101400684B CN 101400684 B CN101400684 B CN 101400684B CN 2005800478205 A CN2005800478205 A CN 2005800478205A CN 200580047820 A CN200580047820 A CN 200580047820A CN 101400684 B CN101400684 B CN 101400684B
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Classifications
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- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
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Abstract
具有抗MRSA(抗甲氧苯青霉素金黄色葡萄球菌)活性、具有与已知药物不同的母核结构及作用机制的化合物可以用作新型抗菌剂。作为对付MRSA的药物,过去一直使用万古霉素,然而最近却产生了有如曾被报道的对万古霉素耐药的肠球菌(VRE)等耐药菌株,因此,期望其他的新型药物。以通式表示的噻唑类化合物具有抗MRSA和抗VRE的活性,所以可以作为医药使用[式中,R式表示取代基或氨基]。
Description
技术领域
本发明涉及一类对甲氧苯青霉素耐药的金黄色葡萄球菌(以下略称MRSA)及对万古霉素耐药的肠球菌(VRE)具有抗菌活性的新型化合物。
背景技术
MRSA是对金黄色葡萄球菌的治疗药物——β-内酰胺类抗生素产生耐药性的菌株,20世纪80年代在日本国内即有报道。近年来,多剂耐药性MRSA成为主流,院内感染在很多医院成为极大的问题。
具有抗MRSA活性、具有与已知药物不同的母核结构及作用机制的化合物可以用作新型抗菌剂。
作为对付MRSA的药物,过去一直使用万古霉素,然而最近却产生了有如曾被报道的对万古霉素耐药的肠球菌(VRE)等耐药菌株,因此,人们期待着其他的药物。
具有抗菌活性的噻唑类化合物过去已经知道的有诺西肽(Nosiheptide)。(非专利文献1)。
非专利文献1:K.Umemura等,Bull.Chem.Soc.Jpn,.71,1391-1396(1998)。
发明内容
本发明的目的旨在提供对MRSA及VRE具有抑制活性的新型生理活性物质。
本发明解决问题的技术方案是:
为了完成前述目的,本发明者等从土壤和植物中分离了多种菌株,并对这些菌株的代谢产物进行了种种研究,结果发现:一种菌株产生的化合物对MRSA及VRE具有极强抑制活性,从而完成了本发明。
亦即:以化学结构式1表示的噻唑类化合物。
式中,R为化学结构式2表示的取代基或氨基。
以下为,R的化学结构式
下面,将R以化学结构式2表示的取代基的化合物定为WSS2258,R为氨基的化合物定为WSS2260。
产生WSS2258及WSS2260的菌株系本发明者等从中国云南省的土壤中分离的放线菌,本菌株的委托编号FERM BP-1035,2004年4月12日委托于“日本独立行政法人产业技术综合研究所特许生物寄托中心”。
A.形态特征
基内菌丝生长良好,分枝,不断裂,未形成气生菌丝,由基内菌丝长出较短的菌丝,其顶端形成孢囊。孢囊为球形及亚球形,其表面呈皱纹状,直径大小约为4-10μm。成熟孢囊释放的孢子大小约为1-1.5μm。
B.培养特征
28℃,在各种培养基内培养3小时后,肉眼观察的结果列于下述表1。颜色的标示采用“日本规格协会”JIS颜色名录(1985年)的系统颜色名称。
表1
培养基 | 生长 | 基内菌丝的颜色 | 气生菌丝 | 孢子的生长 | 可溶性色素 |
酵母-麦芽-琼脂培养基(ISP2) | 良好 | 黄土色 | 无 | 无 | 无 |
麦片粥-琼脂培养基(ISP3) | 良好 | 琥珀色 | 无 | 良好 | 无 |
淀粉-无机盐-琼脂培养基(ISP4) | 非常良好 | 褐色 | 无 | 无 | 无 |
甘油-天冬氨酸-琼脂培养基(ISP5) | 良好 | 金黄色 | 无 | 良好 | 无 |
蛋白胨-酵母-琼脂培养基(ISP6) | 良好 | 金黄色 | 无 | 无 | 无 |
酪氨酸-琼脂培养基(ISP6) | 非常良好 | 金黄色 | 无 | 非常良好 | 无 |
C.生理学特征
(1)生长温度范围
·生长温度范围:18-32℃。
·最适生长温度范围:25-28℃。
(2)黑素样色素的产生:无。
(3)碳源的利用
30℃,在pridham-gotryb培养基内培养2周后,肉眼观察的结果列于表2。
表中的「+」表示生长,「W」表示生长较弱。
表2
L-阿拉伯糖 | W | L-鼠李糖 | W |
D-木糖 | + | 棉子糖 | + |
D-葡萄糖 | + | 环己六醇 | + |
D-果糖 | W | D-甘露醇 | + |
蔗糖 | + |
D.化学分类学特征
从菌体成分细胞壁中检测出内消旋二氨基庚二酸,细胞壁的类型为II型。整个菌体的糖份检测为阿拉伯糖,糖的类型系D型。作为主要的维生素K3含有MK9(H4)。磷脂类型为只有磷脂酰乙醇氨(PE)的P II型。
E.基于16SrDNA的系统解析
为决定本菌16SrDNA范围的部分碱基排列,通过数据库进行了检索(DDBJ:DNA Database bank of Japan)。结果表明,被确认为同一性高于98%的菌株仅为游动放线菌属(Actinoplanes)。
以上述结果为基础,按照放线菌的分离及鉴定的方法(“日本放线菌学会”编,2001年)进行了鉴定,结果表明,将本菌株分类为属于游动放线菌属的放线菌是恰当的,并将本菌株命名为Sp.放线菌-TA0455(Actinoplanes sp.-TA0455)。
WSS2258及WSS2260的制备可以大致参照生产一般发酵产物的情形,在含有各种营养物质的培养基上,于需气性条件下,将TA0455菌株进行培养。
培养基主要使用液体培养基,由碳源、氮源及无机盐构成,根据需要,可以加入维生素类、前体物质及消沫剂,pH调至7附近。碳源可以单独或混合使用葡萄糖、蔗糖、糊精、甘油及淀粉等。氮源可以单独或混合使用肉汤、麦片粥、酵母浸膏、大豆粉、polypepton、谷物浸渍液、尿素及铵盐等。无机盐可以单独或混合使用磷酸钾、硫酸镁、氯化钠及碳酸钙等。消沫剂可以使用adecanol及硅化物等。
培养方法可以采用振荡培养、通气搅拌培养等需气性培养,在pH 4~10,温度25~35℃的条件下培养2~5天,最好是在pH6~7,25~28℃培养4天。
本发明化合物系采用常规方法对发酵产物进行精制获得的。即:培养结束后,通过离心分离或过滤得到培养滤液,由钻石牌离子交换树脂HP-20(DiaionHP-20)(商品名,三菱化学公司制造)等聚苯乙烯树脂吸附后,用低级醇、丙酮等有机溶剂溶出。菌丝以低级醇、丙酮等有机溶剂提取。然后合并菌丝提取液及得自吸附树脂的溶出液,减压浓缩,除去有机溶剂,残留物用乙酸乙酯、氯仿或正丁醇等非水溶性有机溶剂溶解,浓缩该液至糖浆状。将此糖浆再次溶于苯、乙酸乙酯、丙酮、甲醇或氯仿等有机溶剂中,采用硅胶柱层析、凝胶过滤柱层析、填充了逆层分配用十八烷基硅烷(ODS)的柱层析以及高效液相色谱等方法可以精制分离本发明化合物。
由上述方法得到的WSS2258及WSS2260,通过其分子量、紫外吸收光谱、1H-NMR谱及13C-NMR谱等的解析,确证为前述结构。
WSS2258的理化性质如下:
(a)外观:黄色粉末
(b)分子量:1206
(c)分子式:C51H43N13O11S6
(d)高分辨质谱(HR-TOF):
实测值:1206.1625
理论值:1206.1608(按C51H43N13O11S6计算)。
(e)1H-NMR谱:
在氘代二甲基亚砜中,以500MHz频率测定的结果如图1。
(f)13C-NMR谱:
在氘代二甲基亚砜中,以125MHz频率测定的结果如图2。
(g)对溶剂的溶解性:
在二甲基亚砜、氯仿中略溶,在水、己烷、甲醇、乙醚、丙酮及乙酸乙酯中不溶。
(h)碱性、酸性、中性的区别:中性。
WSS2260的理化性质如下:
(a)外观:黄色粉末
(b)分子量:1137
(c)分子式:C48H40N12O10S6
(d)高分辨质谱(HR-TOF):
实测值:1137.1375
理论值:1137.1393(按C48H40N12O10S6计算)。
(e)比旋度:[α]D 25:80.91(c 0.26,CHCl3)。
(f)1H-NMR谱:
在氘代二甲基亚砜中,以500MHz频率测定的结果如图1。
(g)13C-NMR谱:
在氘代二甲基亚砜中,以125MHz频率测定的结果如图2。
(h)对溶剂的溶解性:
在二甲基亚砜、氯仿中略溶,在水、己烷、甲醇、乙醚、丙酮及乙酸乙酯中不溶。
(i)碱性、酸性、中性的区别:中性。
本发明的有益效果是:已经究明本发明化合物对于MRSA和VRE具有抑制活性。
附图说明
图1表示WSS2258在氘代二甲基亚砜中,以500MHz频率测定的1H-NMR谱。
图2表示WSS2258在氘代二甲基亚砜中,以125MHz频率测定的13C-NMR谱。
图3表示WSS2260在氘代二甲基亚砜中,以500MHz频率测定的1H-NMR谱。
图4表示WSS2260在氘代二甲基亚砜中,以125MHz频率测定的13C-NMR谱。
具体实施方式
下面,列举实验例和试验例对本发明进行具体说明。
实施例1 WSS2258及WSS2260的制备
(1)将含有2.5%可溶性淀粉、1%葡萄糖、0.5%鱼粉、0.3%Pharmamwdia、0.3%NZ case、0.2%酵母浸膏及0.2%碳酸钙的液体培养基60ml置入300ml的三角瓶中,120℃,2大气压下灭菌20分钟。随后,在该无菌培养基内接种Sp.放线菌-TA0455,28℃,200rpm,旋转振荡培养3天,作为种子培养。
其次,将由2%麦片粥、1%葡萄糖、0.5%糊精、1%Pharmamedia、0.5%鱼粉及0.5%糖蜜组成的液体培养基100ml置入500ml的三角瓶内,其中加入前述种子培养液2ml,28℃,200rpm,旋转振荡培养3天,作为前期培养。
再者,使用2个50L容积的培养槽,在与前期培养相同组成的无菌培养基各30L中,加入前述培养液600ml,28℃,200rpm,旋转振荡培养5天。
培养结束后,向所得60L培养液中加入30L正丁醇,搅拌,离心分离,分取菌丝及正丁醇提取组分。减压蒸馏正丁醇提取液,得到褐色油状物质120.27g。(2)将前步实验的120.27g油状物溶于750ml水-甲醇(10∶90)的混合溶液中,加入己烷750ml,搅拌,离心分离,减压浓缩水-甲醇层至干。将所得65.35g褐色物质溶于氯仿-甲醇混合溶剂内,加入200ml硅胶[Silica Gel 60(Merck公司制)],减压浓缩,使之吸附。将吸附物置于800ml用氯仿调制过的硅胶上层,1000ml氯仿洗涤,以氯仿-甲醇(99∶1-80∶20)的混合溶剂顺次溶出。合并其中以混合溶剂(96∶4)溶出的组分,减压浓缩至干,得到褐色物质2.014g。残留物中加入甲醇20ml,过滤,将所得沉淀323.1mg溶于氯仿,采用以氯仿-甲醇(8∶1)混合溶剂为展层剂的薄层层析(TLC)[薄层板硅胶F254(Merck公司制)]进行组分分离。刮取Rf0.62-Rf0.56的部分,所得硅胶用氯仿-甲醇(1∶1)混合溶剂提取,减压浓缩至干,得到69.3mg WSS2258。同样,刮取Rf0.06-Rf0.37的部分,所得硅胶用氯仿-甲醇(1∶1)混合溶剂提取,减压浓缩至干,得到36.3mgWSS2260。
试验例1对MRSA的最小抑菌浓度(MIC)的测定
(试验药品)
将WSS2258、WSS2260及用作对照品的万古霉素溶于二甲基亚砜(DMSO),分别配成10mg/ml,试验使用以灭菌水稀释成目的浓度的溶液。
(试验菌株)
抗甲氧苯青霉素的金黄色葡萄球菌(MRSA)SA-9(临床分离菌株)
(试验方法)
采用下述微量液体稀释法测定最小抑菌浓度。
从培养一夜的心浸液琼脂培养基刮取菌落,浊度调至MeFarland 0.5。摄取在含有药品的培养基内,使最终接种菌量达到5×105CFU。35℃,培养17小时,将肉眼未见菌丝生长的最小浓度定义为MIC(μg/ml),评价结果列于表2。
表3
试验药品 | MIC(μg/ml) |
WSS2258 | 0.06 |
WSS2260 | 0.03 |
盐酸万古霉素 | 2 |
试验例2对VRE的最小抑菌浓度(MIC)的测定
(试验药品)
将WSS2258、WSS2260及用作对照品的linezoride溶于二甲基亚砜(DMSO),分别配成10mg/ml,试验使用以灭菌水稀释成目的浓度的溶液。
(试验菌株)
抗万古霉素的肠球菌[VRE,(van A)保存,临床分离菌株]
(试验方法)
采用下述微量液体稀释法测定最小抑菌浓度。
从培养一夜的心浸液琼脂培养基刮取菌落,浊度调至MeFarland 0.5。摄取在含有药品的培养基内,使最终接种菌量达到5×105CFU。35℃,培养17小时,将肉眼未见菌丝生长的最小浓度定义为MIC(μg/ml),评价结果列于表3。
表4
试验药品 | MIC(μg/ml) |
WSS2258 | 0.03 |
WSS2260 | 0.03 |
盐酸万古霉素 | 4 |
产业应用的可能性
本发明化合物对于MRSA和VRE具有很强的抗菌活性,所以可以作为医药使用。
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