CN107556296B - 一种2-羟基-3-氮杂环色酮类化合物及其合成方法和在抗真菌药物中的应用 - Google Patents
一种2-羟基-3-氮杂环色酮类化合物及其合成方法和在抗真菌药物中的应用 Download PDFInfo
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Abstract
本发明涉及一种2‑羟基‑3‑氮杂环色酮类化合物具有如右结构:其中R3是被氢、甲基、硝基或氰基取代的五元含氮芳杂环;R4、R5、R7分别独立的选自氢、氟、氯、溴或碘;R6选自氢、氟、氯、溴、碘、C1‑C6的烃氧基、C1‑C6的烃氨基、苯氧基、被1个或多个C1‑C6烃基或C1‑C6烃氧基取代的苯氧基。本发明的化合物具有制备抗真菌类药物用途,对常见致病真菌以及深部真菌感染都具有较强的抑菌活性,并且毒性低、稳定性好、抗真菌谱广。
Description
技术领域
本发明涉及一种抗真菌的2-羟基3-氮杂环色酮类化合物及其合成方法和其在制备抗真菌药物中的应用。
背景技术
色酮及其衍生物是广泛存在于自然界中的一大类天然产物,结构丰富多样,包括色酮丁内酯,二聚色酮丁内酯,氧杂蒽酮,杜英生物碱等,而且它们均具有抗炎,抗病毒,抗氧化等生物活性。因此,关于这类天然产物的全合成研究一直都备受有机合成化学家们的关注。
活性研究表明,色酮类化合物具有明显的抗真菌活性,目前文献报道的色酮类化合物,多以合成得到为主。早在19世纪末,人们便已经从一种伞形科阿米芹的果实中提取出了呋喃并色酮(Khellin),并被作为第一个色酮类药物临床应用。1902年,Heywang和Kostanecki对一种色酮的合成方法进行了报道。自此以后,对色酮及其衍生物的研究与开发日渐受到更多人的关注。
色酮类化合物,因其具有的特殊的化学结构和生物活性,已经引起国际上药物研究者的广泛关注。无论是天然提取物还是合成产物,抑菌新的靶点和作用机制已经成为目前重要的研究方向。近几十年,随着计算机辅助分子设计技术、生物活性筛选技术、分子生物学、基因组学等新技术的应用和日臻成熟,大大加快了抗真菌药物的研发进度。可以预见,随着研究的不断深入,会有更多高效、低毒、广谱的抗真菌药物被研发出并造福于人类。我们运用一种新方法合成出了2羟基色酮,在3位引入不同官能团后,以期待合成出一系列具有更高的生物活性以及更好的选择性和安全性的2-羟基-3-氮杂环色酮类化合物。
发明内容
本发明目的是提供一种2-羟基-3-氮杂环色酮类化合物及其合成方法和在抗真菌和抑菌药物中的应用。
本发明所涉及的2-羟基-3-氮杂环色酮类化合物,其化学结构如下:
R6选自氢、氟、氯、溴、碘、C1-C6的烃氧基;
式(I)化合物的合成方法,是将化合物(III)、碱、18-冠醚-6溶于有机溶剂中,与二氧化碳气体反应,关环后生成化合物(IV),调酸得到化合物(I)。
所述化合物(III)的结构式如下:
所述化合物(IV)的结构式如下:
其中,X表示F或Cl;
R6的定义同式(I);
所述有机溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、二氧六环、乙腈、四氢呋喃中的至少一种。优选N,N-二甲基甲酰胺、二甲亚砜。
所述碱性化合物选自碱金属碳酸盐、碱金属氢氧化物、碱金属醋酸盐或三乙胺、二乙基异丙胺、N-甲基哌啶、N-乙基哌啶、N-甲基吗啉、N-乙基吗啉、吡啶、4-甲基吡啶中的至少一种。优选碳酸钾、碳酸铯、无水乙酸钠。
本发明的合成方法是一种通用方法,适合于合成色酮化合物及其衍生物,对芳环上的多种官能团具有高的容忍度,因此事实上对色酮类化合物及其衍生物中的取代基个数和种类并无特别限制。
本发明式(I)化合物还包括其在药物制剂学上所容许的盐。
本发明提供所述2-羟基-3-氮杂环色酮类化合物在制备治疗真菌感染疾病的人用药物或动物用药物中的应用。
所述药物中除含有活性成分2-羟基-3-氮杂环色酮类化合物外,还含有与药物上可接受的载体、助剂和/或稀释剂,组成组合物。
所述药物的剂型是溶液、霜剂、栓剂、膏剂或溶液剂。
本发明还提供所述2-羟基-3-氮杂环色酮类化合物作为农业和园艺杀菌剂的应用。
所述杀菌剂中除含有活性成分2-羟基-3-氮杂环色酮类化合物外,还含有与药物上可接受的载体、助剂和/或稀释剂,组成组合物。
通过测定最低抑菌浓度MIC(即化合物能抑制试验微生物生长的浓度),对本发明2-羟基-3-氮杂环色酮类化合物的抗真菌活性进行了体外评价。试验证实,本发明2-羟基-3-氮杂环色酮类化合物具有广谱抗真菌活性,在人体及动物(特别是哺乳动物)体内具有药理学活性,可与普通化疗可接受的稀释剂或载体相混合,或用其他的赋形剂,制成溶液、霜剂、栓剂、软膏、溶液等剂型,以药物的形式进行局部涂抹使用,对于真菌感染病具有明显的疗效。除了用于制备抗真菌的人用或动物用抗真菌药物外,本发明2-羟基-3-氮杂环色酮类化合物还可以用于农业和园艺的植物杀菌剂,对各种植物病原体疾病如稻瘟病、大麦和小麦的粉霉病及其他各种寄主植物(如黄瓜、苹果、葡萄)的粉霉病、小麦的锈病、燕麦的冠锈和其他各种寄主的锈病及其他寄主植物的病原性腐烂等的防治非常有效。
具体实施方式
下面通过具体实施例对本发明的合成方法进行说明。应当注意到,这里给出的描述和实施例仅仅是为了描述本发明的具体实施方式,使技术人员更容易理解本发明,它们并非意欲限定本发明的范围。
实施例1,式(I)2-羟基-3-氮杂环色酮的合成制备反应式如下:
制备步骤如下:
单口烧瓶中加入1-(2,4-二氟苯基)-2-(1,2,4-三氮唑-1-基)乙酮18.4mmol,DMSO50mL、K2CO3 92mmol,18-冠醚-6 18.4mmol,通入二氧化碳气体常温下搅拌10h。反应毕,将反应液倒入50mL水中,用稀盐酸调pH至酸性,析出固体,抽滤得到类白色固体,无水甲醇重结晶得式(I1)产物2-羟基-3-(1,2,4-三氮唑-1-基)-7氟色酮-14.9mmol,收率81%。
1H NMR(400MHz,DMSO-d6):12.23(s,1H),9.16(s,1H),8.53(s,1H),7.97~8.01(m,1H),7.36~7.39(m,1H),7.22~7.27(m,1H)。
实施例2,式(I)2-羟基-3-氮杂环色酮的合成制备反应式如下
制备步骤如下:
单口烧瓶中加入1-(2,4-二氯-5-氟苯基)-2-(咪唑-1-基)乙酮18.4mmol,DMSO50mL、K2CO3 92mmol,18-冠醚-6 18.4mmol,通入二氧化碳气体常温下搅拌10h。反应毕,将反应液倒入50mL水中,用稀盐酸调pH至酸性,析出固体,抽滤得到类白色固体,无水甲醇重结晶得式(I2)产物2-羟基-3-(咪唑-1-基)-6-氟-7-氯色酮-15.2mmol,收率83%。
1H NMR(400MHz,DMSO-d6):12.46(s,1H),8.58(s,1H),8.27(s,1H),7.92(d,1H),7.38(d,1H),7.12(s,1H)。
实施例3~实施例9:式(I)2-羟基-3-氮唑环色酮类化合物的制备
以(III)化合物为原料,制备产物式(I)化合物(目标产物为表1中的式(I3)~(I9)各化合物),制备步骤同实施例1,反应式如下
实施例3~实施例9中,产物式(I)2-羟基-3-氮唑环色酮类化合物各基团选择及制备用试剂和检测数据均列于表1。
表1
实施例10:体外抗真菌活性实验
1、实验用菌株
近平滑念珠菌、孢子丝菌、啤酒酵母菌曲霉菌、白色念珠菌、光滑念珠菌、热带念珠菌、红色毛癣菌、青霉菌、疣状毛癣菌、紫色毛癣菌、新生隐球菌、克柔氏念珠菌、絮状表皮癣菌、石膏样毛癣菌。
2、试药及材料
试验用材料:
改良马丁培养基、96孔培养板、DMSO
对照药物:氟康唑
3、实验方法
(1)抗菌药液的制备
将受试药物分别用DMSO溶解,配成25.6g/L的溶液,于-20℃以下保存备用。试验前将低温冷藏的受试药液取出,在35℃恒温箱中融化,用RPMI1640稀释10倍,备用。
(2)接种液的制备
哥受试念珠菌株(近平滑念珠菌,白色念珠菌,光滑念珠菌,热带念珠菌)在改良马丁培养基上转种,将其用质量分数为0.85%的无菌盐水制成悬液。用血细胞计数板计数孢子,调整含菌量,使集落形成单位为1×106~5×106CFU/mL。接种时用RPMI-1640培养液将其稀释200倍后,再稀释10倍,CFU值调至0.5×103~6.0×103CFU/mL,备用。
(3)MIC板制备
无菌操作下,在灭菌的96孔聚乙烯板的第1号孔加RPMI-1640培养液100μL,作为空白对照。第2号孔加菌液190μL,第3-12号孔加配置好的菌液100μL。然后在2号孔中加入10μL受试药液,按10级倍比稀释2-11号孔的浓度,使各孔的最终浓度为128,64,32,16,8,4,2,1,0.5,0.25mg/L,第12号孔不加受试药液作为生长对照。各MIC板密闭后置于35℃普通空气孵箱中,孵育满24h判断结果。
(4)结果判断
用酶标分析仪于620nm测各孔的OD值,以OD值下降80%以上的最低浓度作为MIC值。当MIC值高于128mg/L时计为>128mg/L;当MIC值低于0.25mg/L时计为≤0.25mg/L。
(5)重复观察与统计
上述试验需要至少重复三次,当出现MIC值单一跳孔时,则记录为最大的抑制细菌浓度,当MIC值出现两个或两个以上跳孔时,则重新进行试验。
4、抗真菌敏感性试验结果
通过初步的MIC测定发现,受试化合物具有广谱抗真菌活性,其中实施例(1)和实施例(8)的色酮类化合物抑制真菌活性更为显著,对以上受试菌株的MIC值均小于10mg/L。
Claims (5)
3.根据权利要求2所述的合成方法,其特征是所述有机溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、二氧六环、乙腈、四氢呋喃中的至少一种;所述碱选自碱金属碳酸盐、碱金属氢氧化物、碱金属醋酸盐或三乙胺、二乙基异丙胺、N-甲基哌啶、N-乙基哌啶、N-甲基吗啉、N-乙基吗啉、吡啶、4-甲基吡啶中的至少一种。
4.一种权利要求1所述2-羟基-3-氮杂环色酮类化合物在制备抗真菌剂中的应用。
5.根据权利要求4所述的应用,其特征是所述抗真菌剂中除含有活性成分2-羟基-3-氮杂环色酮类化合物外,还含有药物上可接受的载体、助剂和/或稀释剂。
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