CN109999026B - 一种噻吩甲酰胺类化合物在制备抗口蹄疫药物中的应用 - Google Patents

一种噻吩甲酰胺类化合物在制备抗口蹄疫药物中的应用 Download PDF

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CN109999026B
CN109999026B CN201910320027.1A CN201910320027A CN109999026B CN 109999026 B CN109999026 B CN 109999026B CN 201910320027 A CN201910320027 A CN 201910320027A CN 109999026 B CN109999026 B CN 109999026B
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吴叔文
周海兵
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Abstract

本发明公开了一种噻吩甲酰胺类化合物在制备抗口蹄疫药物中的应用，属于医药技术领域。该噻吩甲酰胺类化合物或其药理或生理上可接受的盐，可以有效抑制口蹄疫病毒的复制，且对细胞的毒性较低，显示此类化合物在制备抗口蹄疫药物中的应用前景。

Description

一种噻吩甲酰胺类化合物在制备抗口蹄疫药物中的应用
技术领域
本发明属于医药技术领域，涉及一种噻吩甲酰胺类化合物在制备抗口蹄疫药物中的应用。
背景技术
口蹄疫(foot-and-mouth disease，FMD)是由口蹄疫病毒引起的烈性传染病,主要感染偶蹄动物，患病动物的口、舌、唇、蹄、乳房等部位发生水泡并破溃形成烂斑。人和非偶蹄动物也可被感染，但症状较轻。猪、牛、羊等主要的家畜均可感染此病，并形成全球大规模流行，所以国际兽疫局(OIE)将该病列为A类家畜传染病之首。该病的发病率几乎达100％，一般病程呈良性经过，死亡率只有2％～3％，犊牛及仔猪和被恶性病型感染，死亡率可达50％～70％。除动物死亡造成直接经济损失外，动物在患病期间肉和奶的生产停止、病后肉和奶产量长期减少以及种用价值丧失也可造成较大的损失。最为严重的是该病传染性极强，对病畜和怀疑处于潜伏期间的同群动物必须紧急处理，对疫点周围的广大范围必须隔离封锁，禁止动物移动和畜产品调运上市。由此导致该地区甚至该国家的畜产品进出口贸易停止，造成巨大的经济损失和政治影响。
口蹄疫病原是口蹄疫病毒(foot-and-mouth disease virus，FMDV)。FMDV是小RNA病毒科(Picornaviridae)，口蹄疫病毒属(Aphthovirus)的成员。到目前为止，已发现了7个血清型，即O、A、C型(称欧洲型)，SAT1、SAT2、SAT3(南非1、2、3型，称非洲型)和AsiaⅠ(亚洲Ⅰ型，称亚洲型)，7个血清型可根据核酸同源性大小分为两群,O、A、C和AsiaⅠ为第1群，SAT1、SAT2、SAT3为第2群。群内各型同源性达60％～70％，但两群之间同源性仅为25％～40％,血清型间无血清交叉和交叉免疫现象。即使在同一血清型内不同病毒的抗原性亦有变化。
当前采用疫苗来防控口蹄疫存在很大的缺陷，因此有必要研究新的抗病毒策略以应对该疾病的威胁。一些科研工作者尝试采用干扰素和RNA干扰技术来防控口蹄疫，虽然在细胞水平取得一些进展，但却都未能投入使用。
目前较少有采用化学小分子来防控口蹄疫的报道，设计合成一系列能够较好抑制口蹄疫病毒(FMDV)的活性化合物对于研制口蹄疫药物是十分有利的。申请人于2015年发现并合成了一类基于噻吩甲酰胺骨架的化合物(Jiawei Pan et al,Synthesis of N-benzyl-N-phenylthiophere-2-carboxamide analogues as a novel class ofenterovirus 71ihibitors,RSC Adv,2015,5,55100-55108),该类化合物具有抑制肠道病毒EV71的作用。由于口蹄疫病毒和EV71的致病机制无直接相关性，这类化合物是否可作为口蹄疫病毒抑制剂，还不得而知。
发明内容
为了克服现有技术存在的缺陷与不足，本发明的首要目的是提供一种噻吩甲酰胺类化合物在制备抗口蹄疫病毒药物中的应用。该类化合物对细胞的毒性小，在口蹄疫的预防和治疗方面有一定的应用前景。
为了实现上述目的，本发明采用如下技术方案：
第一方面，本发明提供一种噻吩甲酰胺类化合物或其药理或生理上可接受的盐在制备抗口蹄疫病毒药物中的应用，所述噻吩甲酰胺类化合物的结构如以下通式(I)所示：
Figure GDA0003076826240000021
其中，
R1为
Figure GDA0003076826240000022
R2为H、2-F、3-F、4-F、4-Cl、4-Br、4-Me、4-OMe、4-OH、3-Me或3-CF3；
R3为H、4-F、4-Cl、4-Br、4-NO2、4-CN、4-OMe、4-OH、3-Br、2-Br或2-Br-4-F。
优选地，上述应用中，所述噻吩甲酰胺类化合物的结构如下表1所示的化合物：
表1
Figure GDA0003076826240000031
Figure GDA0003076826240000041
Figure GDA0003076826240000051
进一步地，上述应用中，所述噻吩甲酰胺类化合物是下列化合物：
N-(4-溴苄基)-N-(4-氟苯基)噻吩-2-甲酰胺、
N-(4-溴苄基)-N-(4-氟苯基)呋喃-2-甲酰胺、
N-苄基-N-苯基噻吩-2-甲酰胺、
N-(4-溴苄基)-N-苯基噻吩-2-甲酰胺、
N-(4-氯苄基)-N-(4-氟苯基)噻吩-2-甲酰胺、
N-(4-氯苄基)-N-(对甲苯基)噻吩-2-甲酰胺、
N-(4-氯苄基)-N-(4-氯苯基)噻吩-2-甲酰胺、
N-(4-溴苄基)-N-(4-溴苯基)噻吩-2-甲酰胺、
N-(4-溴苄基)-N-(间甲苯基)噻吩-2-甲酰胺、
N-(4-溴苄基)-N-(4-氯苯基)噻吩-2-甲酰胺、
N-(4-氟苯基)-N-(4-甲氧基苄基)噻吩-2-甲酰胺、
N-(4-溴苄基)-N-(2-氟苯基)噻吩-2-甲酰胺。
第二方面，本发明提供一种药物组合物在制备抗口蹄疫病毒药物中的应用，所述药物组合物包含上述噻吩甲酰胺类化合物或其药理或生理上可接受的盐，以及药学上可接受的载体或赋形剂。
本发明涉及的噻吩甲酰胺类化合物，可以有效抑制口蹄疫病毒的复制，其对细胞的毒性小，可用于制备抗口蹄疫药物。
具体实施方式
通过以下详细说明可以进一步理解本发明的特点和优点。所提供的实施例仅是对本发明方法的说明，而不以任何方式限制本发明揭示的其余内容。
实验例1：噻吩甲酰胺类化合物生物活性测试
(1)噻吩甲酰胺类化合物细胞毒性测定:
黄色的噻唑兰，简称MTT，可透过细胞膜进入细胞内，活细胞线粒体中的琥珀脱氢酶能使外源性MTT还原为难溶于水的蓝紫色的针状Formazan结晶并沉积在细胞中，结晶物可被20％(质量比体积)SDS溶解，用酶联免疫检测仪在595nm波长处测定其光吸收值，可间接反映细胞数量。
实验时，将BHK-21细胞以每孔2×104的密度传至96孔板中，在37℃培养24小时后，吸走培养基，将含有各种浓度梯度化合物的细胞培养基加到每个孔。24小时后，每孔加入5mg/mL的MTT溶液，细胞板在37℃的CO2孵化器中培养4h。接着将助溶液加入到溶血细胞，在37℃孵化3h，酶标仪测定595nm波长下的OD值。化合物的抑制率(％)＝[1-(E-N)/(P-N)]×100，其中“E”代表给药组的OD值，“P”代表未给药组的OD值，“N”代表空白组OD值。化合物的半数抑制浓度(CC50)作为该化合物细胞毒性的指标。
(2)噻吩甲酰胺类化合物抗口蹄疫病毒活性实验：
通过病毒蚀斑数减少分析来评估化合物的抗病毒活性。铺满BHK-21细胞的6孔板按照70PFU/孔接入口蹄疫病毒(FMDV,Akesu/58/2002)，40分钟后除去含病毒培养基并加入含有特定浓度待测药物的培养基，培养基含有终浓度为0.5％agarose。在37℃5％CO2条件下培养48-72小时后，用3％的福尔马林固定细胞，用0.5％结晶紫对细胞进行染色并计算病毒蚀斑数。EC50是指特定药物有效抑制病毒产生蚀斑数至对照孔的50％所需的浓度。
表2本发明噻吩甲酰胺类化合物抗口蹄疫病毒活性
Figure GDA0003076826240000061
Figure GDA0003076826240000071
上述实验结果表明：合成的化合物大多数具有很好的抗口蹄疫病毒活性，例如化合物PJW 1(EC50＝0.083μM，SI＝283.5)、PJW 2(EC50＝0.076μM，SI＝886.3)、PJW 6(EC50＝0.094μM，SI＝804.5)、PJW 7(EC50＝0.120μM，SI＝306.5)、PJW 10(EC50＝0.211μM，SI＝248.2)等，尤其是化合物PJW 2、PJW 6和PJW 7显示出非常好的抗口蹄疫病毒活性和非常高的选择性。显示该类化合物在口蹄疫的预防和治疗方面有很强的应用前景。

Claims (2)

1.一种噻吩甲酰胺类化合物或其药理或生理上可接受的盐在制备抗口蹄疫病毒药物中的应用，其特征在于，所述噻吩甲酰胺类化合物是下列化合物：
N-（4-溴苄基）-N-（4-氟苯基）噻吩-2-甲酰胺、
N-（4-溴苄基）-N-（4-氟苯基）呋喃-2-甲酰胺、
N-苄基-N-苯基噻吩-2-甲酰胺、
N-（4-溴苄基）-N-苯基噻吩-2-甲酰胺、
N-（4-氯苄基）-N-（4-氟苯基）噻吩-2-甲酰胺、
N-（4-氯苄基）-N-（对甲苯基）噻吩-2-甲酰胺、
N-（4-氯苄基）-N-（4-氯苯基）噻吩-2-甲酰胺、
N-（4-溴苄基）-N-（4-溴苯基）噻吩-2-甲酰胺、
N-（4-溴苄基）-N-（间甲苯基）噻吩-2-甲酰胺、
N-（4-溴苄基）-N-（4-氯苯基）噻吩-2-甲酰胺、
N-（4-氟苯基）-N-（4-甲氧基苄基）噻吩-2-甲酰胺、
N-（4-溴苄基）-N-（2-氟苯基）噻吩-2-甲酰胺。
2.一种药物组合物在制备抗口蹄疫病毒药物中的应用，其特征在于所述药物组合物包含权利要求1所述的噻吩甲酰胺类化合物或其药理或生理上可接受的盐，以及药学上可接受的载体或赋形剂。
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Citations (1)

* Cited by examiner, † Cited by third party
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WO2008116156A2 (en) * 2007-03-21 2008-09-25 The Regents Of The University Of Michigan Methods and compositions for treating diseases and conditions associated with mitochondrial function

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008116156A2 (en) * 2007-03-21 2008-09-25 The Regents Of The University Of Michigan Methods and compositions for treating diseases and conditions associated with mitochondrial function

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* Cited by examiner, † Cited by third party
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Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors;Jiawei Pan et al.;《RSC Adv》;20151231;第5卷;第55100–55108页 *

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