CN114796204A - 安莎三烯类化合物在抗病毒感染药物中的用途及制备方法 - Google Patents
安莎三烯类化合物在抗病毒感染药物中的用途及制备方法 Download PDFInfo
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Abstract
本发明涉及医药技术领域,关于安莎三烯类化合物在制备抗严重急性呼吸综合征冠状病毒2(SARS‑CoV‑2)、蜱传脑炎病毒(TBEV)、西尼罗病毒(WNV)、黄热病毒(YFV)和基孔肯雅热病毒(CHIKV)感染药物或药物组合物中的用途及制备方法。
Description
技术领域
本发明属于医药技术领域,具体涉及一类微生物发酵获取的安莎三烯类化合物在制备抗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)、蜱传脑炎病毒(TBEV)、西尼罗病毒(WNV)、黄热病毒(YFV)和基孔肯雅热病毒(CHIKV)感染药物中的用途及制备方法。
背景技术
近年来出现的由严重急性呼吸综合征冠状病毒2(Severe Acute RespirartorySyndrome Coronavirus 2,SARS-CoV-2)引起的严重急性呼吸系统综合征,即COVID-19(CoronaVirus Disease 2019,新型冠状病毒肺炎),在全球大规模流行,严重威胁人类生命安全,给经济和社会带来严重损害。目前用于COVID-19的治疗措施主要包括小分子抗病毒药物(如蛋白酶抑制剂、聚合酶抑制剂)、生物大分子药物(如高效价免疫球蛋白、单克隆抗体)和疫苗等,其中小分子药物具有易吸收、分子小、能够穿透细胞膜、易于大规模工业化生产等优点,是药物研发的重点。
在针对SARS-CoV-2作用的小分子药物研发中,蛋白酶抑制剂和RNA聚合酶抑制剂取得突破性进展。
3CLpro是SARS-CoV-2病毒自身编码中剪切和加工RNA的主要蛋白酶,帕克洛维(paxlovid,一种含有帕罗韦德和利托那韦两种成分的复合制剂)是辉瑞研发的靶向3CLpro的蛋白酶抑制剂,已获得紧急使用授权,对轻、中症COVID-19成年患者有效,可大大降低患者的重症率及病死率。
RNA聚合酶抑制剂通过RNA依赖的RNA聚合酶(RdRp)有效地结合到新生RNA链中,从而导致病毒复制提前终止,已有药物包括瑞德西韦(remdesivir)、莫那匹韦(molnupiravir)和法维拉韦(favipiravi),均为核苷类似物的前体药物。
瑞德西韦2020年10月22日被FDA批准上市,是用于治疗COVID-19的第一个获批药物,现有结果表明瑞德西韦对重、危重型患者效果差,应尽早、及时应用。莫那匹韦于2021年11月4日获批上市,是全球第一款获批用于治疗成人轻中症SARS-CoV-2感染的口服药物。法维拉韦于2014年3月上市,用于成人新型或复发流感的治疗,目前日本、俄罗斯等国推荐轻、中症COVID-19患者使用。尽管上述疫苗和药物对遏制COVID-19疫情有一定作用,由于病毒不断变异,仍需开发新型小分子药物,包括从天然产物中筛选和发现抗病毒活性物质。
蜱传脑炎病毒(Tick-borne encephalitis virus,TBEV)又称森林脑炎病毒,为黄病毒科黄病毒属。蜱传脑炎(TBE)是由TBEV引起的以中枢神经系统病变为主要特征的自然疫源性疾病。人感染病毒的主要途径是被携带TBEV的蜱虫叮咬,还可因摄入TBEV污染的奶制品而感染。TBE的分布具有明显的地域性,与传播媒介密切相关。近年来,在中国东北、俄罗斯东部及日本北部TBE的发病呈现上升趋势,疫区范围也在不断扩大。目前用于预防TBEV感染的灭活疫苗的免疫原性较低,诱导中和抗体的维持时间较短,且在林区职业人群以外可能暴露人群的接种率较低。目前无TBE特异治疗药物。
西尼罗病毒(West Nile virus,WNV)属黄病毒科黄病毒属,为单股正链RNA病毒,可引起人和动物发生西尼罗河热和西尼罗病毒脑膜脑炎,库蚊是其主要的传播媒介,鸟类是该病毒的中间宿主,而人和马则是终端宿主。WNV病广泛分布于非洲、中东、欧洲的部分地区。1999年夏季,WNV首次登陆美国,随后几年内在北美和中美洲迅速传播,导致美国和加拿大等国家历史上虫媒病毒感染的最大流行。目前尚无针对WNV感染的人用疫苗以及治疗药物。虽然我国至今没有WNV感染疫情发生,但有输入性传播的可能。
黄热病毒(Yellow fever virus,YFV)与寨卡病毒(ZIKV)、西尼罗河病毒(WNV)和登革热病毒(DENV)等同属黄病毒科黄病毒属,是以伊蚊为传播媒介,当前主要流行于非洲和南美洲的热带、亚热带地区。黄热病毒可引起严重危害人类健康的黄热病,表现为黄疸,出血、甚至多系统的器官衰竭。虽有减毒疫苗,但疫苗在流行区的接种覆盖率有限,每年均有疫情发生。我国近年来曾有多例输入性感染者。目前尚无针对YFV感染的特异治疗药物。
基孔肯雅热病毒(Chikungunya fever virus,CHIKV)属于披膜病毒科甲病毒属,主要由埃及伊蚊和白蚊伊蚊为传播媒介,基因组为单股正链RNA,可致基孔肯雅热,虽致死率不高,但被感染人群丧失劳动力,导致严重的社会影响与经济损失。CHIKV于1952-1953年在坦桑尼亚首次分离,随后在非洲和亚洲地区暴发流行。2005年后CHIKV再次在全球多地数次暴发,并在法国、意大利、中国出现散在的输入性病例,特别是CHIKV东中南非型E1蛋白发生突变(E1-A226V)使其可有效通过白蚊伊蚊传播,不仅对热带和亚热带地区,还对白蚊伊蚊广泛存在的温带地区的民众构成了潜在威胁。目前尚无针对CHIKV感染的疫苗以及特异治疗药物。
发明内容
本发明旨在克服上述缺陷,提供一种能够特异性治疗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)、蜱传脑炎病毒(TBEV)、西尼罗病毒(WNV)、黄热病毒(YFV)和基孔肯雅热病毒(CHIKV)感染病症的药物。具体地,本发明提供了一种活性物质的用途,其特征在于:
上述活性物质为安莎三烯类化合物;
上述用途为如下用途中的至少一种:
用途A、用于制备抗SARS-CoV-2病毒感染的药物;
用途B、用于制备抗蜱传脑炎病毒感染的药物;
用途C、用于制备抗西尼罗病毒感染的药物;
用途D、用于制备抗黄热病毒感染的药物;
用途E、用于制备抗基孔肯雅热病毒感染的药物。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述用途还可以为如下用途中的至少一种:
用途A、用于制备预防或治疗SARS-CoV-2病毒感染的药物;
用途B、用于制备预防或治疗蜱传脑炎病毒感染的药物;
用途C、用于制备预防或治疗西尼罗病毒感染的药物;
用途D、用于制备预防或治疗黄热病毒感染的药物;
用途E、用于制备预防或治疗基孔肯雅热病毒感染的药物。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述安莎三烯类化合物选自如下结构所示的化合物,或其立体异构体,几何异构体,互变异构体,消旋体,氘代同位素衍生物,水合物,溶剂化物,代谢产物以及药学上可接受的盐或前药;
其中,R为环状结构上的一个或多个的取代基;
上述取代基可选自氢、羟基、酮(酮基指,环上的一个碳原子与O形成C=O键)、卤素、烷氧基、氨基、硝基、巯基、腈基、烷基、环烷基、羧基、芳基、芳香性杂环基、饱和杂环基、烷氧基、芳氧基、芳香性杂环基氧基或饱和杂环基;
上述R’为羟基或酯基;
上述R”为羟基或酯基。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述酯基的结构如下所示:
其中,R4选自烷烃、环状烃。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述安莎三烯类化合物选自如下结构所示的化合物:
其中,R1、R2彼此相同或不同,并且各自独立的为氢、羟基、酮、甲氧基、卤素、氨基、硝基、巯基、腈基、烷基、环烷基、羧基、芳基、芳香性杂环基、饱和杂环基、烷氧基、芳氧基、芳香性杂环基氧基或饱和杂环基;
其中,R4选自烷基、环状烃基。
R4为含1-8个碳原子数量的直链、支链或环状烃,直连或支链烃上含有0-3个双键,或含有羟基、甲氧基、卤素、氨基、硝基、巯基、腈基等取代;环状烃含有环烷基、环烯基、饱和杂环基、芳基、芳香性杂环基所取代。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述药物指以安莎三烯类化合物为唯一活性成份,
或
上述药物指包含安莎三烯类化合物的药物组合物。
关于药物组合物,指安莎三烯类化合物与药理学上允许的盐,如:无机盐或有机酸盐等组分进行复配;
上述的无机酸为盐酸、硫酸、磷酸、氢溴酸或硝酸;上述的有机酸为乙酸、马来酸、富马酸、酒石酸、琥珀酸、乳酸、甲磺酸、对甲苯磺酸、水杨酸或草酸等。
一般还可含有常规药物载体。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述安莎三烯类化合物在药物中的含量为0.1~99wt%。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述药物的给药剂型选自散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述药物的给药途径剂型选自注射给药剂型、胃肠道给药剂型、皮肤给药剂型。
进一步地,本发明提供的一种活性物质的用途,其特征还在于:
上述安莎三烯类化合物的制备,包括以下步骤:
S1.将菌种接种到种子培养基培养1-5天;
S2.将种子培养液接种到发酵培养基上进行发酵;
S3.发酵产物用有机溶剂提取,所得的提取物浓缩后得到粗浸膏,经分离纯化或结构改造,获得化合物。
进一步地,本发明提供的安莎三烯类化合物衍生物的制备方法,其特征在于:对菌种进行基因敲除等遗传改造,然后喂养天然底物3-氨基-5-羟基苯甲酸的结构类似物,获得安莎三烯类衍生物。
上述的天然底物3-氨基-5-羟基苯甲酸的结构类似物,选自如下结构所示的化合物:
优选自3-氨基-5-氟-苯甲酸,3-氨基-5-氯-苯甲酸,3-氨基-5-溴-苯甲酸,3-氨基-5-氨基-苯甲酸,3-氨基-5-甲氧基-苯甲酸,3-氨基-4-氟-苯甲酸,3-氨基-4-氯-苯甲酸,3-氨基-4-溴-苯甲酸,3-氨基-4-氨基-苯甲酸,3-氨基-4-甲氧基-苯甲酸,3-氨基-6-羟基-苯甲酸,3-羟基-4-氨基-苯甲酸等。
本发明中所提及的烷基可以为直链或支链的全碳烷基(如:甲基、乙基、丙基、丁基、异丙基、异丁基等等)或含有部分碳原子为氮、氧、硫取代的杂烷基,该烷基碳链上的氢原子中的一个或一个以上为其他基团所取代,此处所指的其他基团可以但不限于为环烷基(以类似于等的形式进行取代,该环烷基环上的任何氢原子还可以为卤素、氰基、烷基、羟基、羧基等基团所取代)、杂环烷基(即、在前述的环烷基的基础上,其烷基环上的至少一个碳原子为氧、硫、氮所替代)、卤素(F,Cl,Br,I)、羧基、氰基(-CN)、磺酸基(-SO4,)、磺酰基(-SO2Ra,Ra为氢、烷基、芳基等)、炔基(-C≡CH,-C≡CRb,Rb为烷基、芳基等)、酰胺基(-C(O)NRxRy,RxRy为烷基、芳基等)、酯基(-C(O)O-Rz,Rz为烷基、芳基等)、芳基、杂芳基、-O-NO2等等基团,优选碳原子数不大于10的烷基;
本发明中所提及的环状烃基可以为环烷基(如:环丙烷、环丁烷、环戊烷、环己烷等)或者环烯烃基(即、环状结构上至少包含一个双键),此外,其环上的一个或多个氢原子为其他基团所取代,此处所指的其他基团可以但不限于为烷基、取代的烷基(同上)、卤素(F,Cl,Br,I)、羧基、氰基(-CN)、磺酸基(-SO4,)、磺酰基(-SO2Ra,Ra为氢、烷基、芳基等)、炔基(-C≡CH,-C≡CRb,Rb为烷基、芳基等)、酰胺基(-C(O)NRxRy,RxRy为烷基、芳基等)、酯基(-C(O)O-Rz,Rz为烷基、芳基等)、芳基、杂芳基、-O-NO2等等基团,优选三元、四元、五元、六元、七元环;
本发明所提及的饱和杂环基,即为上述环烷基上的一个或几个碳原子为氧、硫、氮所代替。
本发明中所提及的芳基指苯、萘、芴等五元及以上的芳香环或苯并芳香环,或环上的一个或多个氢原子为其他基团所取代,此处所指的其他基团可以为烷基、取代的烷基(同上)、卤素(F,Cl,Br,I)、羧基、氰基(-CN)、磺酸基(-SO4,)、磺酰基(-SO2Ra,Ra为氢、烷基、芳基等)、炔基(-C≡CH,-C≡CRb,Rb为烷基、芳基等)、酰胺基(-C(O)NRxRy,RxRy为烷基、芳基等)、酯基(-C(O)O-Rz,Rz为烷基、芳基等)、芳基、杂芳基等等基团。
本发明中所提及的芳香性杂环基指噻吩、吡咯、吡啶、呋喃、咪唑、苯并咪唑、喹啉等五元及以上的芳香杂环或苯并芳香杂环,或环上的一个或多个氢原子为其他基团所取代,此处所指的其他基团可以为烷基、取代的烷基(同上)、卤素(F,Cl,Br,I)、羧基、氰基(-CN)、磺酸基(-SO4,)、磺酰基(-SO2Ra,Ra为氢、烷基、芳基等)、炔基(-C≡CH,-C≡CRb,Rb为烷基、芳基等)、酰胺基(-C(O)NRxRy,RxRy为烷基、芳基等)、酯基(-C(O)O-Rz,Rz为烷基、芳基等)、芳基、杂芳基、-O-NO2等等基团。
本发明所提及的醚基选自甲基醚、苯醚等,通式可用R-O-表示的基团,R可以为上述的烷基、环状烃基、饱和杂环基、芳基、芳香性杂环基等。
本发明中所提及的酯基为包含-O-C(O)-的基团。
本发明的作用和效果:
在本发明的研究中发现安莎三烯(ansatrienin,trienomycins,也称mycotrienin)类化合物或类似物,如:ansatrienins A2-A4和trienomycins A-L等,这些化合物不但具有一定的抗真菌活性和较强的抗肿瘤活性,还具有良好的抗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)、蜱传脑炎病毒(TBEV)、西尼罗病毒(WNV)、黄热病毒(YFV)和基孔肯雅热病毒(CHIKV)感染作用。
本发明利用病毒易感细胞的实验操作体系,筛选发现安莎三烯类化合物对抗SARS-CoV-2、TBEV、WNV、YFV和CHIKV病毒均具有抑制作用,且细胞毒性较小,可以作为潜在的抗抗SARS-CoV-2、TBEV、WNV、YFV和CHIKV病毒感染药物,具有应用前景。
附图说明
图1、安莎三烯类化合物结构式;
图2、安莎三烯类化合物对细胞的毒性影响;
图3、安莎三烯类化合物体外抗SARS-CoV-2感染的活性;
图4、不同剂量对小鼠体重的影响;
图5、对照组和给药组对小鼠体重的影响;
图6、对照组和给药组对肺组织的影响;
图7、安莎三烯类化合物抑制蜱传脑炎病毒(TBEV)、西尼罗病毒(WNV)、黄热病毒(YFV)、基孔肯雅热病毒(CHIKV)感染的效果;
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。本发明实施例所用试剂除另有注明,均可以从销售公司获得。
本发明所用的Streptomyces flaveolus菌株,购自德国微生物菌种保藏中心,保藏号:DSM 9954。
安莎三烯类化合物的制备方法包括以下步骤:
发酵:将Streptomyces flaveolus DSM 9954菌株接种到种子培养基(4%淀粉,1%大豆蛋白胨,2.1%麦芽提取物,pH 7.0)培养两天,再将种子培养液接种到30升发酵培养基(4%淀粉,1%葡萄糖,2%黄豆粉,pH6.8)进行发酵,28℃,220rpm培养7天得到发酵产物。
提取:再将上述发酵产物用等体积的乙酸乙酯超声提取至提取液基本无色,减压浓缩得粗浸膏120g。
分离:将上述粗浸膏用甲醇溶解,MCI填料拌样,经MCI柱色谱,以甲醇-水梯度洗脱(MeOH/H2O 30%-100%,25mL/min),按流分极性大小收集,根据TLC板-10%的硫酸香草醛显色检测,得到10个组分(Fr.1~Fr.10)。
Fr.9经过Sephadex LH-20凝胶色谱柱,二氯甲烷:甲醇(2:1)为流动相进一步纯化,得到8个组分Fr.9.1-Fr.9.8。
将组分Fr.9.3用高效液相色谱HPLC(甲醇:水=62:38,流速:3ml/min)分离得到trienomycin A(38mg),B(25mg),C(9mg),F(5mg)。
Fr 9.5经过Sephadex LH-20凝胶色谱纯化,二氯甲烷:甲醇(2:1)为流动相进一步纯化,再用高效液相HPLC(甲醇:水=65:35,流速:3ml/min)分离得到ansatrienin A(85mg),ansatrienin B(210mg),trienomycin 3b(4mg),benzoxazomycin(13mg)。
Fr 9.7用Sephadex LH-20凝胶色谱纯化,二氯甲烷:甲醇(2:1)为流动相进一步纯化,再用高效液相HPLC(甲醇:水=76:24,流速:3ml/min)分离得到ansafurantrienin A(23mg),G(9mg),H(4mg)。
2将天然底物3-氨基-5-羟基苯甲酸的结构类似物喂养mycB4基因敲除的Streptomyces flaveolus DSM 9954菌株中,制备衍生物。
参见文献方法【Qu,X.;Lei,C.;Liu,W.Transcriptome mining of activebiosynthetic pathways and their associated products in Streptomyces flaveolus.Angew.Chem.Int.Ed.Engl.2011,50,9651-9654】,利用Streptomyces flaveolus DSM9954孢子与构建质粒之间的接合转移,将安莎三烯生物合成中参与起始单元底物3-氨基-5-羟基苯甲酸(AHBA)合成的基因mycB4进行敲除,构建基因敲除菌株△mycB4。
将△mycB4基因敲除菌株喂养底物AHBA的类似物,包括但不限于3-氨基-5-氟-苯甲酸,3-氨基-5-氯-苯甲酸,3-氨基-5-溴-苯甲酸,3-氨基-5-氨基-苯甲酸,3-氨基-5-甲氧基-苯甲酸,3-氨基-4-氟-苯甲酸,3-氨基-4-氯-苯甲酸,3-氨基-4-溴-苯甲酸,3-氨基-4-氨基-苯甲酸,3-氨基-4-甲氧基-苯甲酸,3-氨基-6-羟基-苯甲酸,3-羟基-4-氨基-苯甲酸等,在基因敲除菌株△mycB4的发酵培养过程中进行喂养,按照上述方法进行发酵、培养、提取和分离。
将3-氨基-5-F-苯甲酸按照上述方法进行喂养和发酵,将10L的发酵提取物进行提取,发酵提取物的MCI柱、Sephadex LH-20凝胶色谱柱和HPLC(甲醇:水=75:25,流速:2.5ml/min)制备,获得新颖的含有氟原子的新衍生物22-fluorotrienomycin B(11mg)。
本发明从Streptomyces flaveolus DSM 9954次级代谢产物中分离得到的化合物,经过NMR和MS数据分析,以及与文献数据比对,结构式确定如图1所示。
Trienomycin A:白色粉末,ESI-MS m/z:623.3820[M+H]+,分子式C36H50N2O7,不饱和度为13。其NMR数据归属如下:1H NMR(600MHz,CDCl3)δH:7.59(s,1H),7.48(s,1H),6.47(s,1H),6.24(m,2H),6.10(dd,J=7.1,2.9Hz,2H),6.03(d,J=6.8Hz,2H),5.58(dd,J=5.3,7.2Hz,2H),5.18(brs,1H),4.92(m,1H),4.63(s,1H),4.40(p,J=7.0Hz,1H),4.12(brs,1H),3.48(s,1H),3.39(s,3H),2.76(dd,J=10.6,3.6Hz,1H),2.59(dd,J=3.8,8.6Hz,1H),2.47-2.51(m,3H),2.32(m,1H),2.19–2.07(m,2H),1.96(m,1H),1.86(m,3H),1.79(m,7H),1.66(m,2H),1.41(m,3H),1.35(d,J=7.1Hz,3H),1.22(m,7H),0.92(d,J=6.8Hz,3H);13C NMR(150MHz,CDCl3)δC:176.8(C-30),173.1(C-27),168.8(C-1),157.4(C-22),144.3(C-18),138.7(C-20),138.5(C-14),134.3(C-5),133.7(C-7),133.5(C-8),130.8(C-4),129.6(C-6),129.5(C-9),125.0(C-15),112.2(C-19),111.1(C-23),106.0(C-21),78.8(C-3),75.6(C-11),68.6(C-13),56.9(C-26),48.7(C-28),45.2(C-31),43.7(C-2),39.7(C-12),36.4(C-17),33.4(C-10),29.7(C-16),29.6(C-32),29.5(C-36),25.8(C-34),25.8(C-33),25.7(C-35),20.5(C-25),17.9(C-29),10.0(C-24)。
Trienomycin B:白色粉末,ESI-MS m/z:597.3518[M+H]+,分子式C34H48N2O7,不饱和度为12。其NMR数据归属如下:1H NMR(600MHz,CDCl3)δH:7.69(s,1H),7.46(s,1H),6.47(s,1H),6.22(s,1H),6.10(dd,J=9.1,5.0Hz,2H),6.03(dd,J=8.1,5.7Hz,1H),5.63–5.52(m,2H),5.19(t,J=6.9Hz,1H),4.93(dd,J=8.8,5.8Hz,1H),4.64(d,J=4.2Hz,1H),4.42(m,1H),4.13–4.08(m,1H),3.48(d,J=5.5Hz,1H),3.37(s,3H),2.76(dd,J=7.7,3.6Hz,1H),2.63–2.55(m,1H),2.51(dd,J=12.4,5.6Hz,2H),2.47–2.40(m,2H),2.31(ddd,J=14.8,9.1,2.3Hz,2H),2.24–2.15(m,2H),2.06(d,J=2.1Hz,2H),1.96(s,1H),1.88(dd,J=9.1,4.3Hz,1H),1.78(s,3H),1.37(d,J=7.1Hz,3H),0.90-0.94(m,9H);13C NMR(150MHz,CDCl3)δC:173.3(C-30),173.0(C-27),168.9(C-1),157.4(C-22),144.2(C-18),138.6(C-20),138.4(C-14),134.3(C-5),133.8(C-7),133.5(C-8),130.8(C-4),129.6(C-6),129.5(C-9),125.0(C-15),112.3(C-19),111.1(C-23),106.1(C-21),78.9(C-3),75.6(C-11),68.6(C-13),56.9(C-26),48.8(C-28),45.7(C-31),43.7(C-2),39.7(C-12),36.4(C-17),33.3(C-10),29.6(C-16),26.3(C-32),22.6(C-33),22.6(C-34),20.5(C-25),17.8(C-29),10.0(C-24)
Trienomycin C:白色粉末,ESI-MS m/z:597.3450[M+H]+,分子式C34H48N2O7,不饱和度为12。其NMR数据归属如下:1H NMR(600MHz,CD3OD)δH:7.04(t,J=2.1Hz,1H),6.48–6.38(m,2H),6.16–6.04(m,3H),5.64–5.53(m,2H),5.26–5.20(m,1H),4.87–4.80(m,1H),4.48–4.44(m,1H),4.36–4.25(m,2H),4.04(ddt,J=9.8,8.0,5.3Hz,1H),2.98–2.89(m,1H),2.88–2.80(m,1H),2.78–2.70(m,1H),2.61–2.35(m,5H),2.34–2.19(m,3H),2.05(ddt,J=10.1,7.1,3.9Hz,1H),1.94(ddd,J=9.1,7.0,4.5Hz,2H),1.87–1.73(m,3H),1.68(dd,J=2.3,1.4Hz,1H),1.58(ddd,J=8.7,7.4,7.4Hz,2H),1.43–1.35(m,3H),1.20(d,J=6.9Hz,1H),0.96(d,J=6.9Hz,1H),0.93–0.86(m,3H);13C NMR(150MHz,CD3OD)δC:173.2(C-30)169.0(C-27),167.4(C-1),157.4(C-22),144.1(C-18),138.6(C-20),138.4(C-14),134.2(C-5),133.9(C-7),133.4(C-8),130.8(C-4),129.6(C-6),129.5(C-9),124.7(C-15),112.3(C-19),111.3(C-23),106.1(C-21),79.2(C-3),75.6(C-11),68.5(C-13),56.7(C-26),48.7(C-28),43.7(C-31),42.8(C-2),39.5(C-12),36.3(C-17),33.3(C-10),29.7(C-16),29.5(C-32),27.3(C-33),20.5(C-34),20.0(C-25),17.6(C-29),10.0(C-24)
Trienomycin F:白色粉末,ESI-MS m/z:595.3378[M+H]+,分子式C34H46N2O7,不饱和度为13。其NMR数据归属如下:1H NMR(600MHz,CD3OD)δH:7.01(t,J=2.1Hz,1H),6.48–6.40(m,3H),6.39–6.35(m,1H),6.20–5.97(m,5H),5.57(ddd,J=6.6,9.3,5.2Hz,2H),5.21(d,J=6.5Hz,1H),4.33(d,J=7.3Hz,1H),4.04(ddd,J=9.8,8.4,4.3Hz,2H),2.72(dd,J=6.9,4.3Hz,1H),2.59–2.37(m,7H),2.22(s,5H),2.00–1.86(m,4H),1.82–1.77(m,4H),1.77–1.71(m,6H),1.60(d,J=6.7Hz,3H),1.41(d,J=7.3Hz,3H),1.38–1.26(m,6H),0.88(d,J=6.9Hz,3H);13C NMR(150MHz,CD3OD)δC:173.7(C-30),172.5(C-27),170.9(C-1),158.7(C-22),144.9(C-18),140.2(C-20),139.9(C-14),135.4(C-31),135.1(C-32),134.6(C-5),133.1(C-7),132.5(C-8),132.5(C-4),130.8(C-6),130.7(C-9),125.6(C-15),113.3(C-19),112.8(C-23),107.0(C-21),81.7(C-3),76.3(C-11),69.6(C-13),56.7(C-26),48.8(C-28),44.8(C-2),40.1(C-12),37.4(C-17),33.6(C-10),30.6(C-16),21.0(C-25),17.0(C-29),14.1(C-34),12.4(C-33),10.0(C-24)。
Ansatrienin 3b:白色粉末,ESI-MS m/z:613.3421[M+H]+,分子式C34H48N2O8,不饱和度为12。其NMR数据归属如下:1H NMR(600MHz,CDCl3)δH:7.69(s,1H),7.46(s,1H),6.48(s,1H),6.23(m,2H),6.13(m,4H),5.60(dd,J=15.5,6.7Hz,1H),5.55(dd,J=14.8,6.6Hz,1H),5.18(brs,1H),4.93(m,1H),4.63(m,1H),4.23,(p,J=6.8Hz,1H)4.01(m,1H),2.76(dd,J=6.9,4.3Hz,1H),2.59–2.37(m,5H),2.30(m,2H),2.22(m,1H),2.00–1.86(m,4H),1.95(m,1H),1.85(m,1H),1.79(s,3H),1.62(m,2H),1.39(d,J=6.7Hz,3H),1.38–1.23(m,5H),0.88(d,J=6.9Hz,9H);13C NMR(150MHz,CDCl3)δC:173.6(C-30),173.3(C-27),169.8(C-1),149.2(C-22),145.7(C-14),141.4(C-19),137.9(C-14),133.9(C-5),133.5(C-7),132.5(C-8),131.6(C-4),129.6(C-6),129.2(C-9),125.5(C-15),116.0(C-20),114.7(C-23),107.6(C-21),79.9(C-3),75.8(C-11),68.6(C-13),56.7(C-26),50.9(C-28),45.5(C-31),43.1(C-2),40.1(C-12),33.8(C-17),31.8(C-10),29.8(C-16),26.3(C-32),21.0(C-25),17.0(C-29),22.5(C-33),22.5(C-34),20.5(C-25),17.8(C-29),9.8(C-24)。
Ansatrienin A:白色粉末,ESI-MS m/z:637.3422[M+H]+,分子式C36H48N2O8,不饱和度为14。1H NMR(600MHz,CD3OD)δH:7.36(s,1H),6.50(s,1H),6.04(m,4H),5.64(dd,J=14.7,7.7Hz,1H),5.56(m,1H),5.28(t,J=7.3Hz,1H),4.89(m,1H),4.62(s,1H),4.28(m,1H),3.98(m,1H),3.32(s,3H),2.85(m,1H),2.,69(dd,J=11.9,3.9Hz,1H),2.57(m,1H),2.38(m,3H),2.20(m,2H),2.05(m,2H),1.85(m,3H),2.78(s,3H),1.43(m,2H),1.34(d,J=6.9Hz,3H),0.93(d,J=6.9Hz,3H)。13C NMR(150MHz,CD3OD)δC:190.0(C-22),183.4(C-19),179.2(C-30),173.7(C-27),172.5(C-1),147.6(C-14),140.3(C-18),134.8(C-5),134.4(C-7),133.9(C-8),133.3(C-4),132.8(C-9),130.8(C-6),130.7(C-15),130.7(C-23),124.9(C-20),115.4(C-21),81.2(C-3),75.9(C-11),69.4(C-13),56.8(C-26),49.9(C-28),45.8(C-31),44.9(C-2),41.2(C-12),33.3(C-10),30.7(C-17),30.5(C-32),30.4(C-36),26.8(C-16),26.8(C-35),26.7(C-34),26.6(C-33),20.7(C-25),17.2(C-29),10.0(C-24)。
Ansatrienin B:白色粉末,ESI-MS m/z:639.3638[M+H]+,分子式C36H50N2O8,不饱和度为13。其NMR数据归属如下:1H NMR(600MHz,CD3OD)δH:6.57(d,J=2.9Hz,1H),6.48(d,J=2.9Hz,1H),6.21(dd,J=15.0,10.5Hz,2H),6.12–6.05(m,2H),5.67(ddd,J=9,4.5,5.3Hz,1H),5.50–5.43(m,1H),5.19–5.15(m,1H),4.70(m,1H),4.33–4.26(m,1H),4.12(ddd,J=8.4,8.7,4.7Hz,1H),3.33(s,3H),2.90(dd,J=6.6,5.2Hz,1H),2.83(dd,J=6.7,4.7Hz,1H),2.60–2.54(m,2H),2.30(t,J=3.3Hz,1H),2.29–2.25(m,2H),2.24–2.18(m,2H),1.92(ddd,J=5.6,6.8,3.3Hz,2H),1.82(s,1H),1.80(d,J=5.1Hz,2H),1.73–1.71(m,3H),1.51–1.45(m,2H),1.41(d,J=7.3Hz,3H),1.37–1.35(m,2H),1.34(m,2H),1.32(dd,J=7.6,4.5Hz,2H),1.30–1.26(m,2H),0.96–0.88(m,2H),0.81(d,J=6.9Hz,3H);13C NMR(150MHz,CD3OD)δC:179.2(C-30),173.9(C-27),171.5(C-1),150.7(C-22),142.0(C-14),139.6(C-19),136.6(C-5),135.7(C-7),134.7(C-8),133.2(C-18),131.1(C-4),130.7(C-9),130.6(C-6),127.3(C-20),124.9(C-15),116.3(C-23),108.4(C-21),81.7(C-3),76.5(C-11),69.6(C-13),56.7(C-26),50.2(C-28),45.9(C-31),43.6(C-2),39.6(C-12),33.8(C-10),32.6(C-17),30.8(C-32),30.7(C-36),27.6(C-16),27.0(C-35),26.9(C-34),26.8(C-33),21.0(C-25),17.2(C-29),9.7(C-24)。
Benzoxazomycin白色粉末,ESI-MS m/z:637.3428[M+H]+,分子式C36H50N2O8,不饱和度为13。其NMR数据归属如下:1H NMR(600MHz,CD3OD)δH:0.97(s,1H),6.66(dd,J=15.3,10.2Hz,1H),6.33(d,J=2.9Hz,1H),6.07(dd,J=15.3,10.2Hz,1H),5.76(ddd,J=15.3,9.2,6.3Hz,1H),5.48(m,1H),5.19(m,1H),4.96(dd,J=8.9,3.5Hz,1H),4.73(ddd,J=8.4,4.9,3.3Hz,1H),4.44(d,J=3.2Hz,1H),4.17(m,1H),4.11(dt,J=6.9,3.5Hz,1H),3.87(dd,J=15.2,8.0Hz,1H),3.36(s,3H),2.95(m,1H),2.83(dd,J=16.7,8.1Hz,1H),2.61(dd,J=16.7,8.1Hz,1H),2.42(m,1H),2.34(m,1H),2.16(m,2H),2.05(m,1H),1.85(m,2H),1.75(s,3H),1.66(m,1H),1.41(m,2H),1.27(m,3H),1.12(d,J=6.8Hz,3H),0.97(d,J=6.8Hz,3H)。13C NMR(150MHz,CD3OD)δC:179.1(C-30),173.3(C-27),172.6(C-1),152.1(C-22),141.3(C-14),140.2(C-19),134.4(C-7),133.8(C-8),133.8(C-18),132.3(C-9),127.1(C-6),126.7(C-20),124.0(C-15),113.7(C-23),104.8(C-21),76.8(C-3),76.3(C-11),73.9(C-5),69.0(C-13),63.4(C-4),57.9(C-26),49.8(C-28),45.9(C-31),41.1(C-2),38.9(C-12),33.1(C-10),31.8(C-17),30.6(C-32),30.6(C-36),26.7(C-16),26.7(C-35),26.7(C-34),26.6(C-33),20.3(C-25),16.8(C-29),10.0(C-24)。
Ansafurantrienin A,G和H的理化数据参见文献【Li,H.;Chen,S.;Wang,J.;Zhang,M.;Wu,W.;Liu,W.;Sun,P.Ansafurantrienins,Unprecedented AnsatrieninDerivatives Formed via Photocatalytic Intramolecular[3+2]OxidativeCycloaddition.Org.Lett.2022,24,592-596.】。
22-Fluorotrienomycin B:白色粉末,ESI-MS m/z:599.3443[M+H]+,分子式C34H47N2O6,不饱和度为13。其NMR数据归属如下:1H NMR(600MHz,CD3OD)δH:7.42(d,J=10.9Hz,1H),6.73(s,1H),6.68(d,J=9.3Hz,1H),6.16(m,1H),6.13(m,1H),6.11(m,1H),6.09(m,1H),5.60(dd,J=15.0,8.5Hz,1H),5.58(m,1H),5.24(m,1H),4.85(m,1H),4.64(d,J=3.9Hz,1H),4.26(q,J=7.4Hz,1H),4.04(m,1H),3.32(s,3H),2.75(dd,J=11.8,4.2Hz,1H),2.58(m,1H),2.52(m,2H),2.45(t,J=11.8Hz,1H),2.29(m,1H),2.29(m,1H),2.06(m,2H),1.95(m,1H),1.94(m,1H),1.75(s,3H),1.36(d,J=7.3Hz,3H),1.08(m,1H)0.92(d,J=6.5Hz,3H),0.92(d,J=6.5Hz,3H),0.87(d,J=7.4Hz,3H)。
13C NMR(150MHz,CD3OD)δC:175.6(C-30),173.7(C-27),171.1(C-1),165.0(C-22),163.4(C-22),146.2(C-18),146.1(C-18),141.0(C-20),141.0(C-20),140.1(C-14),135.1(C-5),135.0(C-6),134.6(C-7),132.6(C-4),130.8(C-9),130.6(C-8),125.7(C-15),116.8(C-19),111.8(C-23),111.6(C-23),106.5(C-21),106.3(C-21),81.6(C-3),76.5(C-11),69.7(C-13),56.7(C-26),50.1(C-28),45.8(C-31),45.0(C-2),40.3(C-12),37.2(C-17),33.7(C-10),30.8(C-16),27.4(C-32),22.9(C-33),22.7(C-34),20.8(C-25),17.2(C-29),10.2(C-24)。
实施例2
本发明上述安莎三烯类化合物抗SARS-CoV-2病毒、蜱传脑炎病毒、西尼罗病毒、黄热病毒和基孔肯雅热病毒的体内和体外活性测定。
一、病毒、药物、试剂及其他材料
1.病毒:SARS-CoV-2病毒由海军军医大学生物医学防护教研室从COVID-19患者鼻咽拭子样本中分离培养出,其基因序列参见GenBank Accession No.MT622319。蜱传脑炎病毒、黄热病毒由海军军医大学生物医学防护教研室分离和扩增培养,西尼罗病毒、基孔肯雅热病毒利用反向遗传学技术合成,由幼仓鼠肾BHK细胞扩增培养。所有涉及病毒感染的实验操作均在海军军医大学P3实验室中进行。
2.化合物:安莎三烯类化合物为实施例1中的化合物,由海军军医大学药学系天然药物教研室提供。
3.非洲绿猴肾细胞VeroE6、人肝癌细胞系Huh7以及人宫颈癌细胞Hela-hACE2(表达ACE2基因变异体),购自中国科学院上海细胞所,由中国人民解放军海军军医大学生物医学防护教研室保存。
4.DMEM细胞培养液为美国Hyclone公司产品,用时添加10%胎牛血清、非必需氨基酸、氨苄青霉素和链霉素(各100U/ml),培养液添加剂均为美国Thermo Fisher公司产品。
5.细胞消化液,含0.25%胰蛋白酶,用磷酸盐缓冲液配制。
6.CCK8细胞活性和增殖检测试剂盒为美国MedChemExpress公司产品。
7.兔抗SARS-CoV-2核衣壳蛋白多克隆抗体购自北京义翘神州科技股份有限公司(Sino Biological#40143-T62)。小鼠蜱传脑炎病毒多克隆抗体、西尼罗病毒多克隆抗体、黄热病毒多克隆抗体、基孔肯雅热病毒多克隆抗体由海军军医大学生物医学防护教研室用甲醛灭活的蜱传脑炎病毒免疫小鼠而制备。
8.荧光素Alexa Fluor 488-标记的抗小鼠IgG为美国Thermo Fisher公司产品。
9.雄性叙利亚金黄地鼠、C57BL/6小鼠购自北京维通利华实验动物技术有限公司。
二、实验方法和结果:
(一)安莎三烯类化合物对细胞的毒性
分别将培养的人肝癌细胞系Huh7和非洲绿猴肾细胞VeroE6接种于96孔板,每孔10000个细胞,培养液100μL,12小时后,吸除原培养液,每孔内分别加入浓度梯度稀释的安莎三烯类化合物的完全DMEM培养液100μL,终浓度分别为2.5、5、10、20、40和80μM,每个浓度重复3孔,以80μM药物的溶剂DMSO含量作为不加药物的对照。置于37℃、5%CO2孵箱内培养。48小时后,每孔加入CCK8细胞活性和增殖检测检测试剂10μL,置于37℃、5%CO2孵箱内,30分钟后用多功能酶标仪检测每孔对450nm波长的吸光值,根据不同浓度药物处理孔与溶剂孔450nm吸光值的差异评价药物的细胞毒性。
结果显示,当浓度等于或低于80μM时,11种安莎三烯类化合物处理的两种细胞与DMSO溶剂处理的细胞均无明显差异。图2显示80μM时,11种安莎三烯类化合物处理的Huh7细胞与DMSO溶剂处理细胞的450nm吸光值。
(二)安莎三烯类化合物抗SARS-CoV-2感染的活性
1、安莎三烯类化合物在细胞感染模型中抗SARS-CoV-2病毒的活性检测
将传代培养的人宫颈癌细胞Hela-hACE2接种于96孔板,每孔10000个细胞,培养液100μL,培养12小时。随后每孔加入50μL含1000PFU SARS-CoV-2的完全DMEM培养液;同时以及从最高浓度20μM开始连续二倍稀释至最低浓度0.0625μM的安莎三烯类化合物50μL(用DMEM培养液稀释),用瑞德西韦(Remdesivir)作为阳性对照,用含等体积溶剂DMSO作为阴性对照,每个浓度重复3孔,以加等体积溶剂DMSO作为不加药物的对照,置于37℃、5%CO2孵箱内培养。
20小时后,用免疫荧光技术检测病毒对细胞的感染情况,具体操作如下:吸除培养板中的培养液,每孔加100μL甲醇,将培养板至于-20℃冰箱,20分钟后,取出培养板,吸除甲醇,每孔以磷酸盐缓冲液(PBS)洗孔一次,随后加入100μL含3%牛血清白蛋白(BSA)的PBS(以下简称3%BSA-PBS),置于水平摇床上,室温缓慢摇1小时,吸除培养板中的3%BSA-PBS,每孔加100μL含抗SARS-CoV-2多克隆抗体的1%BSA-PBS(抗体500倍稀释),室温缓慢摇1小时,吸除培养板中的抗SARS-CoV-2多克隆抗体工作液,每孔以PBS洗3次,随后加入100μL含荧光素Alexa Fluor 488-标记的抗小鼠IgG的1%BSA-PBS(荧光素抗体1500倍稀释),室温避光缓慢摇1小时,吸除培养板中的荧光素抗体工作液,每孔加入DAPI细胞核染色液100μL,室温避光缓慢摇10分钟,吸除培养板中的DAPI细胞核染色液,每孔以PBS洗3次,用细胞成像及分析系统(BioTek Cytation 5 Imaging Reader)对每孔细胞的荧光分布进行拍照。每孔拍照四个视野,分析、计算绿色荧光阳性细胞相对溶剂处理孔细胞的相对百分率,即病毒感染率,图3显示各种安莎三烯类化合物在0.625μM浓度时的感染率。根据各浓度梯度药物处理孔的阳性细胞百分率,计算药物对SARS-CoV-2感染的感染率(%)=1-(药物处理孔阳性细胞数/溶剂处理孔阳性细胞数)*100%。根据各浓度的感染率,计算IC50值。结果显示,11种安莎三烯类化合物对SARS-CoV-2的IC50;IC50(ansafurantrienin H)=1.056μM;IC50(ansafurantrienin A)=0.8774μM;IC50(ansafurantrienin G)=0.7978μM;IC50(ansatrienin A)=0.8165μM;IC50(ansatrienin B)=0.4696μM;IC50(ansatrienin 3b)=2.946μM;IC50(trienomycin A)=0.3068μM;IC50(trienomycin B)=0.4709μM;IC50(trienomycin C)=3.825μM;IC50(trienomycin F)=3.432μM;IC50(benzoxazamycin)=3.769μM,2-fluorotrienomycin B(0.3174μM)。结果显示,11种安莎三烯类化合物能有效抑制SARS-CoV-2感染Hela-hACE2细胞。
2、Ansatrienin B对C57BL/6小鼠的毒性检测
Ansatrienin B干粉先以DMSO初步溶解,然后以含40%PEG300-5%Tween80的PBS充分溶解,以腹腔注射方式给药,剂量设置20mg/Kg/天、10mg/Kg/天、5mg/Kg/天,每天一次,检测ansatrienin B对C57BL/6小鼠体重影响。当天(在腹腔注射给药前)开始称小鼠体重,此后每天在注射给药前称小鼠体重,记录小鼠体重。
小鼠体重变化如图4所示:20mg/Kg/天给药量的C57BL/6小鼠体重变化较大,且体重恢复时间较长,10mg/Kg/天给药量对小鼠体重影响小且体重恢复时间短,因此后续实验用10mg/Kg/天处理SARS-CoV-2感染动物。
3、Ansatrienin B保护叙利亚金黄地鼠抵抗SARS-CoV-2病毒感染的效果
ansatrienin B干粉先以DMSO初步溶解,然后以含40%PEG300-5%Tween80的PBS充分溶解,以腹腔注射方式给药,剂量10mg/Kg/天,每天一次。8周龄、雄性叙利亚金黄地鼠共12只,随机分为两组,分别为:1、给药组,同时病毒攻击和给药,即病毒滴鼻攻击后立即腹腔注射给药,6只小鼠;2、DMSO组,即病毒滴鼻攻击后立即腹腔注射DMSO稀释液,6只小鼠。以滴鼻方式进行病毒攻击,剂量1.8*108PFU SARS-CoV-2病毒。从病毒攻击当天(滴鼻病毒前)开始称小鼠体重,此后每天在腹腔注射给药前称小鼠体重,记录仓鼠体重。仓鼠体重变化如图5所示:DMSO组和给药组体重记录数值从病毒攻击后的第二天开始降低,但从第三天开始给药组相对于DMSO组体重下降比率小,并且给药组体重在病毒攻击后第7天开始回升,攻击后第11天体重恢复攻病毒攻击前水平;但DMSO组体重在病毒攻击后第9天开始回升,攻击后第14天体重恢复攻病毒攻击前水平。
为了检测病毒攻击后对叙利亚金黄地鼠肺部组织引起病变情况,在病毒攻击后第4天,对3只叙利亚金黄地鼠进行断颈处理后取肺器官,进行肺部切片HE染色观察。结果如图6所示,ansatrienin B药物处理有效保护叙利亚金黄地鼠抵抗SARS-CoV-2病毒感染。
上述体外和体内实验结果均表明,安莎三烯类化合物具有显著抑制SARS-CoV-2病毒感染的活性,可用于制备抗SARS-CoV-2病毒感染的药物。
(三)安莎三烯类化合物抑制蜱传脑炎病毒、西尼罗病毒、黄热病毒、基孔肯雅热病毒感染的活性
为了观察安莎三烯类化合物对蜱传脑炎病毒(TBEV)、西尼罗病毒(WNV)、黄热病毒(YFV)、基孔肯雅热病毒(CHIKV)是否具有抗抑制活性,我们进一步对安莎三烯类化合物(ansatrienin A、B、trienomycin A、benzoxazomycin、22-fluorotrienomycin B)进行了抗蜱传脑炎病毒、西尼罗病毒、黄热病毒、基孔肯雅热病毒活性的量化检测,即检测不同浓度时的抗病毒活性。药物设置了连续2倍稀释的四个浓度梯度20、10、5、2.5μM。检测方法中,除了药物处理设置浓度梯度外,其他与(二)中上述相同。病毒感染的细胞经病毒抗体和荧光抗体结合以及细胞核染色以后,用细胞成像及分析系统进行细胞拍照,每孔拍照四个视野,分析、计算绿色荧光阳性细胞的百分率,即病毒感染率(图7)。
上述体外和体内实验结果均表明,安莎三烯类化合物具有显著抑制SARS-CoV-2病毒、蜱传脑炎病毒、西尼罗病毒、黄热病毒和基孔肯雅热病毒感染的活性,可用于制备抗SARS-CoV-2病毒、蜱传脑炎病毒、西尼罗病毒、黄热病毒、基孔肯雅热病毒感染的药物。
以上上述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。本发明要求保护范围由所附的权利要求书及其等同物界定。
Claims (10)
1.一种活性物质的用途,其特征在于:
所述活性物质为安莎三烯类化合物;
所述用途为如下用途中的至少一种:
用途A、用于制备抗SARS-CoV-2病毒感染的药物;
用途B、用于制备抗蜱传脑炎病毒感染的药物;
用途C、用于制备抗西尼罗病毒感染的药物;
用途D、用于制备抗黄热病毒感染的药物;
用途E、用于制备抗基孔肯雅热病毒感染的药物。
2.如权利要求1所述的一种活性物质的用途,其特征在于:
所述用途还可以为如下用途中的至少一种:
用途A、用于制备预防或治疗SARS-CoV-2病毒感染的药物;
用途B、用于制备预防或治疗蜱传脑炎病毒感染的药物;
用途C、用于制备预防或治疗西尼罗病毒感染的药物;
用途D、用于制备预防或治疗黄热病毒感染的药物;
用途E、用于制备预防或治疗基孔肯雅热病毒感染的药物。
6.如权利要求1所述的一种活性物质的用途,其特征在于:
所述药物指以安莎三烯类化合物为唯一活性成份,
或
所述药物指包含安莎三烯类化合物的药物组合物。
7.如权利要求1所述的一种活性物质的用途,其特征在于:
所述安莎三烯类化合物在药物中的含量为0.1~99wt%。
8.如权利要求1所述的一种活性物质的用途,其特征在于:
所述药物的给药剂型选自散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂;
所述药物的给药途径剂型选自注射给药剂型、胃肠道给药剂型、皮肤给药剂型。
9.如权利要求1所述的一种活性物质的用途,其特征在于:
所述安莎三烯类化合物的制备,包括以下步骤:
S1.将菌种接种到种子培养基培养1-5天;
S2.将种子培养液接种到发酵培养基上进行发酵;
S3.发酵产物用有机溶剂提取,所得的提取物浓缩后得到粗浸膏,经分离纯化获得化合物。
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