新型神经氨酸酶抑制剂的设计合成和药理活性测试
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摘要
目的为防控流感,设计合成新型神经氨酸酶抑制剂,并进行药理活性测试。方法基于苯甲酸类神经氨酸酶抑制剂的结构,拼合具有抗病毒活性的酰基硫脲片段,利用前药原理设计并合成了I和II系列共28个新型神经氨酸酶抑制剂并进行药理活性筛选。药理活性测试选用流感病毒菌株A/FM/1/47(H1N1),分别进行神经氨酸酶单一浓度(10μmol·L~(-1))抑制率和病毒抑制活性测试。结果药理结果显示化合物I-2,I-5,I-11和I-12具有较好的病毒抑制活性,其中I-11的活性最佳,病毒抑制率达到70.50%,优于oseltamivir。结论通过对28个化合物进行初步构效关系研究,为后续此类新型神经氨酸酶抑制剂的研究提供基础。
OBJECTIVE To design, synthesis novel neuraminidase inhibitors and detect their pharmacological activity for inhibite virus. METHODS The antiviral acyl thiourea fragments were integrated with the benzoic acid structure of neuraminidase inhibitors. Based on the pro-drug principle, 28 compounds were designed and synthesized and conduct the pharmacological activity screening. A/FM/1/47(H1 N1) strain was selected for the pharmacological activity test, and the single concentration(10 μmol·L~(-1)) inhibition rate of neuraminidase and in vitro virus inhibition test were performed respectively.RESULTS The results showed that I-2, I-5, I-11 and I-12 had desirable virus inhibitory activity, I-11 was the best among them.The virus inhibition rate of compound I-11 could reach 70.50%, which was superior to oseltamivir. CONCLUSION Preliminary study on structure-activity relationship of these 28 compounds will provide a basis for the design of the new neuraminidase inhibitors in the following study.
OBJECTIVE To design, synthesis novel neuraminidase inhibitors and detect their pharmacological activity for inhibite virus. METHODS The antiviral acyl thiourea fragments were integrated with the benzoic acid structure of neuraminidase inhibitors. Based on the pro-drug principle, 28 compounds were designed and synthesized and conduct the pharmacological activity screening. A/FM/1/47(H1 N1) strain was selected for the pharmacological activity test, and the single concentration(10 μmol·L~(-1)) inhibition rate of neuraminidase and in vitro virus inhibition test were performed respectively.RESULTS The results showed that I-2, I-5, I-11 and I-12 had desirable virus inhibitory activity, I-11 was the best among them.The virus inhibition rate of compound I-11 could reach 70.50%, which was superior to oseltamivir. CONCLUSION Preliminary study on structure-activity relationship of these 28 compounds will provide a basis for the design of the new neuraminidase inhibitors in the following study.
引文
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[14]DING Y,DOU J,TENG Z,et al.Antiviral activity of baicalin against influenza A(H1N1/H3N2)virus in cell culture and in mice and its inhibition of neuraminidase[J].Arch Virol,2014,159(12):3269-3278.
[2]MATEOSOVICH M,KLENK H D.Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding[J].Rev Med Virol,2003,13(2):85-97.
[3]VON I,WU W Y,KOK G B,et al.Rational design of potent sialidase-based inhibitors of influenza virus replication[J].Nature,1993,363(6428):418-423.
[4]DUNN C J,GOA K L.Zanamivir:a review of its use in influenza[J].Drugs,1999,58(4):761-784.
[5]KIM C U,LEW W,WILLIAMS M A,et al.Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site:design,synthesis,and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity[J].J Am Chem Soc,1997,119(4):681-690.
[6]MCCLELLAN K,PERRY C M.Oseltamivir:a review of its use in influenza[J].Drugs,2001,61(2):263-283.
[7]CHAND P,KOTIAN P L,DEHGHANI A,et al.Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent anti-influenza activity[J].J Med Chem,2001,44(25):4379-4392.
[8]KUBO S,TOMOZAWA T,KAKUA M,et al.Laninamivir prodrug CS-8958,a long-acting neuraminidase inhibitor,shows superior anti-influenza virus activity after a single administration[J].Antimicrob Agents Chemother,2010,54(3):1256-1264.
[9]DAS K.Antivirals targeting influenza A virus[J].J Med Chem,2012,55(14):6263-6277.
[10]NGUYEN H T,NGUYEN T,MISHIN V P,et al.Antiviral susceptibility of highly pathogenic avian influenza A(H5N1)viruses isolated from poultry,Vietnam,2009-2011[J].Emerg Infect Dis,2013,19(12):1963-1971.
[11]SAMSON M,PIZZOMO A,ABED Y,et al.Influenza virus resistance to neuraminidase inhibitors[J].Antiviral Res,2013,98(2):174-185.
[12]SUDBECK E A,JEDRZEJAS M J,SINGH S,et al.Guanidinobenzoic acid inhibitors of influenza virus neuraminidase[J].J Mol Biol,1997,267(3):584-594.
[13]王德传,郁洁,周雨,等.苯甲酸硫脲类抗流感病毒化合物及其制备方法和用途:中国,104447481A[P].2015-03-25.
[14]DING Y,DOU J,TENG Z,et al.Antiviral activity of baicalin against influenza A(H1N1/H3N2)virus in cell culture and in mice and its inhibition of neuraminidase[J].Arch Virol,2014,159(12):3269-3278.