丙型肝炎病毒NS3/NS4A蛋白酶抑制剂的设计与合成
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摘要
丙型肝炎是人类常见的病毒性传染病，我国发病率约3.2％，目前临床上没有特效药，只能使用常规的抗病毒药或干扰素，效果并不理想，副作用大，因此迫切需要开发疗效好、副作用低的特效药。本论文介绍了丙型肝炎病毒(HCV)的生物学特征，及在病毒复制周期中的抗病毒药物作用靶点。在此基础上，阐述了治疗丙型肝炎病毒药物的研究进展概况，其中针对HCV NS3／NS4A酶抑制剂的研究较为活跃，NS3／NS4A蛋白酶为含有锌离子的金属蛋白酶，已有两个化合物进入到临床阶段，但均为肽类化合物，使用上受到一定的限制。
双苯并咪唑甲烷类化合物为高活性的非肽类HCV NS3／NS4A酶抑制剂。本文使用SYBYL7.0软件，对已知的非肽类抑制剂双苯并咪唑甲烷类化合物进行3DQSAR分析。以这类化合物为先导，运用生物电子等排原理，设计了具有相似骨架的四大类目标化合物：①用苯并噻唑代替其中的一个苯并咪唑；②用吡啶并咪唑代替其中的一个苯并咪唑；③用苯联噻唑代替其中的一个苯并咪唑；④2-苯基咪唑并[1，2-a]吡啶类化合物。通过对所设计的化合物进行合成和抗病毒活性研究，希望能够发现具有新型结构的活性化合物，进一步深入研究NS3／NS4A酶抑制的构效关系。
本文首次采用了丙二酰胺与邻芳二胺在微波辐射下制备对称性双芳并唑甲烷化合物、用芳并(咪、噻、噁)唑-2-乙酸乙酯与邻芳二胺在微波辐射下制备非对称性双芳并(咪、噻、噁)唑甲烷化合物、用4-取代噻唑-2-乙酸乙酯与邻芳二胺在微波辐射下制备非对称性(4-取代-噻唑-2-基)(1H-芳并咪唑-2-基)甲烷化合物等合成路线，共合成了48个目标化合物，其中41个为新化合物，用~1HNMR，ESI-MS，FT-IR，元素分析对这些化合物进行了全面表征，确定了这些化合物的结构，并对部分化合物进行了~(13)CNMR分析。
在设计并合成的这48个目标化合物中，包括：①双芳并咪唑甲烷类化合物24个(其中含吡啶并咪唑的双芳咪唑甲烷化合物5个，含对称结构的双芳并咪唑甲烷化合物7个，含非对称结构的双芳并咪唑甲烷化合物12个)；②含苯并噻(噁)唑环及苯并咪唑甲烷化合物7个；③(4-取代-噻唑-2-基)(1H-芳并咪唑-2-基)甲烷6个；④咪唑并[1，2-a]吡啶类化合物11个。结构如下：
The treatment of chronic diseases caused by the hepatitis C virus (HCV) is in unmet clinical need, since current therapeutic methods are only partially effective and limited with undesirable side effects. The viral. NS3/NS4A serine protease is the well-investigated target for the development of novel therapeutic agents and set up screening assays for the identification of selective inhibitors. Considerable efforts have been'made to the discovery of several classes of compounds with potential antiviral activity previously and two NS3/NS4A serine protease inhibitors are under preclinic trail.
Bisbenzimidazolylmethanes have high potation for inhibition of the hepatitis C virus (HCV) NS3/NS4A serine protease. The main active ion is the Zn~(2+) in the protease. Displaying highly potent inhibition against NS3/NS4A serine protease and being nonpeptidic, this class of compounds will be the most hopeful anti-HCV agents. A variety of new potential inhibitors of this type have been designed and synthesized, and the steric and electrostatic properties of the reported compounds are analyzed by both the basic and the computer-aided drug-design theories. The 3DQSAR investigation for the reported compounds was also carried out with SYBYL 7.0 software. Replacement of one benzimidazole fragment with benzothiazole or benzoxazole and optimization of the structure to create the new frame of the compounds were also carried out with the exception to find more potent compounds. The purpose of design and synthesis of these compounds is to investigate the QSAR of this class of compounds with the inhibition of HCV NS3/NS4A protease and eventually to develop more potent inhibitors.
Total 48 target compounds have been synthesized by the newly-developed synthetic routes, among which 41 are new compounds. The structure of all the compounds were characterized by ~1H NMR spectroscopy, FT-IR spectroscopy, ESI-Mass spectrometry, and elemental analyses, and the results were in agreement with the proposed structures.
The 48 compounds include 24 diheteroarylmethanes with asymmetric and symmetric structures; 6 (Benzothiazol-2-yl)(heteroaryl-2-yl)methanes; 1
双苯并咪唑甲烷类化合物为高活性的非肽类HCV NS3／NS4A酶抑制剂。本文使用SYBYL7.0软件，对已知的非肽类抑制剂双苯并咪唑甲烷类化合物进行3DQSAR分析。以这类化合物为先导，运用生物电子等排原理，设计了具有相似骨架的四大类目标化合物：①用苯并噻唑代替其中的一个苯并咪唑；②用吡啶并咪唑代替其中的一个苯并咪唑；③用苯联噻唑代替其中的一个苯并咪唑；④2-苯基咪唑并[1，2-a]吡啶类化合物。通过对所设计的化合物进行合成和抗病毒活性研究，希望能够发现具有新型结构的活性化合物，进一步深入研究NS3／NS4A酶抑制的构效关系。
本文首次采用了丙二酰胺与邻芳二胺在微波辐射下制备对称性双芳并唑甲烷化合物、用芳并(咪、噻、噁)唑-2-乙酸乙酯与邻芳二胺在微波辐射下制备非对称性双芳并(咪、噻、噁)唑甲烷化合物、用4-取代噻唑-2-乙酸乙酯与邻芳二胺在微波辐射下制备非对称性(4-取代-噻唑-2-基)(1H-芳并咪唑-2-基)甲烷化合物等合成路线，共合成了48个目标化合物，其中41个为新化合物，用~1HNMR，ESI-MS，FT-IR，元素分析对这些化合物进行了全面表征，确定了这些化合物的结构，并对部分化合物进行了~(13)CNMR分析。
在设计并合成的这48个目标化合物中，包括：①双芳并咪唑甲烷类化合物24个(其中含吡啶并咪唑的双芳咪唑甲烷化合物5个，含对称结构的双芳并咪唑甲烷化合物7个，含非对称结构的双芳并咪唑甲烷化合物12个)；②含苯并噻(噁)唑环及苯并咪唑甲烷化合物7个；③(4-取代-噻唑-2-基)(1H-芳并咪唑-2-基)甲烷6个；④咪唑并[1，2-a]吡啶类化合物11个。结构如下：
The treatment of chronic diseases caused by the hepatitis C virus (HCV) is in unmet clinical need, since current therapeutic methods are only partially effective and limited with undesirable side effects. The viral. NS3/NS4A serine protease is the well-investigated target for the development of novel therapeutic agents and set up screening assays for the identification of selective inhibitors. Considerable efforts have been'made to the discovery of several classes of compounds with potential antiviral activity previously and two NS3/NS4A serine protease inhibitors are under preclinic trail.
Bisbenzimidazolylmethanes have high potation for inhibition of the hepatitis C virus (HCV) NS3/NS4A serine protease. The main active ion is the Zn~(2+) in the protease. Displaying highly potent inhibition against NS3/NS4A serine protease and being nonpeptidic, this class of compounds will be the most hopeful anti-HCV agents. A variety of new potential inhibitors of this type have been designed and synthesized, and the steric and electrostatic properties of the reported compounds are analyzed by both the basic and the computer-aided drug-design theories. The 3DQSAR investigation for the reported compounds was also carried out with SYBYL 7.0 software. Replacement of one benzimidazole fragment with benzothiazole or benzoxazole and optimization of the structure to create the new frame of the compounds were also carried out with the exception to find more potent compounds. The purpose of design and synthesis of these compounds is to investigate the QSAR of this class of compounds with the inhibition of HCV NS3/NS4A protease and eventually to develop more potent inhibitors.
Total 48 target compounds have been synthesized by the newly-developed synthetic routes, among which 41 are new compounds. The structure of all the compounds were characterized by ~1H NMR spectroscopy, FT-IR spectroscopy, ESI-Mass spectrometry, and elemental analyses, and the results were in agreement with the proposed structures.
The 48 compounds include 24 diheteroarylmethanes with asymmetric and symmetric structures; 6 (Benzothiazol-2-yl)(heteroaryl-2-yl)methanes; 1
引文
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