2,4,5-三芳基-1H-吡唑-3(2H)-酮类化合物的合成与生物活性评价

目的 设计合成2,4,5-三芳基-1H-吡唑-3(2H)-酮类化合物,并研究其对ALK5信号通路、COX-1和COX-2信号通路的抑制活性,以期发现新型的ALK5或COX抑制剂。方法 关键中间体3-氧代-2,3-芳基丙酸甲酯（6）可以由两种方法制备：一是由芳基醛（1）与芳基乙酸甲酯（2）Aldol缩合后经Swern氧化的方法得到;二是通过芳基酰氯（5）与芳基乙酸甲酯的钠盐（4）直接缩合得到。化合物6与4-腈基苯肼（7）缩合得到4-（3,4-二芳基-5-氧代吡唑啉-1-基]）苯腈（8）,将化合物8的腈基水解为酰氨得到化合物（9）。应用基于细胞的TGF-Smad2检测评价化合物的ALK5抑制活性; 采用化学发光法测试化合物对COX1和COX2的抑制活性;采用MTT法检测化合物的细胞毒性。结果与结论 本文所合成的化合物和中间体均为新化合物,所有目标化合物和大部分中间体的结构经过了核磁与质谱的确证,其中目标化合物18个。多个化合物显示具有很好的对ALK5信号通路、COX信号通路的抑制活性,并且细胞毒性较小。     

2,5-二芳基-1,3-氧硫戊环化合物的合成及iNOS/PAF双重抑制活性的研究

目的寻找既能抑制iNOS又能拮抗PAF受体的化合物.方法以具有PAF受体拮抗活性的2,4-二芳基-1,3-二硫戊环为先导物,合成其生物电子等排体氧硫戊环化合物,并在其2位芳环上引入具有iNOS抑制活性的基团,测定目标化合物的iNOS抑制活性和PAF受体拮抗活性.结果合成了25个未见文献报道的目标物,其中9个化合物(I2～I7、I10、Ⅱ5、Ⅱ6)的iNOs抑制活性强于正在Ⅲ期临床的iNOS抑制剂氨基胍.PAF受体拮抗活性测试表明,I4活性高于阳性对照药ZH-2,I5活性与ZH-2相当,I 2、I6、I8、I10和Ⅱ5、Ⅱ6活性稍低于ZH-2.结论 I4、I5具有较高的iNOS/PAF双重抑制活性,值得进一步研究.     

1,3,5-三取代吡唑类ALK5抑制剂的合成与生物评价研究

目的 设计合成1,3,5-三取代吡唑类化合物,并研究其对ALK5所介导的TGFβ信号通路的抑制活性,以期发现新型ALK5抑制剂。方法 先以取代的苯甲醛和4-乙酰苯甲腈为原料,合成取代的查儿酮,再与芳基肼或芳基肼盐酸盐反应生成1,3,5-三取代吡唑啉,然后氧化脱氢得到相应的1,3,5-三取代吡唑类化合物,最后对官能团做适当的变换,得到目标化合物。应用基于细胞的TGF-Smad2 检测评价了化合物的ALK5抑制活性。结果与结论 合成目标化合物29个,其结构均经过了核磁与质谱的确证,其中化合物6c显示有较好的ALK5抑制活性。     

2,4-二芳基-1,3-二氧戊环化合物的合成和iNOS/PAF双重抑制活性

目的合成既拮抗PAF受体又抑制iNOS活性的化合物 ,期望能获得治疗败血性休克及有关炎症疾病的新型药物。方法以PAF受体拮抗剂 2 ,4 二芳基 1,3 二硫戊环为先导物 ,合成其生物电子等排体二氧戊环化合物 ,并在其 2位芳环上引入有iNOS抑制活性的基团 ,测定所得化合物的iNOS抑制活性和PAF受体拮抗活性。结果与结论共制备了 2 2个未见文献报道的目标化合物 ,对其中 15个进行iNOS抑制活性测试 ,发现有 3个活性与正在Ⅲ期临床研究的氨基胍相当 ,另有 3个活性强于氨基胍。对上述 6个化合物进行PAF受体抑制活性测定 ,发现 2个活性较强 ,其IC50 分别为 2 2 9× 10 -6mol/L和 2 5 7× 10 -6mol/L。     

1, 5-二芳基取代-1, 2, 4-三唑类衍生物的合成、 抗炎活性及其构效关系研究

摘 要：目的 寻找高活性的选择性环氧合酶-2抑制剂，探讨其构效关系。方法 根据已上市的选择性环氧合酶-2抑制剂celecoxib的构效关系以及分子模拟研究的结果，设计了两类1,5-二芳基取代-1,2,4-三唑类衍生物，以1-(4-取代苯基)-3-硫代氨基脲为原料，经多步反应合成目标化合物；用小鼠二甲苯致炎模型对目标化合物进行体外抗炎活性测试。结果与结论 合成了22个未见文献报道的新化合物，所有目标化合物的结构经IR、¹H-NMR、MS谱和元素分析确证。生物活性研究表明，化合物I₃、I₉、I₁₂、I₁₅、II₂、II₃、II₆、II₇具有较强的抗炎活性（P<0.01），其中化合物II₂、 II₃、 II₆的抗炎活性最强。构效关系分析发现，在三唑环1位芳基的对位引入F、Cl、Br吸电子基团以及3位引入磺酰基和甲硫基，对抗炎活性有重要的意义；在三唑环5位芳基的对位引入氨磺酰基，对抗炎活性有较大影响。     

2,6-二取代氨基-1H-咪唑并[4,5-c]吡啶类化合物的设计合成及JNK2抑制活性研究

目的设计合成2,6-二取代氨基-1H-咪唑并[4,5-c]吡啶类目标化合物并进行体外抑制c-Jun氨基末端激酶2(JNK2)活性测试。方法以2,4-二氯-5-硝基吡啶为起始原料,通过两次与胺类化合物的亲核取代并将硝基还原得到中间体,该中间体与不同取代的苯基异硫氰酸酯反应成环得到目标化合物;以迁移率改变法(mobility shift assay)对目标化合物进行抑制JNK2活性实验。结果与结论合成了13个未见文献报道的新化合物,其结构经~1H-NMR、ESI-MS谱确证,纯度经HPLC测定。目标化合物表现出较好的抑制JNK2活性,其中,化合物TY-1和TY-11抑制JNK2活性与先导化合物(CC-930)相当,2,6-二取代氨基-1H-咪唑并[4,5-c]吡啶类目标化合物具有开发为JNK抑制剂的潜力。     

5-芳基-1,2-二氢-1-吡咯里嗪酮类化合物的合成及抗炎镇痛作用

目的 研究5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物的抗炎镇痛作用构效关系，寻找高效低毒、具有抗炎镇痛活性的新型吡咯里嗪酮衍生物。方法 以吡咯里嗪酮为母体，设计并合成了5-芳基-1，2-二氢-1-吡咯里嗪酮类化合物。用二甲苯致小鼠耳肿胀法和小鼠醋酸扭体法测定了该类化合物的抗炎及镇痛活性。结果 用两条路线合成了10个目标化合物，经1H-NMR和MS确证其结构。小鼠试验表明，一些所合成的化合物具有明显的抗炎和／或镇痛作用。结论 化合物Ⅲ1及Ⅲ5的抗炎活性优于对照药布洛芬；化合物Ⅲ5的镇痛活性优于对照药布洛芬；其中化合物Ⅲ5的抗炎及镇痛活性均强于对照药布洛芬，值得进一步研究。     

四氢苯并咪唑类衍生物的合成及其环氧合酶-2抑制活性

目的 寻找新型不良反应小的环氧合酶-2(COX-2)选择性抑制剂.方法 结合典型COX-2选择性抑制剂基本结构特征,设计并合成一系列新型四氢苯并咪唑类化合物.采用化学发光法测试化合物对环氧合酶-2的抑制活性.结果与结论 设计并合成了13个新型四氢苯并咪唑类化合物,其结构经元素分析、1H-NMR、13C-NMR和MS确证,所有化合物均未见文献报道.部分化合物对环氧合酶-2的抑制活性结果表明,化合物1、3、6对COX-2有一定的抑制作用.     

新型6-芳基茚并异喹啉酮衍生物的合成及抗肿瘤活性研究

目的合成一系列新型结构6-芳基茚并异喹啉酮衍生物,并考察目标化合物对DNA拓扑异构酶Ⅰ（TopoⅠ）的抑制活性及其体外抗肿瘤活性。方法以茚和间氯苯甲酸为原料,分别合成高酞酸和4-甲氧基高酞酸;高酞酸通过脱水反应、与亚胺加成反应制得中间体6-芳基茚并异喹啉酮;该中间体与各种氨基取代的氯代物反应得到目标化合物。采用TopoGEN公司的Topoisomerase Ⅰ drug screning kit来测试目标化合物对TopoⅠ的抑制活性;选取人乳腺癌细胞（MCF-7）、非小细胞肺癌细胞（NIH-H460）和人神经胶质瘤细胞（U251）对目标化合物进行体外抗肿瘤活性筛选。结果与结论共合成了17个未见文献报道的新化合物,其结构均经MS（EI）、1H-NMR确证。体外活性筛选结果表明：目标化合物对TopoⅠ表现出良好的抑制作用,且对3种肿瘤细胞表现出较好的抗增殖活性。     

含4-甲基噻唑环的新型二肽基肽酶IV抑制剂的设计、合成及降血糖活性测试

目的：合成一类新型的以4-噻唑环为母体的二肽基肽酶IV (DPP-IV)抑制剂,测试并研究它们的降血糖活性。方法：通过Hantzsch噻唑合成反应制备2-氨基4-甲基噻唑,然后用氯乙酰氯和三乙胺进行氯乙酰化,所得中间体氯乙酰胺经芳基甲胺处理得到目标物,最后,在干燥的乙醚中用氯化氢乙醚溶液处理即可得到目标物的盐酸盐。利用小鼠体内口服葡萄糖耐受量法测定目标化合物在治疗糖尿病方面的活性。结果：合成了21个结构新颖的化合物,结构经过1H-NMR和ESI-MS确认。结论：经过活性测试,发现其中的两个目标化合物具有明显的降血糖作用,其中化合物7f的活性与阳性对照药西他列汀相当,化合物7h的活性则超过阳性对照药,显示了在治疗糖尿病方面的前景。     

Synthesis of pyrazole-based 1,5-diaryl compounds as potent anti-inflammatory agents

Series of 1,5-diaryl pyrazole ester derivatives have been synthesized and found to contain potent inhibitory activity against cyclooxygenase-2 (COX-2) enzyme. The article describes synthesis of the target pyrazole analogs and biological assay using Carrageenan induced rat paw for investigation.     

Cyclooxygenase-2 inhibitors. 1,5-diarylpyrrol-3-acetic esters with enhanced inhibitory activity toward cyclooxygenase-2 and improved cyclooxygenase-2/cyclooxygenase-1 selectivity

The important role of cyclooxygenase-2 (COX-2) in the pathogenesis of inflammation and side effect limitations of current COX-2 inhibitor drugs illustrates a need for the design of new compounds based on alternative structural templates. We previously reported a set of substituted 1,5-diarylpyrrole derivatives, along with their inhibitory activity toward COX enzymes. Several compounds proved to be highly selective COX-2 inhibitors and their affinity data were rationalized through docking simulations. In this paper, we describe the synthesis of new 1,5-diarylpyrrole derivatives that were assayed for their in vitro inhibitory effects toward COX isozymes. Among them, the ethyl-2-methyl-5-[4-(methylsulfonyl)phenyl]-1-[3-fluorophenyl]-1H-pyrrol-3-acetate (1d), which was the most potent and COX-2 selective compound, also showed a very interesting in vivo anti-inflammatory and analgesic activity, laying the foundations for developing new lead compounds that could be effective agents in the armamentarium for the management of inflammation and pain.     

5-Lipoxygenase inhibitors: a patent evaluation (WO2011161615)

1,5-Diarylpyrazoles are privileged scaffolds used for the development of COX-2 (cyclooxygenase 2) selective inhibitors (coxibs). Derivatives of 1,5-diarylpyrazoles are currently being used as 5-lipoxygenase (5-LO) inhibitors for the treatment of respiratory diseases, inflammatory and autoimmune disorders. The following article, which evaluates this patent application, describes 1,5-arylpyrazoles and their pharmacological ability to inhibit 5-LO. Furthermore, the authors describe how these compounds relate to pyrazole derivatives in terms of their synthesis and how they are used for treating several respiratory diseases including: chronic obstructive pulmonary disease (COPD), bronchial asthma and other disorders. The authors have come to the conclusion that this current patent evaluation is insufficient for the complete evaluation of these compounds. However, this does not diminish the importance of the versatile synthesis of 1,5-pyrazole derivatives and their use in the treatment of inflammatory-related pathologies.     

5-Lipoxygenase inhibitors: a patent evaluation (WO2011161615)

1,5-Diarylpyrazoles are privileged scaffolds used for the development of COX-2 (cyclooxygenase 2) selective inhibitors (coxibs). Derivatives of 1,5-diarylpyrazoles are currently being used as 5-lipoxygenase (5-LO) inhibitors for the treatment of respiratory diseases, inflammatory and autoimmune disorders. The following article, which evaluates this patent application, describes 1,5-arylpyrazoles and their pharmacological ability to inhibit 5-LO. Furthermore, the authors describe how these compounds relate to pyrazole derivatives in terms of their synthesis and how they are used for treating several respiratory diseases including: chronic obstructive pulmonary disease (COPD), bronchial asthma and other disorders. The authors have come to the conclusion that this current patent evaluation is insufficient for the complete evaluation of these compounds. However, this does not diminish the importance of the versatile synthesis of 1,5-pyrazole derivatives and their use in the treatment of inflammatory-related pathologies.     

Novel pyrazole derivatives as potential promising anti-inflammatory antimicrobial agents

Four series of 1H-pyrazole derivatives have been synthesized. The first series was synthesized starting by condensing the hydrazine derivatives 1a-d with 4-(1-ethoxycarbonyl-2-oxopropyl)azobenzoic acid 2a in ethanol or glacial acetic acid to generate the corresponding pyrazoline derivatives 3a-d. Likewise, heating 1a-d with 4-(1-acetyl-2-oxopropyl)azobenzoic acid 2b gave rise to the pyrazole derivatives 4a-d. Similarly, reaction of 1a-d with ethyl 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-3-oxobutanoate 2c or 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl azo)pentane-2,4-dione 2d in ethanol or glacial acetic acid led to the corresponding pyrazoline derivatives 5a-d or pyrazole derivatives 6a-d. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 6c, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.     

Synthesis and antiinflammatory activity of 1,5-Diarylimidazoles

A number of 1,5-diarylimidazoles has been synthesized and evaluated for their inhibitory activities of COX-2 catalyzed PGE2 production. 1,5-Diarylimidazoles were obtained from imimes and p-toluenesulfonylmethyl cyanide (TosMIC). Imines were prepared from commercially available amines and aldehydes. Among the compounds tested, 1-(2,4-difluorophenyl)-5-(4-methylsulfonylphenyl)imidazole (2r) showed strong inhibitory activity, however, most diarylimidazoles exhibited little to low inhibitory activities against COX-2 catalyzed PGE2 production.     

Synthesis and selective cyclooxygenase-2 inhibitory activity of a series of novel, nitric oxide donor-containing pyrazoles

The synthesis of a series of novel pyrazoles containing a nitrate (ONO(2)) moiety as a nitric oxide (NO)-donor functionality is reported. Their COX-1 and COX-2 inhibitory activities in human whole blood are profiled. Our data demonstrate that pyrazole ring substituents play an important role in COX-2 selective inhibition, such that a cycloalkyl pyrazole (6b) was found to be a potent and selective COX-2 inhibitor. Other modifications at the 3 position of the central pyrazole ring (17b, 23b, 26b-I) enhanced COX-2 inhibitory potency. Among the pyrazoles synthesized, the oxime (23b) was identified as the most potent COX-2 selective inhibitor. Accordingly, 23b was profiled pharmacologically in the rat after oral administration and shown to possess potent antiinflammatory activity in the carrageenan-induced air-pouch model and less gastric toxicity than a standard COX-2 inhibitor when administered with background aspirin treatment. We suggest that the enhanced gastric tolerance of an NO-donor COX-2 selective inhibitor has the potential to augment the clinical profile of this drug class.     

Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives

We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.     

QSAR analysis of some fused pyrazoles as selective cyclooxygenase-2 inhibitors: a Hansch approach

Quantitative structure activity relationships (QSAR) for two unique series of centrally fused pyrazole ring systems have been studied for selective cyclooxygenase-2 inhibitory activity. Several statistically significant QSAR models were developed and suggest that hydrophobicity of entire molecules and a fluorine atom substitution at position 8 of the non benzene sulphonyl ring fused with central pyrazole core of series 1 compounds is crucial for improved COX-2 selectivity. Various structural and physicochemical stipulations to improve the inhibitory activities of the enzymes among individual series of compounds are also discussed. The conclusions derived may serve as an example to advance the design of new selective COX-2 inhibitors.     

Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1: molecular docking and 3D QSAR analyses

The Lamarckian genetic algorithm of AutoDock 3.0 has been employed to dock 40 1,5-diarylpyrazole class compounds into the active sites of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters and RMSD values compared with the known inhibitor, SC-558 (43), show that these inhibitors interact respectively with COX-2 and COX-1 in a very similar way. The r(2) values of 0.648 for COX-2 and 0.752 for COX-1 indicate that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of 1,5-diarylpyrazoles were reasonably explored, and the COX-2/COX-1 selectivity was demonstrated by the three-dimensional (3D) interaction models of inhibitors complexing with these two enzymes. Using the binding conformations of 1,5-diarylpyrazoles, consistent and highly predictive 3D quantitative structure-activity relationship (QSAR) models were developed by performing comparative molecular field analyses (CoMFA) and comparative molecular similarity analyses (CoMSIA). The q(2) values are 0.635 and 0.641 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by SC-558 (43) and a set of 10 other compounds that were not included in the training set. Mapping these models back to the topology of the active site of COX-2 leads to a better understanding of vital diarylpyrazole compounds and COX-2 interactions. Structure-based investigations and the final 3D QSAR results provided possible guidelines and accurate activity predictions for novel inhibitor design.