非核苷逆转录酶抑制剂新进展

治疗艾滋病的逆转录酶抑制剂主要包括核苷逆转录酶抑制剂(NRTIs,如齐多夫定)和非核苷逆转录酶抑制剂(NNRTIs,如奈韦拉平)。目前至少有30多类非核苷类化合物被发现具有选择性抑制HIV-1逆转录酶的作用,其中已经获得美国FDA批准上市的包括奈韦拉平、地拉夫定和埃法韦伦,还有一些品种正在进行临床试验,其中效果较好的包括MKC-442、trovirdine、loviride等。“第一代”NNRTIs的缺点是容易使病毒产生变异,出现耐药性。“第二代”NNRTIs则活性谱广,不容易产生耐药的变异病毒。属于“第二代”NNRTIs的化合物除了埃法韦伦外,还包括埃法韦伦的衍生物DPC083,咪唑衍生物capravirine,二芳基嘧啶类化合物etravirine、rilpivirine。此外,还有一些喹喔啉、吡嗪酮类、烯基二芳基甲烷等也表现出很好的抗HIV活性。相信在不久的将来,将有更多更有效的非核苷逆转录酶抑制剂为人类的健康带来福音。     

取代基物化参数用于HEPT类HIV-1逆转录酶抑制剂的QSAR研究

用描述取代基电性、立体性和疏水性的物化参数对6-苯硫基取代胸腺嘧啶HETP类化合物进行了结构表征,并对化合物抑制H IV-1逆转录酶的活性进行了QSAR研究。经逐步回归筛选变量后,所建多元线性回归方程复相关系数R2及留一法交互检验R2cv分别为0.904和0.848 7。用预测集样本进行外部预测所得R2ext和Q2ext分别为0.928 9和0.929 4。结果表明,影响化合物活性的主要因素是嘧啶环5位X取代基,其电性和疏水性参数值越小,阻抑能力越强。     

3,4-二氢-2(1H)喹啉酮衍生物的合成研究

对3,4-二氢-2(1H)喹啉酮衍生物1,2,3(R= NO2,NH2,OH;R= H,NO2,NH2)的合成进行了研究。以苯胺和3-氯丙酰氯为原料,制得N-苯基-3-氯丙酰胺,然后经环合得到3,4-二氢-2(1H)喹啉酮,再经由硝化、还原、重氮化水解合成了一系列3,4-二氢-2(1H)喹啉酮衍生物:6-硝基-3,4-二氢-2(1H)喹啉酮(1a),6,8-二硝基-3,4-二氢-2(1H)喹啉酮(1b),6-氨基-3,4-二氢-2(1H)喹啉酮(2a),6,8-二氨基-3,4-二氢-2(1H)喹啉酮(2b),6-氨基-8-硝基-3,4-二氢-2(1H)喹啉酮(2c),6-羟基-3,4-二氢-2(1H)喹啉酮(3a)和6-羟基-8-硝基-3,4-二氢-2(1H)喹啉酮(3b),其中化合物(2c)及(3b)为新化合物。单步产率均在86%以上,路线简单,操作简便,反应条件温和。采用MS,1HNMR对产品进行了定性及结构表征。     

HClO4催化合成3,4-二氢嘧啶-2-酮

HClO4催化下,芳香醛、β-酮酸酯、脲或硫脲(物质的量比1∶1∶1.5)在冰醋酸中环化缩合,合成3,4-二氢嘧啶-2-酮衍生物,反应时间3.5 h,产率75%~98%。     

6,7-二氢-6-甲基-3-甲硫基吡喃[4,3-c]吡唑-4-(2H)-酮衍生物的合成及生物活性

6-甲基-5,6-二氢吡喃-2,4-二酮和二硫化碳、碘甲烷缩合得到5,6-二氢吡喃-2,4-二酮的二硫缩醛化合物,然后和取代肼反应得到1位取代和2位取代6,7-二氢-6-甲基-3-甲硫基吡喃[4,3-c]吡唑-4-(2H)-酮衍生物。其化学结构通过单晶X衍射、1HNMR、13CNMR、元素分析证实。生物活性测试结果初步表明,该类化合物表现出一定的杀菌和对前列腺癌细胞PC3的抑制活性。     

Design,Synthesis, and Biological Evaluation of 2-Aminothiazole Derivatives as Novel Checkpoint Kinase 1 (CHK1) Inhibitors

A series of 2-aminothiazole derivatives were designed, synthesized on the basis of bioisosterism strategy and evaluated for their CHK1 inhibitory activity. Most of them exhibited potent CHK1 inhibition, and excellent antiproliferative activity against MV-4-11 and Z-138 cell lines. Systematic structure-activity relationship (SAR) efforts led to the discovery of a promising compound 8 n , which showed potent CHK1 inhibitory activity with IC₅₀ value of 4.25±0.10 nM, excellent antiproliferative activity against MV-4-11 and Z-138 cells with IC₅₀ value of 42.10±5.77 nM and 24.16±6.67 nM, respectively, as well as moderate oral exposure (AUC_(0−t)=1076.25 h ⋅ ng/mL) in mice. Additionally, treatment of MV-4-11 cells with compound 8 n for 2 h led to robust inhibition of CHK1 autophosphorylation on serine 296. Furthermore, kinase selectivity assay revealed that 8 n displayed acceptable selectivity toward 15 kinases. These results demonstrated that compound 8 n may be a promising potential anticancer agent for further development.     

6,7-二(2-甲氧基乙氧基)喹唑啉-4-酮的合成

以3,4-二羟基苯甲酸乙酯为原料,通过醚化、硝化、还原、成环四步反应合成新型抗癌药物中间体6,7-二(2-甲氧基乙氧基)喹唑啉-4-酮,改进了工艺,考察了各类工艺条件对目标产物收率的影响,得到最适宜反应条件,在优化条件下,总收率为83.7%。     

H4GeW12O40/Cu3(BTC)2催化Biginelli反应合成3,4-二氢嘧啶-2(1H)-酮衍生物

采用浸渍法以金属有机骨架Cu_3(BTC)_2负载锗钨酸(H_4GeW_(12)O_(40))制备H4Ge W_(12)O_(40)/Cu_3(BTC)_2催化剂,并用该催化剂催化芳醛、尿素和乙酰乙酸乙酯通过"一锅法"Biginelli缩合反应,以无水乙醇为溶剂,合成6种3,4-二氢嘧啶-2(1H)-酮衍生物;通过熔点的测定,IR,1H NMR和MS等对产物3,4-二氢嘧啶-2(1H)-酮衍生物进行表征。结果表明:在芳醛用量为0.04 mol,n(芳醛)∶n(乙酰乙酸乙酯)∶n(尿素)=1∶1.5∶1.5,催化剂的用量占反应物料总质量的4.0%,反应温度为90℃,反应时间为90 min的条件下,目标产物收率可达63.0%~76.3%。     

2,3-二氢-1,5-苯并噻庚因-4(5H)-酮及其衍生物合成方法的改进

邻氨基硫酚在邻、对氯甲苯溶剂中分别与丙烯酸、肉桂酸、呋喃丙烯酸反应得到相应的2，3-二氢-1，5-苯并噻庚因．4（5H）．酮及其衍生物（Ia-c），收率分别为87．6％、76．3％和69．5％。用红外光谱、核磁共振光谱、质谱对产物进行了分析，证明所得产物为目标化合物。研究Y2，3．二氢．1，5．苯并噻庚因-4（5H）-酮（Ia）的合成，其优化条件为：n（酚）：n（酸）为1：1，溶剂用量为70mL，加料时反应温度为100℃，加料时间为60min，然后将反应温度升至反应混合物沸点，并将反应过程中产生的水及时去除。     

A Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt To Discover Novel Antidiabetic Agents

Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin-4-one derivatives 8 – 22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC₅₀ values in the micromolar range. 5-(Furan-2-ylmethylene)-2-(4-nitrophenylimino)thiazolidin-4-one ( 17 ) exhibited potency with a competitive type of enzyme inhibition. structure–activity relationship studies revealed various structural facets important for the potency of these analogues. The findings revealed a requirement for a nitro group-including hydrophobic heteroaryl ring for PTP1B inhibition. Molecular docking studies afforded good correlation with experimental results. H-bonding and π–π interactions were responsible for optimal binding and effective stabilization of virtual protein-ligand complexes. Furthermore, in-silico pharmacokinetic properties of test compounds predicted their drug-like characteristics for potential oral use as antidiabetic agents.Additionally, a binding site model demonstrating crucial pharmacophoric characteristics influencing potency and binding affinity of inhibitors has been proposed, which can be employed in the design of future potential PTP1B inhibitors.     

4,5-二氢-3-甲基-1-(4-氯-2-氟苯基)-4-二氟甲基-1,2,4-三唑-5(1H)酮的合成方法

4,5-二氢-3-甲基-1-(4-氯-2-氟苯基)-4-二氟甲基-1,2,4-三唑-5(1H)酮是超高效含氟除草剂唑酮草酯的重要中间体,采用高温氟化的方法,通过优化反应条件,使目标化合物的合成收率达75.4%,含量达97.3%,降低了成本,更利于工业化生产.     

Design,Synthesis, and SAR of Naphthyl‐Substituted Diarylpyrimidines as Non‐Nucleoside Inhibitors of HIV‐1 Reverse Transcriptase

A series of 38 2‐naphthyl‐substituted diarylpyrimidine (DAPY) analogues, characterized by various substitution patterns on the pyrimidine and naphthalene rings, was synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of the HIV‐1 wild‐type and double mutant (K103N+Y181C) strains. Most of the compounds displayed strong activity against wild‐type HIV‐1. The most active compound, with a cyano group at position C6 on the naphthalene ring, exhibited activity against wild‐type HIV‐1 with an EC₅₀ value of 0.002 μM and against the double mutant strain with an EC₅₀ value of 0.24 μM ; the selectivity index (SI) against wild‐type is >180 000, the highest SI value among DAPY analogues. The structure–activity relationship (SAR) of the newly synthesized DAPYs is presented herein.     

1-硝基-2-(2,6-二氨基-4(3H)-氧代嘧啶-5-基)-4-(4-乙氧甲酰苯基)丁烷的合成

1-硝基-2-(2,6-二氨基-4(3H)-氧代嘧啶-5-基)-4-(4-乙氧甲酰苯基)丁烷是合成培美曲塞二钠的关键中间体。研究了以4-碘苯甲酸,2,6-二氨基-4-羟基嘧啶为原料,经酯化,加成,缩合,消除,加成,得目标产物。本法收率高,适合工业化生产。     

催化加氢合成6-氨基-7-氟-2H-1,4-苯并口恶嗪-3(4H)-酮

6-氨基-7-氟-2H-1,4-苯并口恶嗪-3(4H)-酮(Ⅱ)是合成除草剂丙炔氟草胺的关键中间体,该文采用雷尼镍催化加氢还原7-氟-6-硝基-2H-1,4-苯并口恶嗪-3(4H)-酮(Ⅰ)高收率的制得了目标化合物Ⅱ,确定了最佳合成工艺条件:反应温度80℃,反应时间5 h,催化剂用量为原料质量的5%,氢气压力6 MPa,产品的收率95.2%,质量分数98.5%,溶剂和催化剂循环使用5次,对收率和产品质量分数无影响。产品结构经元素分析、红外光谱、核磁共振确证。     

1-(2-氯苯基)-5(4H)-四唑啉酮的合成研究

1 (2 氯苯基 ) 5 (4H) 四唑啉酮 (Ⅰ)可由 2 氯硝基苯经三步合成反应制得。首先 ,2 氯硝基苯经铁粉还原得 2 氯苯胺 (Ⅱ) ,Ⅱ与碳酸二 (三氯甲基 )酯反应得 2 氯苯基异氰酸酯 (Ⅲ ) ,Ⅲ在DMF溶剂中 ,无水三氯化铝催化下与叠氮钠缩合得Ⅰ。三步收率分别为 90 %、80 %、90 % ,总收率为 6 5 %(以邻氯硝基苯计 ) ,产品质量分数达 95 %。     

微波辐射下合成4-(4-氯苯基)-6-甲基-5-乙氧羰基-3,4-二氢嘧啶-2(1H)-酮

研究了微波辐射催化合成标题化合物的方法。最优合成条件:催化剂氨基磺酸0.8g,微波功率240W,辐射时间4min,n4-氯苯甲醛∶n乙酰乙酸乙酯∶n尿素为1.0∶1.2∶1.5,在此条件下产率达94.2%。     

2-(4’-羧基苯基)-1,2-苯并异硒唑-3(2H)-酮的放大合成

为了克服依布硒林亲水性差及气味太重的缺点,同时保留依布硒林抗氧化的特性,参照现有方法放大合成了羧基依布硒林(ebselen)衍生物2-(4’-羧基苯基)-1,2-苯并异硒唑-3(2H)-酮,并对该方法优化、改进,用质谱及红外光谱对目标产物进行了表征。通过对合成的产物进行急性经口毒性试验,发现其经口半数致死量(LD50,medium lethal dose)大于5.5g/Kg,按照急性毒性分级标准确定该依布硒林衍生物属实际无毒级。