中文摘要：
二芳基嘧啶类化合物(DAPYs)作为第二代非核苷类逆转录酶抑制剂,因其对HIV-1耐药株和野生株均有较高的抑制活性,且具有高选择性和高效低毒等特点,自发现以来,一直受到药物研究者的广泛关注。本论文利用分子杂合原理,将二芳基醚类化合物与二芳基嘧啶类化合物进行杂合,设计合成了一类二芳基嘧啶-二芳基醚杂合物(DATEPYs),并应用分子对接研究验证了设计的合理性。目标化合物的合成方法如下:中间体4-((2-巯基嘧啶-4-基)氧基)-3,5-二甲基苯腈(3)和1-叔丁氧羰基-3-(溴甲基)-1H-吲唑(7)在碳酸钾作碱的作用下发生亲核取代反应得到ZX1a;ZX1a在三氟乙酸的作用下脱BOC保护得到目标产物ZX1b。中间体3可以二氯嘧啶为起始原料先与4-羟基-3,5-二甲基苯腈反应再与硫脲反应制得。中间体7可由吲唑-3-甲酸为原料,经还原反应得到吲唑-3-甲醇,然后经过BOC保护得到中间体1-叔丁氧羰基-3-(羟甲基)-1H-吲唑(6),最后发生溴代反应制得。通过核磁共振氢谱、核磁共振碳谱和质谱对目标新化合物进行了表征,并测试了其熔点。本研究还选用与TMC125/WT HIV-1 RT晶体复合物(PDB:3MEC),将目标产物进行了虚拟活性筛选,结果显示目标化合物具有良好的抗HIV-1活性,其中ZX1b的抗HIV-1生物活性打分高于ZX1a。
英文摘要：
Diarylpyrimidines(DAPYs)as the second generation NNRTIs have attracted wide attention of medicinal researchers due to the advantages of high selectivity,unique potency,relatively low toxicity and extremely potent activities against both wild-type(WT)strain and many mutant strains.Based on the strategy of molecular hybridization,a series of diarylpyrimidine-diaryl ether hybrids(DATEPYs)were designed and synthesized by hybridizing diaryl ether compounds and diarylpyrimidine compounds.And the molecular docking studies verified the rationality of the drug design.Targets molecules DATEPYs were prepared according to synthetic procedures as follows:ZX1a were obtained via a nucleophilic substitution reaction of 3 with 7 using K_2CO_3 as base.ZX1a were subject to a simple deprotection to afford the compounds ZX1b under the presentation of trifluoroacetic acid.3 was synthesized via 2,4-dichloropyrimidine reacted with 4-hydroxy-3,5-dimethylbenzonitrile and then reacted with thiourea.1H-indazole-3-carboxylic acid was reduced to 3-(hydroxymethyl)-1H-indazole,7 was synthesized via 3-(hydroxymethyl)-1H-indazole reacted with(BOC)_2O and then reacted with PBr_3.The structures of new target compounds were confirmed by ~1H NMR,~(13)C NMR,and MS,and their melting points were measured.Both target molecules were evaluated by virtual screening using the crystal structure of TMC125/WT HIV-1 RT.The result indicated that target compounds displayed excellent activities against HIV-1,and ZX1b showed higher anti-HIV-1 activity than ZX1a.
