本文選題：艾滋病 + 抑制劑��； 參考：《湘潭大學(xué)》2014年碩士論文

【摘要】：艾滋病（AIDS）全稱為獲得性免疫缺陷綜合癥，是由人類感染免疫缺陷病毒HIV引起的疾病，嚴(yán)重危害著人類的健康和社會經(jīng)濟的發(fā)展。HIV病毒侵入靶細(xì)胞需要輔助受體CCR5或CXCR4的協(xié)助，抑制HIV病毒與CCR5或CXCR4的結(jié)合作用可以有效抑制HIV病毒感染靶細(xì)胞。 近年來，以CCR5為靶標(biāo)的輔助受體抑制劑受到了多個跨國制藥公司和學(xué)術(shù)機構(gòu)的關(guān)注與研究，已發(fā)現(xiàn)了許多CCR5小分子抑制劑，已有一個CCR5抑制劑于2007年上市（輝瑞公司的馬拉維諾）。相比CCR5抑制劑，CXCR4類小分子抑制劑研究較少，目前已發(fā)現(xiàn)的結(jié)構(gòu)為雙環(huán)拉胺類、四氫喹啉苯并咪唑多胺類與胍類抑制劑具有很強的抗HIV活性。然而，單獨使用CCR5或CXCR4抑制劑具有局限性，如單一的輔助受體抑制劑只對各自特異的病毒有效且使用CCR5抑制劑前需要進行病毒檢測，患者長期應(yīng)用CCR5抑制劑可導(dǎo)致HIV病毒變異與CXCR4結(jié)合進入靶細(xì)胞等。 本論文在實驗室前期合成的部分3-甲基吡啶芐基多胺類化合物與四氫喹啉-苯并咪唑多胺類化合物的基礎(chǔ)上，再結(jié)合CCR5和CXCR4受體的結(jié)構(gòu)信息及構(gòu)效關(guān)系的分析，運用藥效團拼接，官能團位置轉(zhuǎn)變或變化等經(jīng)典藥物設(shè)計方法，設(shè)計并合成了一系列新的四氫喹啉芐基多胺類抑制劑，并測定了其抗HIV-1CXCR4病毒株的活性。 具體工作主要包括： 1．以AnorMED公司研究的AMD070為模板，設(shè)計并合成了10個四氫喹啉-芐基氨基多胺類化合物。 2．設(shè)計合成了5個四氫喹啉-芐基胍基多胺類化合物。 3．設(shè)計合成了5個四氫喹啉-哌啶甲酰胺類化合物。 4．本論文所合成得3個系列，共20個全新的目標(biāo)化合物，，結(jié)構(gòu)經(jīng)質(zhì)譜（MS）、核磁共振（1H-NMR）確證，SciFinder檢索證實為新化合物。 5．活性測定結(jié)果表明：四氫喹啉-苯并咪唑多胺類化合物具有較好的抗HIV活性（IC50＜1μmol/L），四氫喹啉-芐基多胺類化合物活性較差（IC50＞8μmol/L）。 目前所得構(gòu)效關(guān)系可為新一輪的抗CCR5及CXCR4雙功能抑制劑優(yōu)化提供借鑒。
[Abstract]:AIDS AIDS AIDS AIDSis a disease caused by human immunodeficiency virus (HIV), which is a disease caused by human immunodeficiency virus (HIV). It is a serious threat to human health and social and economic development. HIV invades target cells with the assistance of CCR5 or CXCR4.Inhibiting the binding of HIV virus to CCR5 or CXCR4 can effectively inhibit the infection of HIV virus in target cells.In recent years, the coreceptor inhibitors targeting CCR5 have attracted the attention and research of many multinational pharmaceutical companies and academic institutions, and many small molecular inhibitors of CCR5 have been found.A CCR5 inhibitor has been listed in 2007 (Pfizer's Malawi Northrop.Compared with CCR5 inhibitor CXCR4 small molecular inhibitors have been found to be bicyclic amines tetrahydroquinoline benzimidazole polyamines and guanidine inhibitors have strong anti- activity.However, the use of CCR5 or CXCR4 inhibitors alone has limitations, such as the fact that a single coreceptor inhibitor is only effective against specific viruses and that virus testing is required before the use of CCR5 inhibitors.Long-term use of CCR5 inhibitors can lead to HIV virus mutation and CXCR4 binding into target cells, etc.Based on the partial synthesis of 3-methylpyridine benzyl polyamines and tetrahydroquinoline-benzimidazolium polyamines, the structural information and structure-activity relationship of CCR5 and CXCR4 receptors were analyzed.A series of novel tetrahydroquinoline benzyl polyamines inhibitors were designed and synthesized by classical drug design methods, such as pharmacophore splicing, functional group position transition or change, and their activity against HIV-1CXCR4 virus strain was determined.Specific efforts include, inter alia:1.Ten tetrahydroquinoline-benzyl amino polyamines were designed and synthesized from AMD070 prepared by AnorMED.2.Five tetrahydroquinoline benzyl guanidine polyamines were designed and synthesized.3.Five tetrahydroquinoline-piperidinamide compounds were designed and synthesized.4.Three series of new target compounds were synthesized in this paper. The structures were confirmed to be new compounds by MS MS NMR 1H-NMRs.5.The results showed that tetrahydroquinoline-benzimidazole polyamines had better anti- activity (IC50 < 1 渭 mol / L), and tetrahydroquinoline benzyl polyamines had lower activity than 8 渭 mol 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1) 路L ~ (-1).At present, the structure-activity relationship can be used as a reference for the optimization of anti-CCR5 and CXCR4 bifunctional inhibitors.
【學(xué)位授予單位】：湘潭大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R914;O626

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 王雪雯;蔣就喜;;抗HIV-1治療研究進展[J];熱帶醫(yī)學(xué)雜志;2013年05期

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