非核苷类HIV-1逆转录酶抑制剂研究 Ⅰ：CH_2-DAPY衍生物的结构优化及构效关系研究 Ⅱ：BP类似物的分子设计、合成及构效关系研究
|
摘要
以HIV-1逆转录酶(RT)为靶点设计高活性的逆转录酶抑制剂,是寻找新型高效抗HIV药物的有效手段之一,目前在已上市的34个抗艾滋病药物中,有19个属于HIV逆转录酶抑制剂。
本组前期系统地对具有极强抗耐药性的非核苷类HIV-1逆转录酶抑制剂(NNRTIs)二芳基嘧啶衍生物(DAPYs)进行了广泛的结构优化,结合已有构效关系,借助SurFlex-Dock模拟软件,本文继续在CH2-DAPYs的亚甲基上引入氢键性更强的肼,以期加强与RT的氢键等作用,设计合成了一系列含腙结构的目标物MXDla-1t (Hyd-CH2-DAPYs),活性测试表明：与本组前期所合成的Oxi-CH2-DAPYs活性相比,Hyd-CH2-DAFYs抗野生型HIV-1ⅢB病毒株、RES056变异病毒株和HIV-2 ROD病毒株的活性普遍提高了2-50倍。大部分化合物抗HIV-1ⅢB活性(EC50=1.7-11.2 nM)比地拉韦啶强5-30倍,比奈韦拉平强10-80倍,活性最高的MXD1k(EC50=1.7nM)比依法韦伦强近5倍。值得注意的是,化合物MXDld表现出较为广谱抗HIV活性,抑制HIV-1 IIIB的活性(EC50=2.4nM)与依曲韦林相当,SI高达18461,抑制RES056变异病毒株和HIV-2 ROD病毒株的浓度也分别为5.1μM和5.8μM。化合物MXDld和MXDlk对HIV-1 RT(WT)酶显示出很强的抑制作用(IC50分别为0.761μM和0.585μM),但对CCR5和CXCR4两个靶点无效(IC50>10μM)。这两个化合物具有专一性的靶酶抑制活性。
二苯甲酮类似物(BPs)是一类对野生型和突变型HIV-1病毒株均具有极强抑制作用的NNRTIs。本文以进入临床Ⅱ期的GW678248为先导物,将二苯甲酮的B环以大体积的萘环取代,通过增强与RT的π-π堆积作用,设计合成了1-萘基苯甲酮系列目标物MXD2a-2y,另外从增加分子柔性进而增强与RT的适应性出发,设计合成了N-苯基芳基甲酰胺系列目标物MXD3a-3v和(±)-二芳基甲醇系列目标物MXD4a-4t。活性测试显示：N-苯基苯甲酰胺类目标物普遍具有较强的抗HIV活性,有15个化合物抗野生型HIV-1ⅢB毒株的浓度低于5.10 nM,治疗指数(SI)高于10616,比齐多夫定强5-30倍,有四个化合物MXD3g (EC50=0.30 nM, SI=1845778), MXD3I (EC50=0.37 nM, SI= 212819), MXD3m (EC50=0.32 nM, SI=260617)和MXD3r (EC50=0.27 nM, SI =271000)显示出极强的抑制HIV-1ⅢB活性,与先导物GW678248基本相当。尤以化合物MXD3m表现出更广谱的抗HIV活性,其对双突变株A17和HIV-2 ROD病毒株的抑制浓度分别为0.10μM和4.37μM。1-萘基苯甲酮类目标物中部分显示出较强的抗HIV-1ⅢB活性,以MXD2i的活性最强(EC50=4.8 nM),毒性也最小(SI=10348)。(±)-二芳基甲醇类目标物均在微摩尔浓度抑制HIV-1ⅢB和A17毒株,与先导物相比(纳摩尔级),活性下降较多,充分证明A、B环间羰基结构对维持二苯甲酮类化合物具有较高抗HIV活性的重要作用。此外,抗HIV-RT(WT)酶水平测试还显示：化合物MXD2a, MXD2i, MXD3m和MXD3u的抑制浓度分别为202.3 nM,2.03 nM,1.14 nM和2.05nM,表现出极强的靶酶抑制作用。
本论文建立了具有较高预测能力的3D-QSAR模型(CoMFA和CoMSIA模型),探讨了目标物的构效关系,为进一步合理设计和开发更加高效的HIV-1 RT抑制剂提供了可靠的理论依据。
It is an efficient method to develop highly potent anti-HIV agents by disrupting the function of HIV-1 reverse transcriptase (RT), which plays a unique role in the HIV-1 life cycle. Up to now,18 reverse transcriptase inhibitors have been approved for the clinical treatment of HIV infection among the 34 currently FDA-approved anti-HIV drugs.
Considerable efforts on the structure modifications of diarylpyrimidine analogues (DAPYs) as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been made by us. To explore more active DAPYs, a hydrazine group was designed to introduce to the CH2 linker of CH2-DAPY with the aim to improve the hydrogen-bonding interactions with RT using SurFlex-Dock protocol, and a series of aryl 2-[(4-cyanophenyl)amino]-4-pyrimidinyl ketone hydrazone derivatives MXDla-1t (Hyd-CH2-DAPYs) were synthesized and evaluated the anti-HIV activity. In terms of the biological activity, the newly synthesized Hyd-CH2-DAPYs exhibited 5-30 folder higher activity than the Oxi-CH2-DAPYs against the chosen HIV strains (HIV-1 IIIB, RES056 and HIV-2 ROD). Most of this class of compounds displayed excellent activity against HIV-1ⅢB, with EC50 in the range of 1.7-13.2 nM. Among them, analogue MXD1k was the best congener and displayed the most potent anti-HIV-1 activity (EC50=1.7 nM). Notably, compound MXDld (EC50=2.4 nM, SI =18461) showed the broad-spectrum inhibitory activity, with EC50 values of 2.4 nM against wild-type HIV-1ⅢB,5.3μM against HIV-1 double mutated strains RES056, and 5.5μM against HIV-2 ROD strain. Furthermore, the activity of compound MXDld and MXDlk against HIV-1 RT(WT), CCR5-tropic HIV virus and CXCR4-tropic HIV virus indicated that the target of Hyd-CH2-DAPYs was wild-type reverse transcriptase only
Benzophenone derivatives (BPs), another type of typical NNRTIs, are very effective to inhibit both wild-type and clinically relevant NNRTI-resistant mutant HIV-1 strains. Led by GW678248, which has been progressed to phaseⅡclinical studies, a series of 1-naphthyl-substituted (B-ring) benzophenone derivatives MXD2a-2y were designed and synthesized in a bid to improve theπ-πinteractions with RT, and also, a series of N-phenylarylformamide derivatives MXD3a-3v and (±)-benzhydrol derivatives MXD4a-4t were designed to enhance the adaptation with RT by improving the flexibility of BPs. The anti-HIV activity of these target molecules were evaluated and indicated that most of N-phenylarylformamide derivatives were highly potent against HIV-1ⅢB with EC50 values ranging from 0.3 nM to 5.1 nM and selectivity index values ranging from 10616 to 271000. Nearly as potent as GW678248, compound MXD3g (EC50=0.30 nM, SI=184578), MXD31 (EC50=0.37 nM, SI=212819), MXD3m (EC50=0.32 nM, SI=260617) and MXD3r (EC50=0.27 nM, SI=271000) showed the highest activity against this type virus. Moreover, all of them were also active to inhibit the double mutant strain A17 with EC50 values of 0.29μM,0.14μM,0.10μM and 0.27μM, respectively. In particular, compound MXD3m, which displayed the broad-spectrum anti-HIV activity, was also effective to inhibit the HIV-2 ROD replication within 4.37 micromolar concentration. In the case of 1-naphthalene-substituted (B-ring) benzophenones, several analogues displayed strong capaticy to inhibit HIV-1ⅢB strain, and MXD2i (EC50=4.8 nM) were the highest inhibitor. For the series of (±)-benzhydrol derivatives, most of them demonstrated micromolar activity against both wild-type HIV-1ⅢB and the double mutant HIV-1 strain. Apparently, (±)-benzhydrol derivatives were less potent than lead compound GW678248 (nanomolar level activity), indicating that the keto group between the A and B rings of BPs was essential to maintain their strong capacity to inhibit all types of HIV-1 virus. Moreover, compound MXD2a, MXD2i, MXD3m and MXD3u displayed strong activity against HIV-RT(WT) enzyme with IC50 values of 202.3 nM,2.03 nM, 1.14 nM and 2.05 nM, respectively.
Finally, the 3D-QSAR (CoMFA and CoMSIA) models of newly synthesized DAPYs and BPs were established, respectively. Based on these models, the further SARs of the title molecules were explored and will provide the basic theory for designing more potent NNRTIs.
本组前期系统地对具有极强抗耐药性的非核苷类HIV-1逆转录酶抑制剂(NNRTIs)二芳基嘧啶衍生物(DAPYs)进行了广泛的结构优化,结合已有构效关系,借助SurFlex-Dock模拟软件,本文继续在CH2-DAPYs的亚甲基上引入氢键性更强的肼,以期加强与RT的氢键等作用,设计合成了一系列含腙结构的目标物MXDla-1t (Hyd-CH2-DAPYs),活性测试表明：与本组前期所合成的Oxi-CH2-DAPYs活性相比,Hyd-CH2-DAFYs抗野生型HIV-1ⅢB病毒株、RES056变异病毒株和HIV-2 ROD病毒株的活性普遍提高了2-50倍。大部分化合物抗HIV-1ⅢB活性(EC50=1.7-11.2 nM)比地拉韦啶强5-30倍,比奈韦拉平强10-80倍,活性最高的MXD1k(EC50=1.7nM)比依法韦伦强近5倍。值得注意的是,化合物MXDld表现出较为广谱抗HIV活性,抑制HIV-1 IIIB的活性(EC50=2.4nM)与依曲韦林相当,SI高达18461,抑制RES056变异病毒株和HIV-2 ROD病毒株的浓度也分别为5.1μM和5.8μM。化合物MXDld和MXDlk对HIV-1 RT(WT)酶显示出很强的抑制作用(IC50分别为0.761μM和0.585μM),但对CCR5和CXCR4两个靶点无效(IC50>10μM)。这两个化合物具有专一性的靶酶抑制活性。
二苯甲酮类似物(BPs)是一类对野生型和突变型HIV-1病毒株均具有极强抑制作用的NNRTIs。本文以进入临床Ⅱ期的GW678248为先导物,将二苯甲酮的B环以大体积的萘环取代,通过增强与RT的π-π堆积作用,设计合成了1-萘基苯甲酮系列目标物MXD2a-2y,另外从增加分子柔性进而增强与RT的适应性出发,设计合成了N-苯基芳基甲酰胺系列目标物MXD3a-3v和(±)-二芳基甲醇系列目标物MXD4a-4t。活性测试显示：N-苯基苯甲酰胺类目标物普遍具有较强的抗HIV活性,有15个化合物抗野生型HIV-1ⅢB毒株的浓度低于5.10 nM,治疗指数(SI)高于10616,比齐多夫定强5-30倍,有四个化合物MXD3g (EC50=0.30 nM, SI=1845778), MXD3I (EC50=0.37 nM, SI= 212819), MXD3m (EC50=0.32 nM, SI=260617)和MXD3r (EC50=0.27 nM, SI =271000)显示出极强的抑制HIV-1ⅢB活性,与先导物GW678248基本相当。尤以化合物MXD3m表现出更广谱的抗HIV活性,其对双突变株A17和HIV-2 ROD病毒株的抑制浓度分别为0.10μM和4.37μM。1-萘基苯甲酮类目标物中部分显示出较强的抗HIV-1ⅢB活性,以MXD2i的活性最强(EC50=4.8 nM),毒性也最小(SI=10348)。(±)-二芳基甲醇类目标物均在微摩尔浓度抑制HIV-1ⅢB和A17毒株,与先导物相比(纳摩尔级),活性下降较多,充分证明A、B环间羰基结构对维持二苯甲酮类化合物具有较高抗HIV活性的重要作用。此外,抗HIV-RT(WT)酶水平测试还显示：化合物MXD2a, MXD2i, MXD3m和MXD3u的抑制浓度分别为202.3 nM,2.03 nM,1.14 nM和2.05nM,表现出极强的靶酶抑制作用。
本论文建立了具有较高预测能力的3D-QSAR模型(CoMFA和CoMSIA模型),探讨了目标物的构效关系,为进一步合理设计和开发更加高效的HIV-1 RT抑制剂提供了可靠的理论依据。
It is an efficient method to develop highly potent anti-HIV agents by disrupting the function of HIV-1 reverse transcriptase (RT), which plays a unique role in the HIV-1 life cycle. Up to now,18 reverse transcriptase inhibitors have been approved for the clinical treatment of HIV infection among the 34 currently FDA-approved anti-HIV drugs.
Considerable efforts on the structure modifications of diarylpyrimidine analogues (DAPYs) as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been made by us. To explore more active DAPYs, a hydrazine group was designed to introduce to the CH2 linker of CH2-DAPY with the aim to improve the hydrogen-bonding interactions with RT using SurFlex-Dock protocol, and a series of aryl 2-[(4-cyanophenyl)amino]-4-pyrimidinyl ketone hydrazone derivatives MXDla-1t (Hyd-CH2-DAPYs) were synthesized and evaluated the anti-HIV activity. In terms of the biological activity, the newly synthesized Hyd-CH2-DAPYs exhibited 5-30 folder higher activity than the Oxi-CH2-DAPYs against the chosen HIV strains (HIV-1 IIIB, RES056 and HIV-2 ROD). Most of this class of compounds displayed excellent activity against HIV-1ⅢB, with EC50 in the range of 1.7-13.2 nM. Among them, analogue MXD1k was the best congener and displayed the most potent anti-HIV-1 activity (EC50=1.7 nM). Notably, compound MXDld (EC50=2.4 nM, SI =18461) showed the broad-spectrum inhibitory activity, with EC50 values of 2.4 nM against wild-type HIV-1ⅢB,5.3μM against HIV-1 double mutated strains RES056, and 5.5μM against HIV-2 ROD strain. Furthermore, the activity of compound MXDld and MXDlk against HIV-1 RT(WT), CCR5-tropic HIV virus and CXCR4-tropic HIV virus indicated that the target of Hyd-CH2-DAPYs was wild-type reverse transcriptase only
Benzophenone derivatives (BPs), another type of typical NNRTIs, are very effective to inhibit both wild-type and clinically relevant NNRTI-resistant mutant HIV-1 strains. Led by GW678248, which has been progressed to phaseⅡclinical studies, a series of 1-naphthyl-substituted (B-ring) benzophenone derivatives MXD2a-2y were designed and synthesized in a bid to improve theπ-πinteractions with RT, and also, a series of N-phenylarylformamide derivatives MXD3a-3v and (±)-benzhydrol derivatives MXD4a-4t were designed to enhance the adaptation with RT by improving the flexibility of BPs. The anti-HIV activity of these target molecules were evaluated and indicated that most of N-phenylarylformamide derivatives were highly potent against HIV-1ⅢB with EC50 values ranging from 0.3 nM to 5.1 nM and selectivity index values ranging from 10616 to 271000. Nearly as potent as GW678248, compound MXD3g (EC50=0.30 nM, SI=184578), MXD31 (EC50=0.37 nM, SI=212819), MXD3m (EC50=0.32 nM, SI=260617) and MXD3r (EC50=0.27 nM, SI=271000) showed the highest activity against this type virus. Moreover, all of them were also active to inhibit the double mutant strain A17 with EC50 values of 0.29μM,0.14μM,0.10μM and 0.27μM, respectively. In particular, compound MXD3m, which displayed the broad-spectrum anti-HIV activity, was also effective to inhibit the HIV-2 ROD replication within 4.37 micromolar concentration. In the case of 1-naphthalene-substituted (B-ring) benzophenones, several analogues displayed strong capaticy to inhibit HIV-1ⅢB strain, and MXD2i (EC50=4.8 nM) were the highest inhibitor. For the series of (±)-benzhydrol derivatives, most of them demonstrated micromolar activity against both wild-type HIV-1ⅢB and the double mutant HIV-1 strain. Apparently, (±)-benzhydrol derivatives were less potent than lead compound GW678248 (nanomolar level activity), indicating that the keto group between the A and B rings of BPs was essential to maintain their strong capacity to inhibit all types of HIV-1 virus. Moreover, compound MXD2a, MXD2i, MXD3m and MXD3u displayed strong activity against HIV-RT(WT) enzyme with IC50 values of 202.3 nM,2.03 nM, 1.14 nM and 2.05 nM, respectively.
Finally, the 3D-QSAR (CoMFA and CoMSIA) models of newly synthesized DAPYs and BPs were established, respectively. Based on these models, the further SARs of the title molecules were explored and will provide the basic theory for designing more potent NNRTIs.
引文
[1]Report of the UN Secretary-General (Uniting for universal access:towards zero new HIV infections, zero discrimination and zero AIDS-related deaths), The 56th UN Assembly,2011.
[2]Barre-Sinoussi, F.; Chermann, J. C.;Rey, F.; Nugeyre, M. T.; Chamaret, S.; Gruest, J.; Dauguet, C.; Axler-Blin, C.; Vezinet-Brun, F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Science.1983,220,868.
[3]Clavel, F.; Guetard, D.; Brun-Vezinet, F.; Chamaret, S.; Rey, M.-A.; Santos-Ferreira, M. O.; Laurent, A. G.; Dauguet, C.; Katlama, C.; Rouzioux, C.; Klatzmann, D.; Champalimaud, J. L.; Montagnier, L. Science.1986,233,343.
[4]何严萍.复旦大学博士论文,上海：复旦大学,2004.
[5]刘新泳.抗艾滋病药物研究,北京：人民卫生出版社,2006,24.
[6]Perelson, A. S.; Neumann, A. U.; Markowitz, M.; Leonard, J. M.; Ho, D. D. Science.1996,271,1582.
[7]常俊标.艾滋病的分子生物学及治疗,北京：科学出版社,2001,44.
[8]Root, M. J.; Steger, H. K. Curr. Pharm. Des.2004,10,1805.
[9]Tamamura, H.; Omagari, A.; Oishi, S.; Kanamoto, T.; Yamamoto, N.; Peiper, S. C.; Nakashima, H.; Otaka, A.; Fujii, N. Bioorg. Med. Chem. Lett.2000,10, 2633.
[10]Yang, H.;Lin, X. F.;Padilla, F.; Gabriel, S. D.; Heilek, G.; Ji, C.; Sankuratri, S.; De Rosier, A.; Berry, P.; Rotstein, D. M. Bioorg. Med. Chem. Lett.2009,19, 209.
[11]Parker, C. G.; Domaoal, R. A.; Anderson, K. S.; Spiegel, D. A. J. Am. Chem. Soc.2009,131,16392.
[12]Meanwell, N. A.; Wallace, O. B.; Wang, H.; Deshpande, M.; Pearce, B. C.; Trehan, A.; Yeung, K.-S.; Qiu, Z.; KiM, W. J. J.; Robinson, B. A.; Gong, Y.-F.; Heidi, W. H.-G.; Blair, W. S.; Shi, P.-Y.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009,19,5136.
[13]De Clercq, E. Rev. Med.Virol.2009,19,287.
[14]McColl, D. J; Chen X. Antivir. Res.2010,85,101.
[15]Wensing, A. M.; van Maarseveen, N. M.; Nijhuis, M. Antivir. Res.2010,85, 59.
[16]Steitz, T. A. J. Biol. Chem.1999,274,17395.
[17]Klumpp, K.; Mirzadegan, T. Curr. Pharm. Des.2006,12,1909.
[18]Akira, O.; Eric, O. Proc. Natl. Acad. Sci. USA.2001,98,13925.
[19]D'Aloja, P.; Olivetta, E.; Bona, R.; Nappi, F.; Pedacchia, D.; Pugliese, K.; Ferrari, G.; Verani, P.; Federico, M. J. Virol.1998,72,4308.
[20]Buckman, J. S.; Bosche, W. J.; Gorelick, R. J. J. Virol.2003,77,1469.
[21]Stephenson, J. JAMA.1997,277,614.
[22]Rousseau, M.-N.; Vergne, L.; Montes, B.; Peeters, M.; Reynes, J.; Delaporte, E.; Segondy, M. AIDS.2001,26,36.
[23]Hsiou, Y.; Ding, J.; Das, K.; Jr Clark, A. D.; Hughes, S. H.; Arnod, E. Structure. 1996,4,853.
[24]Jacobo-Molina, A.; Ding, J.; Nanni, R. G.; Clark, A. D.; Jr Lu, X.; Tantillo, C.; Williams, R. L.; Kamer, G.; Ferris, A. L.; Clark, P. Proc. Natl. Acad. Sci. USA.1993,90,6320.
[25]Rodgers, D. W.; Gamblin, S. J.; Harris, B. A.; Ray, S.; Culp, J. S.; Hellmig, D. J. W.; Debouck, C.; Harrison, S. C. Proc. Natl. Acad. Sci. USA.1995,92,1222.
[26]Http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVand AIDSActivities/ucml 18915.htm
[27]Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; Broder, S. Proc. Natl. Acad. Sci. USA.1985,82,7096.
[28]Ren, J. S.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; Stammers, D. Nat. Struct. Biol.1995,2,293.
[29]De Clercq, E. Ⅱ Farmaco.2001,56,3.
[30]Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M. J.; Breslin, H. J.; Raeymaeckers, A.; Van Gelder, J.; Woestenborghs, R.; Heykants, J.; Schellekens, K.; Janssen, M. A. C.; De Clercq, E.; Janssen, P. A. J. Nature. 1990,343,470.
[31]De Clercq, E. Chem. Biodivers.2004,1,44.
[32]朱骏杰,曹江营,展鹏,赵翠荣,刘新泳.中国新药杂志,2009,18,206.
[33]孟歌.中国医药导报,2010,7,9.
[34]Zhan, P.; Liu, X. Y. Expert Opin. Ther. Patents.2011,21,717.
[35]Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H.; McMahon, J. B.; Currens, M. J.; Buckheit, R. W.; Hughes, S. H.; Cragg, G. M.; Boyd, M. R. J. Med.Chem.1992,35,2735.
[36]Richman, D. D.; Dousson, C. B.; Storer, R.; Moussa, A.; Randall, J.; Bridges, E.; Liuzzi, M.; Jakubik, J.; Seifer, M.; Standring, D. Presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, 2007; Abstract 489.
[37]Zhang, H.; Oberg, B.; Bottiger, D.; Phillips, D.; Romeo, J. F.; Thom, M.; Vrang, L. Presented at the XV International AIDS Conference, Bangkok, Thailand, July 12-16,2004, Abstract TuPeB4667.
[38]Girardet, J.-L.; Koh, Y.-H. De La Rosa, M.; Gunic, E.; Zhang, Z.; Hamatake, R.; Yeh, L. Presented at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 17-20,2007, Abstract 3285.
[39]Bonneau, P.; Robinson, P.; Duan, J.; Doyon, L.; Simoneau, B.; Yoakim, C.; Garneau, M.; Bos, M.; Cordingley, M.; Brenner, B.; Spira, B.; Wainberg, M.; Huang, F., Drda, K.; Ballow, C.; Mayers, D. Presented at the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 22-25, 2005, Abstract 558.
[40]Van Roey, J.; Von Schoen-Angerer, T.; Ford, N.; Calmy, A. Drug Discov. Today. 2008,13,601.
[41]Ding, J.; Das, K.; Tantillo, C.; Zhang, W.; Jr Clark, A. D.; Jessen, S.; Lu, X.; Hsiou, Y.; Jacobo-Molina, A.; Andries, K.; Pauwels, R.; Moereels, H.; Koymans, L.; Janssen, P. A. J.; Jr Smith, R. H.; Kroeger Koepke, M.; Michejda, C. J.; Hughes, S. H.; Arnold, E. Structure.1995,3,365.
[42]Ren, J.; Esnouf, R.; Hopkins, A.; Ross, C.; Jones, Y.; Stammers, D. Nat. Struct. Biol.1995,2,915.
[43]De Clercq, E. Med. Res. Rev.1996,16,125.
[44]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull.2006,54,1248.
[45]Meng, G; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull.2003,51,779.
[46]He, Y. P.; Kuang, Y. P.; Chen, F. E.; Wang, S. X.; Ji, L.; De Clercq, E.; Panecouque, C. Monatshefte for Chemie.2005,136,1233.
[47]Sun, G. F.; Chen X. X.; Chen, F. E.; Wang, Y. P.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull.2005,53,886.
[48]Sun, G. F.; Kuang, Y. Y.; Wang, S. X.; Chen, F. E. Synth. Commun.2004,34, 2229.
[49]Meng, G.; Kuang, Y. Y.; Ji, L.; Chen, F. E. Synth. Commun.2005,35,1095.
[50]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,50,1778.
[51]Ji, L.; Chen, F. E.; Xie, B.; De Clercq, E.;Balzarini, J.; Pannecouque, C. Eur. J. Med. Chem.2007,42,198.
[52]Wang, Y P.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem.2008,16,3887.
[53]He, Y P.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem. Lett.2004,14,3173.
[54]He, Y P.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Chem.2004,32,536.
[55]Sun, G. F.; Kuang, Y Y.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Arch. Pharm.2005,338,457.
[56]Liang, Y. H.; Zeng, Z. S.; Liu, Z. Q.; Feng, X. Q.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2010,18,2370.
[57]Zeng, Z. S.; Liang Y H.; Feng, X. Q.; Chen, F. E.; Pannecouque, C.; Balzarini, J.; De Clercq, E. ChemMedChem 2010,5,837.
[58]Feng, X. Q.; Zeng, Z. S.; Liang, Y H.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2010,18,2370.
[59]Liang, Y H.; Zeng, Z. S.; Liu, Z. Q.; Feng, X. Q.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2010,18,4601.
[60]Zeng, Z. S.; He, Q. Q.; Liang, Y H.; Feng, X. Q.; Chen, F. E., De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem.2010,18,5039.
[61]Feng, X. Q.; Liang, Y. H.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,219.
[62]Liang,Y H.;Feng,X.Q.;Zeng,Z.S.;Chen,F.E.Balzarini,J.；Pannecouque,C. De Clercq,E.ChemMedChem.2009,4,1537.
[63]Xiong,Y Z.;Chen,F.E.;De Clercq,E.；Balzarini,J.；Pannecouque,C.Eur.J. Med.Chem.2008,43,1230.
[64]Xiong,Y Z.;Chen,F.E.;De Clercq,E.;Balzarini,J.;Pannecouque,C.Chem. Biodiver.2009,6,561.
[65]Xiong,Y Z.;Chen,F.E.;De Clercq,E.;Balzarini,J.;Pannecouque,C.Acta Chimica Sinica.,2006,64,1627.
[66]Hazen,R.J.;Harvey,R.J.;St Clair,M.H.；Ferris,R.G.；Freeman,G.A.； TidWell,J.H.；Schaller,L.T.;Cowan,J.R.;Short,S.A.;Romines,K.R. Antimicrob. Agents Chemother.2005,49,4465.
[67]Chan,J.H.;Freeman,G.A.;Tidwell,J.H.;Romines,K.R.；Schaller,L.T. Cowan,J.R.;Gonzales,S.S.;Lowell,G.S.;Andrews Ⅲ,C.;Reynolds,D.J., Med.Chem.2004,47,1175.
[68]Ferris,R.G.;Hazen,R.J.;Roberts,G.B.;St Clair,M.H.;Chan,J.H.; Romines,K.R.;Freeman,G.A.;Tidwell,J.H.;Schaller,L.T.;Cowan,J.R. Antimicrob. Agents Chemother.2005,49,4046.
[69]Romines,K.R.;Freeman,G.A.;Schaller,L.T.;Cowan,J.R.;Gonzales,S.S.; Tidwell,J.H.;Andrews Ⅲ,C.W.;Stammers,D.K.;Hazen,R.J.;Ferris,R.G. J.Med Chem.2006,49,727.
[70]Ren,J.;Chamberlain,P.P.;Stamp,A.;Short,S.A.;Weaver,K.L.;Romines, K.R.;Hazen,R.;Freeman,A.;Ferris,R.G.;Andrews,C.W.,Med.Chem. 2008,51,5000.
[71]Tucker,T.J.;Saggar,S.;Sisko,J.T.;Tynebor,R.M.;Williams,T.M.;Felock, P.J.;Flynn,J.A.;Lai,M.T.;Liang,Y.;McGaughey,G.Bioorg.Med.Chem. Lett.2008,18,2959.
[72]San Juan,A.A.Bioorg.Med.Chem.Lett.2008,18,1181.
[73]Pauwels,R.;Andries,K.;Debyset,Z.;Van Daele,P.;Schols,D.;Stoffels,P.; De Vreese,K.;Woestenborghs,R.;Vandamine,A.M.;Janssen,C.G.M.; Anne,J.;Cauwenbergh,G.;Desmyter,J.;Heykants,J.;Janssen,M.A.C.;De Clercq,E.;Janssen,P.A.J.Proc.Natl.Acad.Sci.U.S.A.1993,90,1711.
[74]Romero,D.L.;Morge,R.A.;Genin,M.J.;Biles,C.;Busso,M.;Resnick,L. Althaus,I.W.;Reusser,F.;Thomas,R.C.;Tarpley,W.G.J.Med Chem.1993, 36,1505.
[75]Nottet,H.S.；Oteman,M.H.；Visser,M.R.；Verhoef,J.J.Antimicrob. Chemother.1994,33,366.
[76]Ludovici,D.W.；Kukla,M.J.；Grous,P.G.；Krishnan,S.；Andries,K.；De Bethune,M.-P.；Azijn,H.；Pauwels,R.；De Clercq,E.；Arnold,E.；Janssen,P. A.J.Biorg.Med.Chem.Lett.2001.11,2225.
[77]Ludovici,D.W.；Kavash,R.W.；Kukla,M.J.；Ho,C.Y.；YP,H.；De Corte,B. L.；Andries,K.；De Bethune,M.-P.；Azijn,H.；Pauwels,R.；Moereels,H.E.L.； Heeres,J.；Koymans,L.M.H.；De Jonge,M.R.；Van Aken,K.J.A.；Daeyaert, F.F.D.；Lewi,P.J.；Das,K.；Arnold,E.；Janssen,P.A.J.Bioorg.Med.Chem. Lett.2001,2229.
[78]Ludovici,D.W.；De Corte,B.L.；Kukla,M.J.；Ye,H.；Ho,C.Y.；Lichtenstein, M.A.；Kavash,R.W.；Andries,K.；De Bethune,M.-P.；Azijn,H.；Pauwels,R.； Lewi,P.J.；Heeres,J.；Koymans,L.M.；De Jonge,M.R.；Van Aken,K.J.； Daeyaert,F.F.；Das,K.；Arnold E.；Janssen P.A.J.Bioorg.Med.Chem.Lett. 2001,11,2235.
[79]Das,K.；Jr Clark,A.D.；Lewi,P.J.；Heeres,J.；De Jonge,M.R.；Koymans,L. M.H.；Vinkers,H.M.；Daeyaert,F.；Ludovici,D.W.；Kukla,M.J.；De Corte, B.；Kavash,R.W.；Ho,C.Y.；Ye,H.；Lichtenstein,M.A.；Andries,K.； Pauwels,R.；De Bethune,M.-P.；Boyer,P.L.；Clark,P.；Hughes,S.H.；Janssen, P.A.J.；Arnold,E.,Med.Chem.2004,47,2550.
[80]Guillemont,J.；Pasquier,E.；Palandjian,P.；Vernier,D.；Gaurrand,S.；Lewi,P. J.；Heeres,J.；De Jonge,M.R.；Koymans,L.M.H.；Daeyaert,F.F.D.；Vinkers, M.H.；Arnold,E.；Das,K.；Pauwels,R.；Andries,K.；De Bethune,M.-P.； Bettens,E.；Hertogs,K.；Wigerinck,P.；Timmerman,P.；Janssen,P.A.J., Med.Chem.2005,48,2072.
[81]Tian,X.；Qin,B.；Lu,H.；Lai,W.；Jiang,S.；Lee,K.一H.；Chen,C.H.；Xie,L. Bioorg.Med.Chem.Lett.2009,19,5482.
[82]Heeres,J.；De Jonge,M.R.；Koymans,L.M.H.；Daeyaert,F.F.D.；Vinkers, M.；Van Aken,K.J.A.；Arnold,E.；Das,K.；Kilonda,A.；Hoornaert,G.J.； Compernolle,F.；Cegla,M.；Azzam,R.A.；Andries,K.；De Bethune,M.-P.； Azijn,H.；Pauwels,R.；Lewi,P.J.；Janssen,P.A.J.,Med.Chem.2005,48, 1910.
[83]Zeevaart,J.G.；Wang,L.；Thakur,V.V.；Leung,C.S.；Tirado-Rives,J.；Bailey, C.M.；Domaoal,R.A.；Anderson,K.S.；Jorgensen,W.L.J.Am.Chem.Soc. 2008,130,9492.
[84]Sweeney,Z.K.;Acharya,S.;Briggs,A.;Dunn,J.P.；Elworthy,T.R.;Fretland, J.；Giannetti,A.M.;Heilek,G.;Li,Y.;Kaiser,A.C.;Martin,M.；Saito,Y.D.； Smith,M.；Suh,J.M.；Swallow,S.；Wu,J.；Hang,J.Q.；Zhou,A.S.；Klumpp, K.Bioorg.Med.Chem.Lett.2008,18,4348.
[85]Mordant,C.;Schmitt,B.;Pasquier,E.;Demestre,C.;Queguiner,L.;Masungi C.；Peeters,A.;Smeulders,L.;Bettens,E.；Hertogs,K.；Heeres,J.；Lewi,P.； Guillemont,J.S.Eur.,Med.Chem.2007,42,567.
[86]曾兆森.复旦大学博士论文,上海：复旦大学,2010.
[87]Chen,F.E.；Zeng,Z.S.；Liang,Y.H.;Feng,X.Q.CN101723903A,2010.
[88]冯筱晴.复旦大学博士论文,上海：复旦大学,2010.
[89]Jacques,P.S.;Wohrl,B.M.;Ottmann,M.；Darlix,J.L.；Le Grice,S.;J.Biol. Chem.1994,269,26472.
[90]Le Grice,S.F.；Cameron,C.E.;Benkovic,S.J.Methods Enzymol.1995,262, 130.
[91]Powell,M.D.;Ghosh,M.；Jacques,P.S.;Howard,K.J.S.;Le Grice,P.;Fay, J.；Bambara,R.A.J.Biol.Chem.1997,272,11157.
[92]Das,K.；Bauman,J.D.；Jr Clark,A.D.；Frenkcl,Y.V.；Lewi,P.J.A.J.； Shatkin,S.H.；Hughes,Arnold,E.Proc.Natl.Acad.Sci.USA.2008,105, 1472.
[93]Orr,D.C.;Figueiredo,H.T.;Mo,C.;Penn,C.R.;Cameron,J.M.J.Biol. Chem.1992,267,4177.
[94]Wyatt,P.G；Bethell,R.C.；Cammack,N.；Charon,D.；Dodic,N.；Dumaitre,B.； Evans,D.N.;Green,D.V.S.;Hopewell,P.L.,Med.Chem.1995,38,1657.
[1]Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E. Prog. Biophys. Mol. Biol.2005, 88,209.
[2]De Clercq, E. Nat. Rev. Drug Discovery 2007,6,1001.
[3]De Corte,B.L.J.Med.Chem.2005,48,1689.
[4]Heeres,J.;Lewi,P.J.;Adv.Antiviral Drug Des.2007,5,213.
[5]a)Ludovici,D.W.;De Corte,B.L.;Kukla,M.J.;Ye,H.;Ho,C.Y.； Lichtenstein,M.A.;Kavash,R.W.;Andries,K.;De Bethune,M.-P.;Azijn,H. Bioorg.Med.Chem.Lett.2001,11,2235.;b)Ludovici,D.W.;Kavash,R.W.; Kukla,M.J.；Ho,C.Y.；Ye,H.；De Corte,B.；Andries,K；De Bethune,M.-P.; Azijn,H.;Pauwels,R.；Bioorg.Med.Chem.Lett.2001,11,2229.
[6]Sarafianos,S.G.；Das,K.;Hughes,S.H.；Arnold,E.Curr.Opin.Struct.Biol. 2004,14,716.
[7]a)Guillemont,J.；Pasquier,E.;Palandjian,P.;Vernier,D.;Gaurrand,S.；Lewi, P.J.；Heeres,J.；De Jonge,M.R.；Koymans,L.M.H.;Daeyaert,F.F.D.J. Med.Chem.2005,48,2072.;b)Heeres,J.;De Jonge,M.R.;Koymans,L.M.H.; Daeyaert,F.F.D.；Vinkers,M.；Van Aken,K.J.A.；Arnold,E.；Das,K.； Kilonda,A.;Hoornaert,G.J.,Med.Chem.2005,48,1910.;c)Janssen,P.A.J.； Lewi,P.J.；Arnold,E.；Daeyaert,F.；De Jonge,M.;Heeres,J.;Koymans,L.； Vinkers,M.;Guillemont,J.;Pasquier,E.J.Med.Chem.2005,48,1901.;d)Tian, X.T.；Qin,B.J.；Wu,Z.Y.;Wang,X.F.;Lu,H.；Morris-Natschke,S.L.;Chen, C.Ho.;Jiang,S.B.;Lee,K.-H.；Xie,L.J.Med.Chem.2010,8287.
[8]Mordant,C.;Schrnitt,B.；Pasquier,E.;Demestre,C.;Queguiner,L.;Masungi, C.;Peeters,A.;Smeulders,L.;Bettens,E.;Hertogs,K.Eur.,Med.Chem. 2007,42,567.
[9]曾兆森.复旦大学博士论文,上海：复旦大学,2010.
[10]Zeng,Z.S.;Liang,Y.H.;Feng,X.Q.;Chen,F.E.;Pannecouque,C.;Balzarini, J.;De Clercq,E.ChemMedChem 2010,5,837.
[11]Chen,F.E.;Zeng,Z.S.；Liang,Y.H.;Feng,X.Q.CN101723903A,2010.
[12]冯筱晴.复旦大学博士论文,上海：复旦大学,2010.
[13]Feng,X.Q.；Zeng,Z.S.;Liang,Y.H.;Chen,F.E.;Pannecouque,C.；Balzarini, J.；De Clercq,E.Bioorg.Med.Chem.2010,,8,2370.
[14]Das,K.；Jr Clark,A.D.；Lewi,P.J.；Heeres,J.；De Jonge,M.R.;Koymans,L. M.H.；Vinkers,H.M.；Daeyaert,F.F.D.；Ludovici,D.W.；Kukla,M.J.；De Corte,B.L.；Kavash,R.W.；Ho,C.Y.；Ye,H.；Lichtenstein,M.A.；Andries, K.;Pauwels,R.；De Bethune,M.-P.;Boyer,P.L.;Clark,P.；Hughes,S.H.; Janssen,P.A.J.;Arnold,E.J.Med.Chem.2004,47,2550
[15]Jain,A.N.J.Comput-Aided.Mol.Des.1996,10,427.
[16]Ruppert, J.; Welch, W.; Jain, A. N. Protein Sci.1997,6,524.
[17]Welch, W.; Ruppert, J.; Jain, A. N. Chem. Biol.1996,3,449.
[18]Jain, A. N. J. Med. Chem.2003,46,499.
[19]Ludovici, D. W.; De Corte, B. L.; Kukla, M. J.; Ye, H.; Ho, C. Y.; Lichtenstein, M. A.; Kavash, R. W.; Andries, K.; De Bethune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.; Heeres, J.; Koymans, L. M.; De Jonge, M. R.; Van Aken, K. J.; Daeyaert, F. F.; Das, K.; Arnold E.; Janssen P. A. J. Bioorg. Med. Chem. Lett. 2001,11,2235.
[20]Feng, X. Q.; Liang, Y. H.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,219.
[21]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,50,1778.
[22]Sieger, G. M.; Klein, D. X. J. Org. Chem.1957,22,951.
[23]Songbai, L.; Ying, Y; Lanny S. L. Org. Lett.2007,9,1947.
[24]Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. J. Virol. Methods.1988,20,309.
[25]杨汉民.细胞生物学实验.北京：高等教育出版社,1997,164.
[26]张鸿卿,连慕兰.细胞生物学实验方法与技术.北京：北京师范大学出版社,1990,55.
[27]Pannecouque, C.; Daelemans, D.; De Clercq, E. Nat. Protoc.2008,3, 427.
[28]Rey, F.; Barre-Sinoussi, F.; Schmidtmayerova, H.; Chermann, J. C. J. Virol. Methods.1987,16,239.
[29]Baba, M.; De Clercq, E.; Iida, S.; Tanaka, H.; Nitta, I.; Ubasawa, M.; Takashima, H.; Sekiya, K.; Umezu, K.; Nakashima, H. Antimicrob. Agents. Chemother.1990,34,2358.
[30]Rey F.; Donker G.; Hirsch I.; Chermann J. C. J. Virol.1991,181,165.
[31]Seki J.; Ikeda R.; Hoshino H. Biochem. Biophys. Res. Commun.1996,227,724.
[32]Xie, X.; He, X.; Zhu, T.; Xu, Y. Z.; Zhou, E. K. CN101531997A,2008.
[33]Liu, A. M. F.; Ho, M. K. C.; Wong, C. S. S.; Chan, J. H. P.; Pau, A. H. M.; Wong, Y. H. J. Biomol. Screen.2003,8,39.
[34]周恩昆.西南大学硕士论文,重庆：西南大学,2009.
[35]Wang, Q.; Ding, Z. H; Liu, J. K.; Zheng, Y. T. Antivir. Res.2004,64,189.
[36]Yu, M. Y.; Li, Z. Y.; Liu, S.; Fan, E. K.; Pannecouque, C.; De Clercq, E.; Liu, X. Y. ChemMedChem 2011,6,826.
[37]Kazmierski, W. M.; Boone, L.; Lawrence, W.; Watson, C.; Kenakin, T. Curr. Drug Targets Infect Disord.2002,2,265.
[38]Wang, S.; He, C. G.; Maguire, M. T.; Clemmons, A. L.; Burrier, R. E.; Guzzi, M. F.; Strader, C. D.; Parker, E. M.; Bayne, M. L. J. Biol. Chem.1998,273, 4754.
[39]陈凯先,蒋华良,嵇汝运.计算机辅助药物设计：原理、方法及应用,上海：上海科学技术出版社,2000,141.
[40]李仁利.药物构效关系.北京：中国医药科技出版社,2004,491.
[41]Cramer Ⅲ, R. D.; Patterson, D. E.; Bunce, J. D. J. Am. Chem. Soc.1988,110, 5959.
[42]Klebe, G.; Abraham, U.; Mietzner, T. J. Med. Chem.1994,37,4130.
[43]Hopfinger, A.3.J. Am. Chem. Soc.1980,102.325.
[44]Crippen, G. M. J. Med. Chem.1979,22,988.
[45]Wold, S.; Ruhe, A.; Wold, H.; Dunn Ⅲ, W. J. J. Sci. Stat. Comput.1984,5,735.
[46]Clark, M; Cramer Ⅲ, R. D. Quant. Struct-Act. Relat.1993,12,137.
[47]a)Kim, K. H.; Martin, Y. C. J. Org. Chem.1991,56,2723.; b)Kim, K. H. Quant. Struct-Act. Relat.1992,11,453.; c)Kim, K. H. Quant. Struct-Act. Relat.1992, 11,309.
[48]a)熊远珍,陈芬儿,冯筱晴.化学学报,2006,64,1627.；b)孟歌,何严萍,陈芬儿.高等学校化学学报,2002,23,1304.；c)何严萍,胡海龙,许辽萨,孟歌,陈芬儿.高等学校化学学报,2005,26,2544.
[49]Folkers, G.; Merz, A.; Rognan, D.3D-QSAR in Drug Design.1993,583.
[1]Zhan,P.；Liu,X.Y.Expert Opin.Ther.Patents.2011,21,717.
[2]朱骏杰,曹江营,展鹏,赵翠荣,刘新泳.中国新药杂志,2009,18,206.
[3]Hazen,R.J.；Harvey,R.J.；St Clair,M.H.；Ferris,R.G.；Freeman,G.A.； Tidwell,J.H.；Schaller,L.T.；Cowan,J.R.；Short,S.A.；Romines,K.R. Antimicrob.Agents Chemother.2005,49,4465.
[4]Chan,J.H.;Freeman,G.A.;Tidwell,J.H.；Romines,K.R.；Schaller,L.T. Cowan,J.R.；Gonzales,S.S.;Lowell,G.S.；Andrews Ⅲ,C.；Reynolds,D.J. Med.Chem.2004,47,1175.
[5]Ferris,R.G.;Hazen,R.J.;Roberts,G.B.;St Clair,M.H.;Chan,J.H.;Romines, K.R.；Freeman,G.A.；Tidwell,J.H.；Schaller,L.T.；Cowan,J.R.Antimfcrob. Agents Chemother.2005,49,4046.
[6]Romines,K.R.;Freeman,G.A.；Schaller,L.T.;Cowan,J.R.；Gonzales,S.S.； Tidwell,J.H.；Andrews Ⅲ,C.W.；Stammers,D.K.；Hazen,R.J.；Ferris,R.G.J. Med.Chem.2006,49,727.
[7]Ren,J.；Chamberlain,P.P.;Stamp,A.;Short,S.A.;Weaver,K.L.；Romines,K. R.；Hazen,R.；Freeman,A.；Ferris,R.G.；Andrews,C.W.J.Med.Chem.2008, 51,5000.
[8]Tucker,T.J.;Saggar,S.;Sisko,J.T.;Tynebor,R.M.;Williams,T.M.;Felock,P. J.；Flynn,J.A.;Lai,M.T.；Liang,Y.；McGaughey,G.Bioorg.Med.Chem.Lett. 2008,18,2959.
[9]San Juan, A. A. Bioorg. Med. Chem. Lett.2008,18,1181.
[10]Sluis-Cremer, N.; Temiz, N. A.; Bahar, I. Curr. HIV. Res.2004,2,323.
[11]Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E., Prog. Biophys. Mol. Biol.2005, 88,209.
[12]陈先红,谢蓝.中国新药杂志,2006,16,182.
[13]a)Feng, X. Q.; Liang, Y. H.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,219.; b)Liang, Y. H.; Feng, X. Q.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,1537.
[14]a)Wang, Y. P.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2008,16,3887.; b)He, Y. P.; Chen, F. E.; Sun, G. F.; Wang, Y. P.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem. Lett.2004,14, 3173.
[15]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,50,1778.
[16]Jain, A. N. J. Comput-Aided. Mol. Des.1996,10,427.
[17]Ruppert, J.; Welch, W.; Jain, A. N. Protein Sci.1997,6,524.
[18]Welch, W.; Ruppert, J.; Jain, A. N. Chem. Biol.1996,3,449.
[19]Jain, A. N. J. Med. Chem.2003,46,499.
[20]Park, K. K.; Jeong, J. Tetrahedron.2005,61,545.
[21]Li, W.; Lai, H.; Ge, Z.; Ding, C.; Zhou, Y. Synthetic commun.2007,37,1595.
[22]Zheng, Y. T.; Ben, K. L.; Jin, S.W. Acta Pharmacol. Sin.2000,21,179.
[23]Wang, R. R.; Yang, L. M.; Wang, Y. H.; Pang, W.; Tam, S. C.; Tien, P.; Zheng, Y. T. Biochem. Biophys. Res. Commun.2009,382,540.
[24]Macias, F. A.; De Siqueira, J.; Chinchilla, M. N.; Marin, D.; Varela, R. M.; Molinillo, J. M. G. J. Agric. Food Chem.2006,54,9843.
[25]苏砚溪.河南化工,2002,4,20。
[26]Pushkareva, Z. V.; Kokoshko, Z. Yu. Zh. Obshch. Khim.1954,24,870.
[27]Brown, J. P.; McCall, E. B. J. Chem. Soci.1955,3681.
[28]a)Andrews, C. W.; Chan, J. H.; Freeman, G. A.; Romines, K. R.; Tidwell, J. H. WO 01/17982,2001.; b)Chan, J. H. WO 02/070470,2002.; c)Chan, J. H. US 2004/0122064,2004.; d)Chan, J. H. US 2006/0009651,2006.
[29]Wyatt, P. G.; Bethell, R. C.; Cammack, N.; Charon, D.; Dodic, N.; Dumaitre, B.; Evans, D. N.; Green, D. V. S.; Hopewell, P. L. J. Med. Chem.1995,38,1657.
[1]陈凯先,蒋华良等,计算机辅助药物设计:原理、方法及应用,上海:上海科学技术出版社,2000,1引.
[2]李仁利.药物构效关系.北京:中国医药科技出版社,2004,419.
[3]Cramer III,R.D.:Patterson,D.E.:Bunee,J.D.J.Am.hCem.OSc.1988,110,5959.
[4] Klebe, G; Abraham, U.; Mietzner, T. J. Med. Chem. 1994, 37, 4130.
[5] Ren, J.; Chamberlain, P. P.; Stamp, A.; Short, S. A.; Weaver, K. L.; Romines,K. R.; Hazen, R.; Freeman, A.; Ferris, R. G.; Andrews, C. W. J. Med. Chem.2008, 51, 5000.
[6] Folkers, G.; Merz, A.; Rognan, D. 3D-QSAR in Drug Design. 1993, 583.
[7] Sun Juan, A. A. Bioorg. Med. Chem. Lett. 2008, 18, 1181.
[2]Barre-Sinoussi, F.; Chermann, J. C.;Rey, F.; Nugeyre, M. T.; Chamaret, S.; Gruest, J.; Dauguet, C.; Axler-Blin, C.; Vezinet-Brun, F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Science.1983,220,868.
[3]Clavel, F.; Guetard, D.; Brun-Vezinet, F.; Chamaret, S.; Rey, M.-A.; Santos-Ferreira, M. O.; Laurent, A. G.; Dauguet, C.; Katlama, C.; Rouzioux, C.; Klatzmann, D.; Champalimaud, J. L.; Montagnier, L. Science.1986,233,343.
[4]何严萍.复旦大学博士论文,上海：复旦大学,2004.
[5]刘新泳.抗艾滋病药物研究,北京：人民卫生出版社,2006,24.
[6]Perelson, A. S.; Neumann, A. U.; Markowitz, M.; Leonard, J. M.; Ho, D. D. Science.1996,271,1582.
[7]常俊标.艾滋病的分子生物学及治疗,北京：科学出版社,2001,44.
[8]Root, M. J.; Steger, H. K. Curr. Pharm. Des.2004,10,1805.
[9]Tamamura, H.; Omagari, A.; Oishi, S.; Kanamoto, T.; Yamamoto, N.; Peiper, S. C.; Nakashima, H.; Otaka, A.; Fujii, N. Bioorg. Med. Chem. Lett.2000,10, 2633.
[10]Yang, H.;Lin, X. F.;Padilla, F.; Gabriel, S. D.; Heilek, G.; Ji, C.; Sankuratri, S.; De Rosier, A.; Berry, P.; Rotstein, D. M. Bioorg. Med. Chem. Lett.2009,19, 209.
[11]Parker, C. G.; Domaoal, R. A.; Anderson, K. S.; Spiegel, D. A. J. Am. Chem. Soc.2009,131,16392.
[12]Meanwell, N. A.; Wallace, O. B.; Wang, H.; Deshpande, M.; Pearce, B. C.; Trehan, A.; Yeung, K.-S.; Qiu, Z.; KiM, W. J. J.; Robinson, B. A.; Gong, Y.-F.; Heidi, W. H.-G.; Blair, W. S.; Shi, P.-Y.; Lin, P.-F. Bioorg. Med. Chem. Lett. 2009,19,5136.
[13]De Clercq, E. Rev. Med.Virol.2009,19,287.
[14]McColl, D. J; Chen X. Antivir. Res.2010,85,101.
[15]Wensing, A. M.; van Maarseveen, N. M.; Nijhuis, M. Antivir. Res.2010,85, 59.
[16]Steitz, T. A. J. Biol. Chem.1999,274,17395.
[17]Klumpp, K.; Mirzadegan, T. Curr. Pharm. Des.2006,12,1909.
[18]Akira, O.; Eric, O. Proc. Natl. Acad. Sci. USA.2001,98,13925.
[19]D'Aloja, P.; Olivetta, E.; Bona, R.; Nappi, F.; Pedacchia, D.; Pugliese, K.; Ferrari, G.; Verani, P.; Federico, M. J. Virol.1998,72,4308.
[20]Buckman, J. S.; Bosche, W. J.; Gorelick, R. J. J. Virol.2003,77,1469.
[21]Stephenson, J. JAMA.1997,277,614.
[22]Rousseau, M.-N.; Vergne, L.; Montes, B.; Peeters, M.; Reynes, J.; Delaporte, E.; Segondy, M. AIDS.2001,26,36.
[23]Hsiou, Y.; Ding, J.; Das, K.; Jr Clark, A. D.; Hughes, S. H.; Arnod, E. Structure. 1996,4,853.
[24]Jacobo-Molina, A.; Ding, J.; Nanni, R. G.; Clark, A. D.; Jr Lu, X.; Tantillo, C.; Williams, R. L.; Kamer, G.; Ferris, A. L.; Clark, P. Proc. Natl. Acad. Sci. USA.1993,90,6320.
[25]Rodgers, D. W.; Gamblin, S. J.; Harris, B. A.; Ray, S.; Culp, J. S.; Hellmig, D. J. W.; Debouck, C.; Harrison, S. C. Proc. Natl. Acad. Sci. USA.1995,92,1222.
[26]Http://www.fda.gov/ForConsumers/byAudience/ForPatientAdvocates/HIVand AIDSActivities/ucml 18915.htm
[27]Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; Broder, S. Proc. Natl. Acad. Sci. USA.1985,82,7096.
[28]Ren, J. S.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; Stammers, D. Nat. Struct. Biol.1995,2,293.
[29]De Clercq, E. Ⅱ Farmaco.2001,56,3.
[30]Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M. J.; Breslin, H. J.; Raeymaeckers, A.; Van Gelder, J.; Woestenborghs, R.; Heykants, J.; Schellekens, K.; Janssen, M. A. C.; De Clercq, E.; Janssen, P. A. J. Nature. 1990,343,470.
[31]De Clercq, E. Chem. Biodivers.2004,1,44.
[32]朱骏杰,曹江营,展鹏,赵翠荣,刘新泳.中国新药杂志,2009,18,206.
[33]孟歌.中国医药导报,2010,7,9.
[34]Zhan, P.; Liu, X. Y. Expert Opin. Ther. Patents.2011,21,717.
[35]Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H.; McMahon, J. B.; Currens, M. J.; Buckheit, R. W.; Hughes, S. H.; Cragg, G. M.; Boyd, M. R. J. Med.Chem.1992,35,2735.
[36]Richman, D. D.; Dousson, C. B.; Storer, R.; Moussa, A.; Randall, J.; Bridges, E.; Liuzzi, M.; Jakubik, J.; Seifer, M.; Standring, D. Presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, 2007; Abstract 489.
[37]Zhang, H.; Oberg, B.; Bottiger, D.; Phillips, D.; Romeo, J. F.; Thom, M.; Vrang, L. Presented at the XV International AIDS Conference, Bangkok, Thailand, July 12-16,2004, Abstract TuPeB4667.
[38]Girardet, J.-L.; Koh, Y.-H. De La Rosa, M.; Gunic, E.; Zhang, Z.; Hamatake, R.; Yeh, L. Presented at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 17-20,2007, Abstract 3285.
[39]Bonneau, P.; Robinson, P.; Duan, J.; Doyon, L.; Simoneau, B.; Yoakim, C.; Garneau, M.; Bos, M.; Cordingley, M.; Brenner, B.; Spira, B.; Wainberg, M.; Huang, F., Drda, K.; Ballow, C.; Mayers, D. Presented at the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 22-25, 2005, Abstract 558.
[40]Van Roey, J.; Von Schoen-Angerer, T.; Ford, N.; Calmy, A. Drug Discov. Today. 2008,13,601.
[41]Ding, J.; Das, K.; Tantillo, C.; Zhang, W.; Jr Clark, A. D.; Jessen, S.; Lu, X.; Hsiou, Y.; Jacobo-Molina, A.; Andries, K.; Pauwels, R.; Moereels, H.; Koymans, L.; Janssen, P. A. J.; Jr Smith, R. H.; Kroeger Koepke, M.; Michejda, C. J.; Hughes, S. H.; Arnold, E. Structure.1995,3,365.
[42]Ren, J.; Esnouf, R.; Hopkins, A.; Ross, C.; Jones, Y.; Stammers, D. Nat. Struct. Biol.1995,2,915.
[43]De Clercq, E. Med. Res. Rev.1996,16,125.
[44]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull.2006,54,1248.
[45]Meng, G; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull.2003,51,779.
[46]He, Y. P.; Kuang, Y. P.; Chen, F. E.; Wang, S. X.; Ji, L.; De Clercq, E.; Panecouque, C. Monatshefte for Chemie.2005,136,1233.
[47]Sun, G. F.; Chen X. X.; Chen, F. E.; Wang, Y. P.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Chem. Pharm. Bull.2005,53,886.
[48]Sun, G. F.; Kuang, Y. Y.; Wang, S. X.; Chen, F. E. Synth. Commun.2004,34, 2229.
[49]Meng, G.; Kuang, Y. Y.; Ji, L.; Chen, F. E. Synth. Commun.2005,35,1095.
[50]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,50,1778.
[51]Ji, L.; Chen, F. E.; Xie, B.; De Clercq, E.;Balzarini, J.; Pannecouque, C. Eur. J. Med. Chem.2007,42,198.
[52]Wang, Y P.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem.2008,16,3887.
[53]He, Y P.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem. Lett.2004,14,3173.
[54]He, Y P.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Chem.2004,32,536.
[55]Sun, G. F.; Kuang, Y Y.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Arch. Pharm.2005,338,457.
[56]Liang, Y. H.; Zeng, Z. S.; Liu, Z. Q.; Feng, X. Q.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2010,18,2370.
[57]Zeng, Z. S.; Liang Y H.; Feng, X. Q.; Chen, F. E.; Pannecouque, C.; Balzarini, J.; De Clercq, E. ChemMedChem 2010,5,837.
[58]Feng, X. Q.; Zeng, Z. S.; Liang, Y H.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2010,18,2370.
[59]Liang, Y H.; Zeng, Z. S.; Liu, Z. Q.; Feng, X. Q.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2010,18,4601.
[60]Zeng, Z. S.; He, Q. Q.; Liang, Y H.; Feng, X. Q.; Chen, F. E., De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem.2010,18,5039.
[61]Feng, X. Q.; Liang, Y. H.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,219.
[62]Liang,Y H.;Feng,X.Q.;Zeng,Z.S.;Chen,F.E.Balzarini,J.；Pannecouque,C. De Clercq,E.ChemMedChem.2009,4,1537.
[63]Xiong,Y Z.;Chen,F.E.;De Clercq,E.；Balzarini,J.；Pannecouque,C.Eur.J. Med.Chem.2008,43,1230.
[64]Xiong,Y Z.;Chen,F.E.;De Clercq,E.;Balzarini,J.;Pannecouque,C.Chem. Biodiver.2009,6,561.
[65]Xiong,Y Z.;Chen,F.E.;De Clercq,E.;Balzarini,J.;Pannecouque,C.Acta Chimica Sinica.,2006,64,1627.
[66]Hazen,R.J.;Harvey,R.J.;St Clair,M.H.；Ferris,R.G.；Freeman,G.A.； TidWell,J.H.；Schaller,L.T.;Cowan,J.R.;Short,S.A.;Romines,K.R. Antimicrob. Agents Chemother.2005,49,4465.
[67]Chan,J.H.;Freeman,G.A.;Tidwell,J.H.;Romines,K.R.；Schaller,L.T. Cowan,J.R.;Gonzales,S.S.;Lowell,G.S.;Andrews Ⅲ,C.;Reynolds,D.J., Med.Chem.2004,47,1175.
[68]Ferris,R.G.;Hazen,R.J.;Roberts,G.B.;St Clair,M.H.;Chan,J.H.; Romines,K.R.;Freeman,G.A.;Tidwell,J.H.;Schaller,L.T.;Cowan,J.R. Antimicrob. Agents Chemother.2005,49,4046.
[69]Romines,K.R.;Freeman,G.A.;Schaller,L.T.;Cowan,J.R.;Gonzales,S.S.; Tidwell,J.H.;Andrews Ⅲ,C.W.;Stammers,D.K.;Hazen,R.J.;Ferris,R.G. J.Med Chem.2006,49,727.
[70]Ren,J.;Chamberlain,P.P.;Stamp,A.;Short,S.A.;Weaver,K.L.;Romines, K.R.;Hazen,R.;Freeman,A.;Ferris,R.G.;Andrews,C.W.,Med.Chem. 2008,51,5000.
[71]Tucker,T.J.;Saggar,S.;Sisko,J.T.;Tynebor,R.M.;Williams,T.M.;Felock, P.J.;Flynn,J.A.;Lai,M.T.;Liang,Y.;McGaughey,G.Bioorg.Med.Chem. Lett.2008,18,2959.
[72]San Juan,A.A.Bioorg.Med.Chem.Lett.2008,18,1181.
[73]Pauwels,R.;Andries,K.;Debyset,Z.;Van Daele,P.;Schols,D.;Stoffels,P.; De Vreese,K.;Woestenborghs,R.;Vandamine,A.M.;Janssen,C.G.M.; Anne,J.;Cauwenbergh,G.;Desmyter,J.;Heykants,J.;Janssen,M.A.C.;De Clercq,E.;Janssen,P.A.J.Proc.Natl.Acad.Sci.U.S.A.1993,90,1711.
[74]Romero,D.L.;Morge,R.A.;Genin,M.J.;Biles,C.;Busso,M.;Resnick,L. Althaus,I.W.;Reusser,F.;Thomas,R.C.;Tarpley,W.G.J.Med Chem.1993, 36,1505.
[75]Nottet,H.S.；Oteman,M.H.；Visser,M.R.；Verhoef,J.J.Antimicrob. Chemother.1994,33,366.
[76]Ludovici,D.W.；Kukla,M.J.；Grous,P.G.；Krishnan,S.；Andries,K.；De Bethune,M.-P.；Azijn,H.；Pauwels,R.；De Clercq,E.；Arnold,E.；Janssen,P. A.J.Biorg.Med.Chem.Lett.2001.11,2225.
[77]Ludovici,D.W.；Kavash,R.W.；Kukla,M.J.；Ho,C.Y.；YP,H.；De Corte,B. L.；Andries,K.；De Bethune,M.-P.；Azijn,H.；Pauwels,R.；Moereels,H.E.L.； Heeres,J.；Koymans,L.M.H.；De Jonge,M.R.；Van Aken,K.J.A.；Daeyaert, F.F.D.；Lewi,P.J.；Das,K.；Arnold,E.；Janssen,P.A.J.Bioorg.Med.Chem. Lett.2001,2229.
[78]Ludovici,D.W.；De Corte,B.L.；Kukla,M.J.；Ye,H.；Ho,C.Y.；Lichtenstein, M.A.；Kavash,R.W.；Andries,K.；De Bethune,M.-P.；Azijn,H.；Pauwels,R.； Lewi,P.J.；Heeres,J.；Koymans,L.M.；De Jonge,M.R.；Van Aken,K.J.； Daeyaert,F.F.；Das,K.；Arnold E.；Janssen P.A.J.Bioorg.Med.Chem.Lett. 2001,11,2235.
[79]Das,K.；Jr Clark,A.D.；Lewi,P.J.；Heeres,J.；De Jonge,M.R.；Koymans,L. M.H.；Vinkers,H.M.；Daeyaert,F.；Ludovici,D.W.；Kukla,M.J.；De Corte, B.；Kavash,R.W.；Ho,C.Y.；Ye,H.；Lichtenstein,M.A.；Andries,K.； Pauwels,R.；De Bethune,M.-P.；Boyer,P.L.；Clark,P.；Hughes,S.H.；Janssen, P.A.J.；Arnold,E.,Med.Chem.2004,47,2550.
[80]Guillemont,J.；Pasquier,E.；Palandjian,P.；Vernier,D.；Gaurrand,S.；Lewi,P. J.；Heeres,J.；De Jonge,M.R.；Koymans,L.M.H.；Daeyaert,F.F.D.；Vinkers, M.H.；Arnold,E.；Das,K.；Pauwels,R.；Andries,K.；De Bethune,M.-P.； Bettens,E.；Hertogs,K.；Wigerinck,P.；Timmerman,P.；Janssen,P.A.J., Med.Chem.2005,48,2072.
[81]Tian,X.；Qin,B.；Lu,H.；Lai,W.；Jiang,S.；Lee,K.一H.；Chen,C.H.；Xie,L. Bioorg.Med.Chem.Lett.2009,19,5482.
[82]Heeres,J.；De Jonge,M.R.；Koymans,L.M.H.；Daeyaert,F.F.D.；Vinkers, M.；Van Aken,K.J.A.；Arnold,E.；Das,K.；Kilonda,A.；Hoornaert,G.J.； Compernolle,F.；Cegla,M.；Azzam,R.A.；Andries,K.；De Bethune,M.-P.； Azijn,H.；Pauwels,R.；Lewi,P.J.；Janssen,P.A.J.,Med.Chem.2005,48, 1910.
[83]Zeevaart,J.G.；Wang,L.；Thakur,V.V.；Leung,C.S.；Tirado-Rives,J.；Bailey, C.M.；Domaoal,R.A.；Anderson,K.S.；Jorgensen,W.L.J.Am.Chem.Soc. 2008,130,9492.
[84]Sweeney,Z.K.;Acharya,S.;Briggs,A.;Dunn,J.P.；Elworthy,T.R.;Fretland, J.；Giannetti,A.M.;Heilek,G.;Li,Y.;Kaiser,A.C.;Martin,M.；Saito,Y.D.； Smith,M.；Suh,J.M.；Swallow,S.；Wu,J.；Hang,J.Q.；Zhou,A.S.；Klumpp, K.Bioorg.Med.Chem.Lett.2008,18,4348.
[85]Mordant,C.;Schmitt,B.;Pasquier,E.;Demestre,C.;Queguiner,L.;Masungi C.；Peeters,A.;Smeulders,L.;Bettens,E.；Hertogs,K.；Heeres,J.；Lewi,P.； Guillemont,J.S.Eur.,Med.Chem.2007,42,567.
[86]曾兆森.复旦大学博士论文,上海：复旦大学,2010.
[87]Chen,F.E.；Zeng,Z.S.；Liang,Y.H.;Feng,X.Q.CN101723903A,2010.
[88]冯筱晴.复旦大学博士论文,上海：复旦大学,2010.
[89]Jacques,P.S.;Wohrl,B.M.;Ottmann,M.；Darlix,J.L.；Le Grice,S.;J.Biol. Chem.1994,269,26472.
[90]Le Grice,S.F.；Cameron,C.E.;Benkovic,S.J.Methods Enzymol.1995,262, 130.
[91]Powell,M.D.;Ghosh,M.；Jacques,P.S.;Howard,K.J.S.;Le Grice,P.;Fay, J.；Bambara,R.A.J.Biol.Chem.1997,272,11157.
[92]Das,K.；Bauman,J.D.；Jr Clark,A.D.；Frenkcl,Y.V.；Lewi,P.J.A.J.； Shatkin,S.H.；Hughes,Arnold,E.Proc.Natl.Acad.Sci.USA.2008,105, 1472.
[93]Orr,D.C.;Figueiredo,H.T.;Mo,C.;Penn,C.R.;Cameron,J.M.J.Biol. Chem.1992,267,4177.
[94]Wyatt,P.G；Bethell,R.C.；Cammack,N.；Charon,D.；Dodic,N.；Dumaitre,B.； Evans,D.N.;Green,D.V.S.;Hopewell,P.L.,Med.Chem.1995,38,1657.
[1]Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E. Prog. Biophys. Mol. Biol.2005, 88,209.
[2]De Clercq, E. Nat. Rev. Drug Discovery 2007,6,1001.
[3]De Corte,B.L.J.Med.Chem.2005,48,1689.
[4]Heeres,J.;Lewi,P.J.;Adv.Antiviral Drug Des.2007,5,213.
[5]a)Ludovici,D.W.;De Corte,B.L.;Kukla,M.J.;Ye,H.;Ho,C.Y.； Lichtenstein,M.A.;Kavash,R.W.;Andries,K.;De Bethune,M.-P.;Azijn,H. Bioorg.Med.Chem.Lett.2001,11,2235.;b)Ludovici,D.W.;Kavash,R.W.; Kukla,M.J.；Ho,C.Y.；Ye,H.；De Corte,B.；Andries,K；De Bethune,M.-P.; Azijn,H.;Pauwels,R.；Bioorg.Med.Chem.Lett.2001,11,2229.
[6]Sarafianos,S.G.；Das,K.;Hughes,S.H.；Arnold,E.Curr.Opin.Struct.Biol. 2004,14,716.
[7]a)Guillemont,J.；Pasquier,E.;Palandjian,P.;Vernier,D.;Gaurrand,S.；Lewi, P.J.；Heeres,J.；De Jonge,M.R.；Koymans,L.M.H.;Daeyaert,F.F.D.J. Med.Chem.2005,48,2072.;b)Heeres,J.;De Jonge,M.R.;Koymans,L.M.H.; Daeyaert,F.F.D.；Vinkers,M.；Van Aken,K.J.A.；Arnold,E.；Das,K.； Kilonda,A.;Hoornaert,G.J.,Med.Chem.2005,48,1910.;c)Janssen,P.A.J.； Lewi,P.J.；Arnold,E.；Daeyaert,F.；De Jonge,M.;Heeres,J.;Koymans,L.； Vinkers,M.;Guillemont,J.;Pasquier,E.J.Med.Chem.2005,48,1901.;d)Tian, X.T.；Qin,B.J.；Wu,Z.Y.;Wang,X.F.;Lu,H.；Morris-Natschke,S.L.;Chen, C.Ho.;Jiang,S.B.;Lee,K.-H.；Xie,L.J.Med.Chem.2010,8287.
[8]Mordant,C.;Schrnitt,B.；Pasquier,E.;Demestre,C.;Queguiner,L.;Masungi, C.;Peeters,A.;Smeulders,L.;Bettens,E.;Hertogs,K.Eur.,Med.Chem. 2007,42,567.
[9]曾兆森.复旦大学博士论文,上海：复旦大学,2010.
[10]Zeng,Z.S.;Liang,Y.H.;Feng,X.Q.;Chen,F.E.;Pannecouque,C.;Balzarini, J.;De Clercq,E.ChemMedChem 2010,5,837.
[11]Chen,F.E.;Zeng,Z.S.；Liang,Y.H.;Feng,X.Q.CN101723903A,2010.
[12]冯筱晴.复旦大学博士论文,上海：复旦大学,2010.
[13]Feng,X.Q.；Zeng,Z.S.;Liang,Y.H.;Chen,F.E.;Pannecouque,C.；Balzarini, J.；De Clercq,E.Bioorg.Med.Chem.2010,,8,2370.
[14]Das,K.；Jr Clark,A.D.；Lewi,P.J.；Heeres,J.；De Jonge,M.R.;Koymans,L. M.H.；Vinkers,H.M.；Daeyaert,F.F.D.；Ludovici,D.W.；Kukla,M.J.；De Corte,B.L.；Kavash,R.W.；Ho,C.Y.；Ye,H.；Lichtenstein,M.A.；Andries, K.;Pauwels,R.；De Bethune,M.-P.;Boyer,P.L.;Clark,P.；Hughes,S.H.; Janssen,P.A.J.;Arnold,E.J.Med.Chem.2004,47,2550
[15]Jain,A.N.J.Comput-Aided.Mol.Des.1996,10,427.
[16]Ruppert, J.; Welch, W.; Jain, A. N. Protein Sci.1997,6,524.
[17]Welch, W.; Ruppert, J.; Jain, A. N. Chem. Biol.1996,3,449.
[18]Jain, A. N. J. Med. Chem.2003,46,499.
[19]Ludovici, D. W.; De Corte, B. L.; Kukla, M. J.; Ye, H.; Ho, C. Y.; Lichtenstein, M. A.; Kavash, R. W.; Andries, K.; De Bethune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.; Heeres, J.; Koymans, L. M.; De Jonge, M. R.; Van Aken, K. J.; Daeyaert, F. F.; Das, K.; Arnold E.; Janssen P. A. J. Bioorg. Med. Chem. Lett. 2001,11,2235.
[20]Feng, X. Q.; Liang, Y. H.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,219.
[21]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,50,1778.
[22]Sieger, G. M.; Klein, D. X. J. Org. Chem.1957,22,951.
[23]Songbai, L.; Ying, Y; Lanny S. L. Org. Lett.2007,9,1947.
[24]Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. J. Virol. Methods.1988,20,309.
[25]杨汉民.细胞生物学实验.北京：高等教育出版社,1997,164.
[26]张鸿卿,连慕兰.细胞生物学实验方法与技术.北京：北京师范大学出版社,1990,55.
[27]Pannecouque, C.; Daelemans, D.; De Clercq, E. Nat. Protoc.2008,3, 427.
[28]Rey, F.; Barre-Sinoussi, F.; Schmidtmayerova, H.; Chermann, J. C. J. Virol. Methods.1987,16,239.
[29]Baba, M.; De Clercq, E.; Iida, S.; Tanaka, H.; Nitta, I.; Ubasawa, M.; Takashima, H.; Sekiya, K.; Umezu, K.; Nakashima, H. Antimicrob. Agents. Chemother.1990,34,2358.
[30]Rey F.; Donker G.; Hirsch I.; Chermann J. C. J. Virol.1991,181,165.
[31]Seki J.; Ikeda R.; Hoshino H. Biochem. Biophys. Res. Commun.1996,227,724.
[32]Xie, X.; He, X.; Zhu, T.; Xu, Y. Z.; Zhou, E. K. CN101531997A,2008.
[33]Liu, A. M. F.; Ho, M. K. C.; Wong, C. S. S.; Chan, J. H. P.; Pau, A. H. M.; Wong, Y. H. J. Biomol. Screen.2003,8,39.
[34]周恩昆.西南大学硕士论文,重庆：西南大学,2009.
[35]Wang, Q.; Ding, Z. H; Liu, J. K.; Zheng, Y. T. Antivir. Res.2004,64,189.
[36]Yu, M. Y.; Li, Z. Y.; Liu, S.; Fan, E. K.; Pannecouque, C.; De Clercq, E.; Liu, X. Y. ChemMedChem 2011,6,826.
[37]Kazmierski, W. M.; Boone, L.; Lawrence, W.; Watson, C.; Kenakin, T. Curr. Drug Targets Infect Disord.2002,2,265.
[38]Wang, S.; He, C. G.; Maguire, M. T.; Clemmons, A. L.; Burrier, R. E.; Guzzi, M. F.; Strader, C. D.; Parker, E. M.; Bayne, M. L. J. Biol. Chem.1998,273, 4754.
[39]陈凯先,蒋华良,嵇汝运.计算机辅助药物设计：原理、方法及应用,上海：上海科学技术出版社,2000,141.
[40]李仁利.药物构效关系.北京：中国医药科技出版社,2004,491.
[41]Cramer Ⅲ, R. D.; Patterson, D. E.; Bunce, J. D. J. Am. Chem. Soc.1988,110, 5959.
[42]Klebe, G.; Abraham, U.; Mietzner, T. J. Med. Chem.1994,37,4130.
[43]Hopfinger, A.3.J. Am. Chem. Soc.1980,102.325.
[44]Crippen, G. M. J. Med. Chem.1979,22,988.
[45]Wold, S.; Ruhe, A.; Wold, H.; Dunn Ⅲ, W. J. J. Sci. Stat. Comput.1984,5,735.
[46]Clark, M; Cramer Ⅲ, R. D. Quant. Struct-Act. Relat.1993,12,137.
[47]a)Kim, K. H.; Martin, Y. C. J. Org. Chem.1991,56,2723.; b)Kim, K. H. Quant. Struct-Act. Relat.1992,11,453.; c)Kim, K. H. Quant. Struct-Act. Relat.1992, 11,309.
[48]a)熊远珍,陈芬儿,冯筱晴.化学学报,2006,64,1627.；b)孟歌,何严萍,陈芬儿.高等学校化学学报,2002,23,1304.；c)何严萍,胡海龙,许辽萨,孟歌,陈芬儿.高等学校化学学报,2005,26,2544.
[49]Folkers, G.; Merz, A.; Rognan, D.3D-QSAR in Drug Design.1993,583.
[1]Zhan,P.；Liu,X.Y.Expert Opin.Ther.Patents.2011,21,717.
[2]朱骏杰,曹江营,展鹏,赵翠荣,刘新泳.中国新药杂志,2009,18,206.
[3]Hazen,R.J.；Harvey,R.J.；St Clair,M.H.；Ferris,R.G.；Freeman,G.A.； Tidwell,J.H.；Schaller,L.T.；Cowan,J.R.；Short,S.A.；Romines,K.R. Antimicrob.Agents Chemother.2005,49,4465.
[4]Chan,J.H.;Freeman,G.A.;Tidwell,J.H.；Romines,K.R.；Schaller,L.T. Cowan,J.R.；Gonzales,S.S.;Lowell,G.S.；Andrews Ⅲ,C.；Reynolds,D.J. Med.Chem.2004,47,1175.
[5]Ferris,R.G.;Hazen,R.J.;Roberts,G.B.;St Clair,M.H.;Chan,J.H.;Romines, K.R.；Freeman,G.A.；Tidwell,J.H.；Schaller,L.T.；Cowan,J.R.Antimfcrob. Agents Chemother.2005,49,4046.
[6]Romines,K.R.;Freeman,G.A.；Schaller,L.T.;Cowan,J.R.；Gonzales,S.S.； Tidwell,J.H.；Andrews Ⅲ,C.W.；Stammers,D.K.；Hazen,R.J.；Ferris,R.G.J. Med.Chem.2006,49,727.
[7]Ren,J.；Chamberlain,P.P.;Stamp,A.;Short,S.A.;Weaver,K.L.；Romines,K. R.；Hazen,R.；Freeman,A.；Ferris,R.G.；Andrews,C.W.J.Med.Chem.2008, 51,5000.
[8]Tucker,T.J.;Saggar,S.;Sisko,J.T.;Tynebor,R.M.;Williams,T.M.;Felock,P. J.；Flynn,J.A.;Lai,M.T.；Liang,Y.；McGaughey,G.Bioorg.Med.Chem.Lett. 2008,18,2959.
[9]San Juan, A. A. Bioorg. Med. Chem. Lett.2008,18,1181.
[10]Sluis-Cremer, N.; Temiz, N. A.; Bahar, I. Curr. HIV. Res.2004,2,323.
[11]Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E., Prog. Biophys. Mol. Biol.2005, 88,209.
[12]陈先红,谢蓝.中国新药杂志,2006,16,182.
[13]a)Feng, X. Q.; Liang, Y. H.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,219.; b)Liang, Y. H.; Feng, X. Q.; Zeng, Z. S.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. ChemMedChem 2009,4,1537.
[14]a)Wang, Y. P.; Chen, F. E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem.2008,16,3887.; b)He, Y. P.; Chen, F. E.; Sun, G. F.; Wang, Y. P.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem. Lett.2004,14, 3173.
[15]Ji, L.; Chen, F. E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. J. Med. Chem. 2007,50,1778.
[16]Jain, A. N. J. Comput-Aided. Mol. Des.1996,10,427.
[17]Ruppert, J.; Welch, W.; Jain, A. N. Protein Sci.1997,6,524.
[18]Welch, W.; Ruppert, J.; Jain, A. N. Chem. Biol.1996,3,449.
[19]Jain, A. N. J. Med. Chem.2003,46,499.
[20]Park, K. K.; Jeong, J. Tetrahedron.2005,61,545.
[21]Li, W.; Lai, H.; Ge, Z.; Ding, C.; Zhou, Y. Synthetic commun.2007,37,1595.
[22]Zheng, Y. T.; Ben, K. L.; Jin, S.W. Acta Pharmacol. Sin.2000,21,179.
[23]Wang, R. R.; Yang, L. M.; Wang, Y. H.; Pang, W.; Tam, S. C.; Tien, P.; Zheng, Y. T. Biochem. Biophys. Res. Commun.2009,382,540.
[24]Macias, F. A.; De Siqueira, J.; Chinchilla, M. N.; Marin, D.; Varela, R. M.; Molinillo, J. M. G. J. Agric. Food Chem.2006,54,9843.
[25]苏砚溪.河南化工,2002,4,20。
[26]Pushkareva, Z. V.; Kokoshko, Z. Yu. Zh. Obshch. Khim.1954,24,870.
[27]Brown, J. P.; McCall, E. B. J. Chem. Soci.1955,3681.
[28]a)Andrews, C. W.; Chan, J. H.; Freeman, G. A.; Romines, K. R.; Tidwell, J. H. WO 01/17982,2001.; b)Chan, J. H. WO 02/070470,2002.; c)Chan, J. H. US 2004/0122064,2004.; d)Chan, J. H. US 2006/0009651,2006.
[29]Wyatt, P. G.; Bethell, R. C.; Cammack, N.; Charon, D.; Dodic, N.; Dumaitre, B.; Evans, D. N.; Green, D. V. S.; Hopewell, P. L. J. Med. Chem.1995,38,1657.
[1]陈凯先,蒋华良等,计算机辅助药物设计:原理、方法及应用,上海:上海科学技术出版社,2000,1引.
[2]李仁利.药物构效关系.北京:中国医药科技出版社,2004,419.
[3]Cramer III,R.D.:Patterson,D.E.:Bunee,J.D.J.Am.hCem.OSc.1988,110,5959.
[4] Klebe, G; Abraham, U.; Mietzner, T. J. Med. Chem. 1994, 37, 4130.
[5] Ren, J.; Chamberlain, P. P.; Stamp, A.; Short, S. A.; Weaver, K. L.; Romines,K. R.; Hazen, R.; Freeman, A.; Ferris, R. G.; Andrews, C. W. J. Med. Chem.2008, 51, 5000.
[6] Folkers, G.; Merz, A.; Rognan, D. 3D-QSAR in Drug Design. 1993, 583.
[7] Sun Juan, A. A. Bioorg. Med. Chem. Lett. 2008, 18, 1181.