Identification of the novel <i>N</i>-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

Citation: Yong Sun, Cui-Lin Lu, Chang-Yuan Wang, Rui-Rui Wang, Ke-Xin Liu, Liu-Meng Yang, Yu-Hong Zhen, Hou-Li Zhang, Chao Wang, Yong-Tang Zheng, Xiao-Dong Ma. Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors[J]. Chinese Chemical Letters, 2015, 26(2): 243-247. doi: 10.1016/j.cclet.2014.11.004 shu

Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

通讯作者: Yong-Tang Zheng,
Xiao-Dong Ma,

基金项目:
This work was supported in part by grants from the National Natural Science Foundation of China (No. 81402788) (No. 81402788)

the Ph.D. Start-up Fund of Natural Science Foundation of Liaoning Province, China (No. 20141115). (No. 20141115)

摘要: Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide. Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase (RT) inhibitors, a new template bearing N-phenylbenzenesulfonamide (PBSA) structure was designed to enhance the interactions with HIV-1 RT. In this manuscript, a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity. The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC50 values ranging of 0.105-14.531 mmol/L. In particular, compound 13f not only has high anti-HIV-1 activity (0.108 mmol/L), but also possesses low toxicity with a TI value of 1816.6. Furthermore, the major interactions of the inhibitor 13f with HIV-1 RT were also investigated using the molecular modelling. Our discovered structure-activity relationships (SARs) of these analogues may serve as an important clue for further optimizations.

关键词:

English

Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

1.
a College of Pharmacy, Dalian Medical University, Dalian 116044, China;
2.
b Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;
3.
c Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China

Corresponding author: Yong-Tang Zheng, Xiao-Dong Ma,

Received Date: 02 September 2014
Available Online: 10 November 2014
Fund Project:

Abstract: Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide. Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase (RT) inhibitors, a new template bearing N-phenylbenzenesulfonamide (PBSA) structure was designed to enhance the interactions with HIV-1 RT. In this manuscript, a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity. The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC50 values ranging of 0.105-14.531 mmol/L. In particular, compound 13f not only has high anti-HIV-1 activity (0.108 mmol/L), but also possesses low toxicity with a TI value of 1816.6. Furthermore, the major interactions of the inhibitor 13f with HIV-1 RT were also investigated using the molecular modelling. Our discovered structure-activity relationships (SARs) of these analogues may serve as an important clue for further optimizations.

Key words:

1. [1] W. Schaefer, W.G. Friebe, H. Leinert, et al., Non-nucleoside inhibitors of HIV-1 reverse transcriptase: molecular modeling and X-ray structure investigations, J. Med. Chem. 36 (1993) 726-732.[1] W. Schaefer, W.G. Friebe, H. Leinert, et al., Non-nucleoside inhibitors of HIV-1 reverse transcriptase: molecular modeling and X-ray structure investigations, J. Med. Chem. 36 (1993) 726-732.
2. [2] J.F. Palella, K.M. Delaney, A.C. Moorman, et al., Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators, N. Engl. J. Med. 338 (1998) 853-860.[2] J.F. Palella, K.M. Delaney, A.C. Moorman, et al., Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators, N. Engl. J. Med. 338 (1998) 853-860.
3. [3] E. De Clerck, New developments in anti-HIV chemotherapy, Curr. Med. Chem. 8 (2001) 1543-1572.[3] E. De Clerck, New developments in anti-HIV chemotherapy, Curr. Med. Chem. 8 (2001) 1543-1572.
4. [4] M.P. de Be´ thune, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009), Antivir. Res. 85 (2010) 75-90.[4] M.P. de Be´ thune, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009), Antivir. Res. 85 (2010) 75-90.
5. [5] R.A. Koup, V.J. Merluzzi, K.D. Hargrave, et al., Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587, J. Infect. Dis. 163 (1991) 966-970.[5] R.A. Koup, V.J. Merluzzi, K.D. Hargrave, et al., Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587, J. Infect. Dis. 163 (1991) 966-970.
6. [6] W.W. Freimuth, Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor, Adv. Exp. Med. Biol. 394 (1996) 279-289.[6] W.W. Freimuth, Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor, Adv. Exp. Med. Biol. 394 (1996) 279-289.
7. [7] S.D. Young, S.F. Britcher, L.O. Tran, et al., L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother. 39 (1995) 2602-2605.[7] S.D. Young, S.F. Britcher, L.O. Tran, et al., L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother. 39 (1995) 2602-2605.
8. [8] L.B. Johnson, L.D. Saravolatz, Etravirine, a next-generation nonnucleoside reversetranscriptase inhibitor, Clin. Infect. Dis. 48 (2009) 1123-1128.[8] L.B. Johnson, L.D. Saravolatz, Etravirine, a next-generation nonnucleoside reversetranscriptase inhibitor, Clin. Infect. Dis. 48 (2009) 1123-1128.
9. [9] S. Moreno, J. Ló pez Aldeguer, J.R. Arribas, et al., The future of antiretroviral therapy: challenges and needs, J. Antimicrob. Chemother. 65 (2010) 827-835.[9] S. Moreno, J. Ló pez Aldeguer, J.R. Arribas, et al., The future of antiretroviral therapy: challenges and needs, J. Antimicrob. Chemother. 65 (2010) 827-835.
10. [10] H. Azijn, I. Tirry, J. Vingerhoets, et al., TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTIresistant HIV-1, Antimicrob. Agents Chemother. 54 (2010) 718-727.[10] H. Azijn, I. Tirry, J. Vingerhoets, et al., TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTIresistant HIV-1, Antimicrob. Agents Chemother. 54 (2010) 718-727.
11. [11] Z. Zhang, R. Hamatake, Z. Hong, Clinical utility of current NNRTIs and perspectives of new agents in this class under development, Antivir. Chem. Chemother. 15 (2004) 121-134.[11] Z. Zhang, R. Hamatake, Z. Hong, Clinical utility of current NNRTIs and perspectives of new agents in this class under development, Antivir. Chem. Chemother. 15 (2004) 121-134.
12. [12] Guidelines for the Use of Antiretro Iral Agents in HIV-1-Infected Adults and Adolescents. http://AIDSinfo.nih.gov (29.10.04).[12] Guidelines for the Use of Antiretro Iral Agents in HIV-1-Infected Adults and Adolescents. http://AIDSinfo.nih.gov (29.10.04).
13. [13] R.M. Grant, F.M. Hecht, M. Warmerdam, et al., Time trends in primary HIV-1 drug resistance among recently infected persons, JAMA 288 (2002) 181-188.[13] R.M. Grant, F.M. Hecht, M. Warmerdam, et al., Time trends in primary HIV-1 drug resistance among recently infected persons, JAMA 288 (2002) 181-188.
14. [14] J.H. Chan, G.A. Freeman, J.H. Tidwell, et al., Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1, J. Med. Chem. 47 (2004) 1175-1182.[14] J.H. Chan, G.A. Freeman, J.H. Tidwell, et al., Novel benzophenones as non-nucleoside reverse transcriptase inhibitors of HIV-1, J. Med. Chem. 47 (2004) 1175-1182.
15. [15] K.R. Romines, G.A. Freeman, L.T. Schaller, et al., Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor, J. Med. Chem. 49 (2006) 727-739.[15] K.R. Romines, G.A. Freeman, L.T. Schaller, et al., Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor, J. Med. Chem. 49 (2006) 727-739.
16. [16] R.G. Ferris, R.J. Hazen, G.B. Roberts, et al., Antiviral activity of GW678248, a novel benzophenone nonnucleoside reverse transcriptase inhibitor, Antimicrob. Agents Chemother. 49 (2005) 4046-4051.[16] R.G. Ferris, R.J. Hazen, G.B. Roberts, et al., Antiviral activity of GW678248, a novel benzophenone nonnucleoside reverse transcriptase inhibitor, Antimicrob. Agents Chemother. 49 (2005) 4046-4051.
17. [17] P.G. Wyatt, R.C. Bethell, N. Cammack, et al., Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase, J. Med. Chem. 38 (1995) 1657-1665.[17] P.G. Wyatt, R.C. Bethell, N. Cammack, et al., Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase, J. Med. Chem. 38 (1995) 1657-1665.
18. [18] X.D. Ma, Q.Q. He, X. Zhang, et al., Synthesis, structure-activity relationships, and docking studies of N-phenylarylformamide derivatives (PAFAs) as non-nucleoside HIV reverse transcriptase inhibitors, Eur. J. Med. Chem. 58 (2012) 504-512.[18] X.D. Ma, Q.Q. He, X. Zhang, et al., Synthesis, structure-activity relationships, and docking studies of N-phenylarylformamide derivatives (PAFAs) as non-nucleoside HIV reverse transcriptase inhibitors, Eur. J. Med. Chem. 58 (2012) 504-512.
19. [19] X.D. Ma, X. Zhang, H.F. Dai, et al., Synthesis and biological activity of naphthylsubstituted (B-ring) benzophenone derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors, Bioorg. Med. Chem. 19 (2011) 4601-4607.[19] X.D. Ma, X. Zhang, H.F. Dai, et al., Synthesis and biological activity of naphthylsubstituted (B-ring) benzophenone derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors, Bioorg. Med. Chem. 19 (2011) 4601-4607.
20. [20] X.D. Ma, X. Zhang, S.Q. Yang, et al., Synthesis and biological evaluation of (±)-benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors, Bioorg. Med. Chem. 19 (2011) 4704-4709.[20] X.D. Ma, X. Zhang, S.Q. Yang, et al., Synthesis and biological evaluation of (±)-benzhydrol derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors, Bioorg. Med. Chem. 19 (2011) 4704-4709.
21. [21] S.X. Gu, X. Zhang, Q.Q. He, et al., Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors, Bioorg. Med. Chem. 19 (2011) 4220-4226.[21] S.X. Gu, X. Zhang, Q.Q. He, et al., Synthesis and biological evaluation of naphthyl phenyl ethers (NPEs) as novel nonnucleoside HIV-1 reverse transcriptase inhibitors, Bioorg. Med. Chem. 19 (2011) 4220-4226.
22. [22] Y.T. Zheng, K.L. Ben, S.W. Jin, Anti-HIV-1 activity of trichobitacin, a novel ribosome-inactivating protein, Acta Pharmacol. Sin. 21 (2000) 179-182.[22] Y.T. Zheng, K.L. Ben, S.W. Jin, Anti-HIV-1 activity of trichobitacin, a novel ribosome-inactivating protein, Acta Pharmacol. Sin. 21 (2000) 179-182.
23. [23] D.S. Goodsell, G.M. Morris, A.J. Olson, Automated docking of flexible ligands: applications of AutoDock, J. Mol. Recognit. 9 (1996) 1-5.[23] D.S. Goodsell, G.M. Morris, A.J. Olson, Automated docking of flexible ligands: applications of AutoDock, J. Mol. Recognit. 9 (1996) 1-5.

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沈阳化工大学材料科学与工程学院沈阳 110142

Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

通讯作者: Yong-Tang Zheng,
Xiao-Dong Ma,

English

Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

Corresponding author: Yong-Tang Zheng, Xiao-Dong Ma,

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

通讯作者: Yong-Tang Zheng, Xiao-Dong Ma,

English

Identification of the novel N-phenylbenzenesulfonamide derivatives as potent HIV inhibitors

Corresponding author: Yong-Tang Zheng, Xiao-Dong Ma,

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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