Citation: Han Sheng, Lei Yuan, Pannecouque Christophe, De Clercq Erik, Zhuang Chunlin, Chen Fener. Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors[J]. Chinese Chemical Letters, ;2020, 31(3): 764-768. doi: 10.1016/j.cclet.2019.11.020 shu

Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors

Han Sheng ^a,b,1 ,
Lei Yuan ^c,1 ,
Pannecouque Christophe ^e ,
De Clercq Erik ^e ,
Zhuang Chunlin ^a,b,*, ,
Chen Fener ^a,b,c,d,*,

a.
Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
b.
Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China
c.
Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
d.
Institute of Pharmaceutical Science and Technology, Zhejiang University of Technology, Hangzhou 310014, China
e.
Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium

zclnathan@163.com

rfchen@fudan.edu.cn

Received Date: 9 October 2019
Revised Date: 11 November 2019
Accepted Date: 12 November 2019
Available Online: 13 November 2019

Figures(4)

Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further oxidation. The best compound 6e with a sulfonyl scaffold displayed EC₅₀ values of 0.0356 μmol/L against WT and 0.0228 μmol/L against HIV K103N mutant strain. More pronounced, it had a lower cytotoxicity (CC₅₀=99.6 μmol/L), higher selectivity index (SI_WT=2799, SI_K103N=4375) and better calculated logarithm of the octanol-water partition coefficient (cLogP) than the lead compound 3. Molecular docking and dynamics provided the binding modes of these compounds with reverse transcriptase, explaining their activity. Collectively, the new compounds could be candidates for anti-HIV drug discovery.
- HIV-1,
- NNRTIs,
- DAPY,
- Sulfur-containing DABPs,
- FBDD
1. [1]
  R.C. Gallo, L. Montagnier, N. Engl. J. Med. 349(2003) 2283-2285. doi: 10.1056/NEJMp038194
2. [2]
  WHO website, HIV/AIDS Fact Sheet (Last Accessed August 26, 2019), https://www.who.int/hiv/data/en/.
3. [3]
  E. De Clercq, J. Med. Chem. 62(2019) 7322-7339. doi: 10.1021/acs.jmedchem.9b00175
4. [4]
  B. Huang, W. Chen, T. Zhao, et al., J. Med. Chem. 62(2019) 2083-2098. doi: 10.1021/acs.jmedchem.8b01729
5. [5]
  D. Kang, H. Zhang, Z. Wang, et al., J. Med. Chem. 62(2019) 1484-1501. doi: 10.1021/acs.jmedchem.8b01656
6. [6]
  Z. Zhou, T. Liu, D. Kang, et al., Org. Biomol. Chem. 16(2018) 1014-1028. doi: 10.1039/C7OB02828H
7. [7]
  V. Namasivayam, M. Vanangamudi, V.G. Kramer, et al., J. Med. Chem. 62(2019) 4851-4883. doi: 10.1021/acs.jmedchem.8b00843
8. [8]
  Y. Hsiou, J. Ding, K. Das, et al., J. Mol. Biol. 309(2001) 437-445. doi: 10.1006/jmbi.2001.4648
9. [9]
  K. Das, E. Arnold, Curr. Opin. Virol. 3(2013) 111-118. doi: 10.1016/j.coviro.2013.03.012
10. [10]
  K. Das, E. Arnold, Curr. Opin. Virol. 3(2013) 119-128. doi: 10.1016/j.coviro.2013.03.014
11. [11]
  C.J. Cohen, J. Andrade-Villanueva, B. Clotet, et al., Lancet 378(2011) 229-237. doi: 10.1016/S0140-6736(11)60983-5
12. [12]
  J. Lindberg, S. Sigurdsson, S. Lowgren, et al., Eur. J. Biochem. 269(2002) 1670-1677. doi: 10.1046/j.1432-1327.2002.02811.x
13. [13]
  J. Ren, J. Milton, K.L. Weaver, et al., Structure 8(2000) 1089-1094. doi: 10.1016/S0969-2126(00)00513-X
14. [14]
  Y. Yang, D. Kang, L.A. Nguyen, et al., Steitz, Elife 7(2018)E36340.
15. [15]
  M.B.Nawrozkij, M.Forgione, A.S.Yablokov, et al., J.Med.Chem.62(2019)604-621. doi: 10.1021/acs.jmedchem.8b01238
16. [16]
  M.T. Lai, V. Munshi, M. Lu, et al., Viruses 8(2016) E263. doi: 10.3390/v8100263
17. [17]
  M. Udier-Blagovi c, J. Tirado-Rives, W.L. Jorgensen, et al., J. Am. Chem. Soc. 125(2003) 6016-6017. doi: 10.1021/ja034308c
18. [18]
  K. Das, A.D. Clark Jr., P.J. Lewi, et al., J. Med. Chem. 47(2004) 2550-2560. doi: 10.1021/jm030558s
19. [19]
  J. Adams, N. Patel, N. Mankaryous, M. Tadros, C.D. Miller, Ann. Pharmacother. 44(2010) 157-165. doi: 10.1345/aph.1M359
20. [20]
  A.Blas-Garcia, J.V.Esplugues, N.Apostolova, Curr.Med.Chem.18(2011)2186-2195. doi: 10.2174/092986711795656180
21. [21]
  European Medicines Agency web site, Pifeltro: European Public Assessment Report-Medicine Overview, 2019. (Last Accessed August 26, 2019) https://www.ema.europa.eu/en/medicines/human/EPAR/pifeltro
22. [22]
  X. Li, B. Chen, L. Lan, et al., Chin. Chem. Lett. 29(2018) 1637-1640. doi: 10.1016/j.cclet.2018.06.003
23. [23]
  Y. Guo, L. Fu, X. Fan, X. Shi, Chin. Chem. Lett. 29(2018) 1167-1170. doi: 10.1016/j.cclet.2018.03.024
24. [24]
  W.H. Zhou, X.G. Xu, J. Li, et al., Chin. Chem. Lett. 28(2017) 422-425. doi: 10.1016/j.cclet.2016.09.001
25. [25]
  S. Han, Y. Sang, Y. Wu, et al., ACS Infect. Dis. (2019), doi: http://dx.doi.org/10.1021/acsinfecdis.9b00229.
26. [26]
  M.D. Shultz, J. Med. Chem. 62(2019) 1701-1714. doi: 10.1021/acs.jmedchem.8b00686
27. [27]
  E.A. Ilardi, E. Vitaku, J.T. Njardarson, J. Med. Chem. 57(2014) 2832-2842. doi: 10.1021/jm401375q
28. [28]
  Z.Y. Wan, J. Yao, T.Q. Mao, et al., Eur. J. Med. Chem. 102(2015) 215-222. doi: 10.1016/j.ejmech.2015.08.007
29. [29]
  Z.Y. Wan, Y. Tao, Y.F. Wang, et al., Bioorg. Med. Chem. 23(2015) 4248-4255. doi: 10.1016/j.bmc.2015.06.048
1. [1]
  Bairu Meng , Zongji Zhuo , Han Yu , Sining Tao , Zixuan Chen , Erik De Clercq , Christophe Pannecouque , Dongwei Kang , Peng Zhan , Xinyong Liu . Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs. Chinese Chemical Letters, 2024, 35(6): 108827-. doi: 10.1016/j.cclet.2023.108827
2. [2]
  Chen Lian , Si-Han Zhao , Hai-Lou Li , Xinhua Cao . A giant Ce-containing poly(tungstobismuthate): Synthesis, structure and catalytic performance for the decontamination of a sulfur mustard simulant. Chinese Chemical Letters, 2024, 35(10): 109343-. doi: 10.1016/j.cclet.2023.109343
3. [3]
  Zhiwei Chen , Heyun Sheng , Xue Li , Menghan Chen , Xin Li , Qiuling Song . Efficient capture of difluorocarbene by pyridinium 1,4-zwitterionic thiolates: A concise synthesis of difluoromethylene-containing 1,4-thiazine derivatives. Chinese Chemical Letters, 2024, 35(4): 108937-. doi: 10.1016/j.cclet.2023.108937
4. [4]
  Xiao-Ming Chen , Lianhui Song , Jun Pan , Fei Zeng , Yi Xie , Wei Wei , Dong Yi . Visible-light-induced four-component difunctionalization of alkenes to construct phosphorodithioate-containing quinoxalin-2(1H)-ones. Chinese Chemical Letters, 2024, 35(11): 110112-. doi: 10.1016/j.cclet.2024.110112
5. [5]
  Qian Wang , Yeping Bian , Gagan Dhawan , Wei Zhang , Alexander E. Sorochinsky , Ata Makarem , Vadim A. Soloshonok , Jianlin Han . FDA approved fluorine-containing drugs in 2023. Chinese Chemical Letters, 2024, 35(11): 109780-. doi: 10.1016/j.cclet.2024.109780
6. [6]
  Wei Sun , Anjing Liao , Li Lei , Xu Tang , Ya Wang , Jian Wu . Research progress on piperidine-containing compounds as agrochemicals. Chinese Chemical Letters, 2025, 36(1): 109855-. doi: 10.1016/j.cclet.2024.109855
7. [7]
  Jingwen Zhao , Jianpu Tang , Zhen Cui , Limin Liu , Dayong Yang , Chi Yao . A DNA micro-complex containing polyaptamer for exosome separation and wound healing. Chinese Chemical Letters, 2024, 35(9): 109303-. doi: 10.1016/j.cclet.2023.109303
8. [8]
  Jun Jiang , Tong Guo , Wuxin Bai , Mingliang Liu , Shujun Liu , Zhijie Qi , Jingwen Sun , Shugang Pan , Aleksandr L. Vasiliev , Zhiyuan Ma , Xin Wang , Junwu Zhu , Yongsheng Fu . Modularized sulfur storage achieved by 100% space utilization host for high performance lithium-sulfur batteries. Chinese Chemical Letters, 2024, 35(4): 108565-. doi: 10.1016/j.cclet.2023.108565
9. [9]
  Feng Cao , Chunxiang Xian , Tianqi Yang , Yue Zhang , Haifeng Chen , Xinping He , Xukun Qian , Shenghui Shen , Yang Xia , Wenkui Zhang , Xinhui Xia . Gelation-pyrolysis strategy for fabrication of advanced carbon/sulfur cathodes for lithium-sulfur batteries. Chinese Chemical Letters, 2025, 36(3): 110575-. doi: 10.1016/j.cclet.2024.110575
10. [10]
  Fangling Cui , Zongjie Hu , Jiayu Huang , Xiaoju Li , Ruihu Wang . MXene-based materials for separator modification of lithium-sulfur batteries. Chinese Journal of Structural Chemistry, 2024, 43(7): 100337-100337. doi: 10.1016/j.cjsc.2024.100337
11. [11]
  Minjun Yin , Yuhui Lin , Manli Zhuang , Wei Xiao , Jie Wu . Photoredox-catalyzed synthesis of α,α-difluoromethyl-β-alkoxysulfones from sulfur dioxide. Chinese Chemical Letters, 2025, 36(3): 109926-. doi: 10.1016/j.cclet.2024.109926
12. [12]
  Jiayi Guo , Liangxiong Ling , Qinwei Lu , Yi Zhou , Xubiao Luo , Yanbo Zhou . Degradation of chloroxylenol by CoS_x activated peroxomonosulfate: Role of cobalt-sulfur ratio. Chinese Chemical Letters, 2025, 36(4): 110380-. doi: 10.1016/j.cclet.2024.110380
13. [13]
  Yan Wang , Huixin Chen , Fuda Yu , Shanyue Wei , Jinhui Song , Qianfeng He , Yiming Xie , Miaoliang Huang , Canzhong Lu . Oxygen self-doping pyrolyzed polyacrylic acid as sulfur host with physical/chemical adsorption dual function for lithium-sulfur batteries. Chinese Chemical Letters, 2024, 35(7): 109001-. doi: 10.1016/j.cclet.2023.109001
14. [14]
  Wujun Jian , Mong-Feng Chiou , Yajun Li , Hongli Bao , Song Yang . Cu-catalyzed regioselective diborylation of 1,3-enynes for the efficient synthesis of 1,4-diborylated allenes. Chinese Chemical Letters, 2024, 35(5): 108980-. doi: 10.1016/j.cclet.2023.108980
15. [15]
  Chunhua Ma , Mengjiao Liu , Siyu Ouyang , Zhenwei Cui , Jingjing Bi , Yuqin Jiang , Zhiguo Zhang . Metal-free construction of diverse 1,2,4-triazolo[1,5-a]pyridines on water. Chinese Chemical Letters, 2025, 36(1): 109755-. doi: 10.1016/j.cclet.2024.109755
16. [16]
  Liangji Chen , Zhen Yuan , Fudong Feng , Xin Zhou , Zhile Xiong , Wuji Wei , Hao Zhang , Banglin Chen , Shengchang Xiang , Zhangjing Zhang . A hydrogen-bonded organic framework containing fluorescent carbazole and responsive pyridyl units for sensing organic acids. Chinese Chemical Letters, 2024, 35(9): 109344-. doi: 10.1016/j.cclet.2023.109344
17. [17]
  Guoping Yang , Zhoufu Lin , Xize Zhang , Jiawei Cao , Xuejiao Chen , Yufeng Liu , Xiaoling Lin , Ke Li . Assembly of Y(Ⅲ)-containing antimonotungstates induced by malic acid with catalytic activity for the synthesis of imidazoles. Chinese Chemical Letters, 2024, 35(12): 110274-. doi: 10.1016/j.cclet.2024.110274
18. [18]
  Liangfeng Yang , Liang Zeng , Yanping Zhu , Qiuan Wang , Jinheng Li . Copper-catalyzed photoredox 1,4-amidocyanation of 1,3-enynes with N-amidopyridin-1-ium salts and TMSCN: Facile access to α-amido allenyl nitriles. Chinese Chemical Letters, 2024, 35(11): 109685-. doi: 10.1016/j.cclet.2024.109685
19. [19]
  . 第41卷第1期封面和目次. Acta Physico-Chimica Sinica, 2025, 41(1): -.
20. [20]
  Huiju Cao , Lei Shi . sp¹-Hybridized linear and cyclic carbon chain. Chinese Chemical Letters, 2025, 36(4): 110466-. doi: 10.1016/j.cclet.2024.110466

Get Citation

PDF

XML

Metrics

PDF Downloads(7)
Abstract views(698)
HTML views(11)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142