Citation: Da Feng, Fenju Wei, Yanying Sun, Prem Prakash Sharma, Tao Zhang, Hao Lin, Brijesh Rathi, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan, Xinyong Liu. Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation[J]. Chinese Chemical Letters, ;2021, 32(12): 4053-4057. doi: 10.1016/j.cclet.2021.02.033 shu

Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation

Da Feng ^a ,
Fenju Wei ^a ,
Yanying Sun ^a ,
Prem Prakash Sharma ^b ,
Tao Zhang ^a ,
Hao Lin ^a ,
Brijesh Rathi ^b ,
Erik De Clercq ^c ,
Christophe Pannecouque ^c ,
Dongwei Kang ^{a, e, *,} ,
Peng Zhan ^{a, d, *,} ,
Xinyong Liu ^{a, d, *,}

a.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China
b.
Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India
c.
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven B-3000, Belgium
d.
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Ji'nan 250012, China
e.
Suzhou Research Institute, Shandong University, Suzhou 215123, China

kangdongwei@126.com

zhanpeng1982@sdu.edu.cn

xinyongl@sdu.edu.cn

Received Date: 29 January 2021
Revised Date: 5 February 2021
Accepted Date: 17 February 2021
Available Online: 19 February 2021

Figures(5)

Drug resistance remains to be a serious problem with type I human immunodeficiency virus (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of novel boronic acid-containing diarylpyrimidine (DAPY) derivatives were designed via bioisosterism and scaffold-hopping strategies, taking advantage of the ability of a boronic acid group to form multiple hydrogen bonds. The target compounds were synthesized and evaluated for their anti-HIV activities and cytotoxicity in MT-4 cells. Compound 10j yielded the most potent activity and turned out to be a single-digit nanomolar inhibitor towards the HIV-1 IIIB [wild-type (WT) strain], L100I and K103N strains, with 50% effective concentration (EC₅₀) values of 7.19–9.85 nmol/L. Moreover, 10j inhibited the double-mutant strain RES056 with an EC₅₀ value of 77.9 nmol/L, which was 3.3-more potent than that of EFV (EC₅₀ = 260 nmol/L) and comparable to that of ETR (EC₅₀ = 32.2 nmol/L). 10j acted like classical NNRTIs with high affinity for WT HIV-1 reverse transcriptase (RT) with 50% inhibition concentration (IC₅₀) value of 0.1837 μmol/L. Furthermore, molecular dynamics simulation indicated that 10j was proposed as a promising molecule for fighting against HIV-1 infection through inhibiting RT activity. Overall, the results demonstrated that 10j could serve as a lead molecule for further modification to address virus-drug resistance.
- HIV-1,
- NNRTIs,
- NNIBP,
- DAPY,
- Boronic acid,
- Molecular dynamics simulation
1. [1]
  P. Zhan, C. Pannecouque, E. De Clercq, X. Liu, J. Med. Chem. 59 (2016) 2849-2878. doi: 10.1021/acs.jmedchem.5b00497
2. [2]
  M. Katane, S. Yamada, G. Kawaguchi, et al., J. Med. Chem. 58 (2015) 7328-7340. doi: 10.1021/acs.jmedchem.5b00871
3. [3]
  D. Kang, T. Zhao, Z. Wang, et al., Commun. Chem. 2 (2019) 74. doi: 10.1038/s42004-019-0174-8
4. [4]
  G. Bec, B. Meyer, M.A. Gerard, et al., J. Am. Chem. Soc. 135 (2013) 9743-9752. doi: 10.1021/ja4018418
5. [5]
  B. Huang, W. Chen, T. Zhao, et al., J. Med. Chem. 62 (2019) 2083-2098. doi: 10.1021/acs.jmedchem.8b01729
6. [6]
  D. Kang, D. Feng, T. Ginex, et al., Acta Pharm. Sin. B 10 (2020) 878-894. doi: 10.1016/j.apsb.2019.08.013
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]
  D. Feng, X. Zuo, L Jing, et al., Eur. J. Med. Chem. 211 (2021) 113063. doi: 10.1016/j.ejmech.2020.113063
9. [9]
  D. Kang, X. Ding, G. Wu, et al., ACS Med. Chem. Lett. 8 (2017) 1188-1193. doi: 10.1021/acsmedchemlett.7b00361
10. [10]
  D. Kang, Z. Fang, B. Huang, et al., J. Med. Chem. 60 (2017) 4424-4443. doi: 10.1021/acs.jmedchem.7b00332
11. [11]
  D. Kang, Z. Fang, Z. Li, et al., J. Med. Chem. 59 (2016) 7991-8007. doi: 10.1021/acs.jmedchem.6b00738
12. [12]
  D. Kang, F.X. Ruiz, D. Feng, et al., J. Med. Chem. 63 (2020) 1298-1312. doi: 10.1021/acs.jmedchem.9b01769
13. [13]
  D. Kang, H. Zhang, Z. Wang, et al., J. Med. Chem. 62 (2019) 1484-1501. doi: 10.1021/acs.jmedchem.8b01656
14. [14]
  P. Zhan, X. Chen, D. Li, et al., Med. Res. Rev. 33 Suppl 1 (2013) E1-E72. doi: 10.1002/med.20241
15. [15]
  Y. Yang, D. Kang, L.A. Nguyen, et al., Elife. 7 (2018) e36340.
16. [16]
  I.W. Windsor, M.J. Palte, J.C. Lukesh, 3rd, et al., J. Am. Chem. Soc. 140 (2018) 14015-14018. doi: 10.1021/jacs.8b07366
17. [17]
  P. C. Trippier, C. McGuigan, Med. Chem. Commun. 1 (2010) 183-198. doi: 10.1039/c0md00119h
18. [18]
  J. Plescia, N. Moitessier, Eur. J. Med. Chem. 195 (2020) 112270. doi: 10.1016/j.ejmech.2020.112270
19. [19]
  P.Y. Chong, J.B. Shotwell, J. Miller, et al., J. Med. Chem. 62 (2019) 3254-3267. doi: 10.1021/acs.jmedchem.8b01719
20. [20]
  P. Zhan, D. Kang, X. Liu, J. Med. Chem. 62 (2019) 3251-3253. doi: 10.1021/acs.jmedchem.9b00415
21. [21]
  J. Du, J. Guo, D. Kang, et al., Chin. Chem. Lett. 31 (2020) 1695-1708. doi: 10.1016/j.cclet.2020.03.028
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]
  Congying Lu , Fei Zhong , Zhenyu Yuan , Shuaibing Li , Jiayao Li , Jiewen Liu , Xianyang Hu , Liqun Sun , Rui Li , Meijuan Hu . Experimental Improvement of Surfactant Interface Chemistry: An Integrated Design for the Fusion of Experiment and Simulation. University Chemistry, 2024, 39(3): 283-293. doi: 10.3866/PKU.DXHX202308097
3. [3]
  Shiyu Hou , Maolin Sun , Liming Cao , Chaoming Liang , Jiaxin Yang , Xinggui Zhou , Jinxing Ye , Ruihua Cheng . Computational fluid dynamics simulation and experimental study on mixing performance of a three-dimensional circular cyclone-type microreactor. Chinese Chemical Letters, 2024, 35(4): 108761-. doi: 10.1016/j.cclet.2023.108761
4. [4]
  Haitao Yin , Liang Meng , Li Li , Jiamu Xiao , Longrui Liang , Nannan Huang , Yansong Shi , Angang Zhao , Jingwen Hou . Polydopamine-modified biochar supported polylactic acid and zero-valent iron affects the functional microbial community structure for 1,1,1-trichloroethane removal in simulated groundwater. Chinese Chemical Letters, 2025, 36(1): 110313-. doi: 10.1016/j.cclet.2024.110313
5. [5]
  Keke Han , Wenjun Rao , Xiuli You , Haina Zhang , Xing Ye , Zhenhong Wei , Hu Cai . Two new high-temperature molecular ferroelectrics [1,5-3.2.2-Hdabcni]X (X = ClO₄⁻, ReO₄⁻). Chinese Chemical Letters, 2024, 35(6): 108809-. doi: 10.1016/j.cclet.2023.108809
6. [6]
  Runze Liu , Yankai Bian , Weili Dai . Qualitative and quantitative analysis of Brønsted and Lewis acid sites in zeolites: A combined probe-assisted 1H MAS NMR and NH3-TPD investigation. Chinese Journal of Structural Chemistry, 2024, 43(4): 100250-100250. doi: 10.1016/j.cjsc.2024.100250
7. [7]
  Huimin Gao , Zhuochen Yu , Xuze Zhang , Xiangkun Yu , Jiyuan Xing , Youliang Zhu , Hu-Jun Qian , Zhong-Yuan Lu . A mini review of the recent progress in coarse-grained simulation of polymer systems. Chinese Journal of Structural Chemistry, 2024, 43(5): 100266-100266. doi: 10.1016/j.cjsc.2024.100266
8. [8]
  Chenghao Ge , Peng Wang , Pei Yuan , Tai Wu , Rongjun Zhao , Rong Huang , Lin Xie , Yong Hua . Tuning hot carrier transfer dynamics by perovskite surface modification. Chinese Chemical Letters, 2024, 35(10): 109352-. doi: 10.1016/j.cclet.2023.109352
9. [9]
  Fang-Yuan Chen , Wen-Chao Geng , Kang Cai , Dong-Sheng Guo . Molecular recognition of cyclophanes in water. Chinese Chemical Letters, 2024, 35(5): 109161-. doi: 10.1016/j.cclet.2023.109161
10. [10]
  Rongjun Zhao , Tai Wu , Yong Hua , Yude Wang . Improving performance of perovskite solar cells enabled by defects passivation and carrier transport dynamics regulation via organic additive. Chinese Chemical Letters, 2025, 36(2): 109587-. doi: 10.1016/j.cclet.2024.109587
11. [11]
  Wenyi Mei , Lijuan Xie , Xiaodong Zhang , Cunjian Shi , Fengzhi Wang , Qiqi Fu , Zhenjiang Zhao , Honglin Li , Yufang Xu , Zhuo Chen . Design, synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells. Chinese Chemical Letters, 2024, 35(5): 108825-. doi: 10.1016/j.cclet.2023.108825
12. [12]
  Huipeng Zhao , Xiaoqiang Du . Polyoxometalates as the redox anolyte for efficient conversion of biomass to formic acid. Chinese Journal of Structural Chemistry, 2024, 43(2): 100246-100246. doi: 10.1016/j.cjsc.2024.100246
13. [13]
  Dan-Ying Xing , Xiao-Dan Zhao , Chuan-Shu He , Bo Lai . Kinetic study and DFT calculation on the tetracycline abatement by peracetic acid. Chinese Chemical Letters, 2024, 35(9): 109436-. doi: 10.1016/j.cclet.2023.109436
14. [14]
  Lihang Wang , Mary Li Javier , Chunshan Luo , Tingsheng Lu , Shudan Yao , Bing Qiu , Yun Wang , Yunfeng Lin . Research advances of tetrahedral framework nucleic acid-based systems in biomedicine. Chinese Chemical Letters, 2024, 35(11): 109591-. doi: 10.1016/j.cclet.2024.109591
15. [15]
  Caihong Mao , Yanfeng He , Xiaohan Wang , Yan Cai , Xiaobo Hu . Synthesis and molecular recognition characteristics of a tetrapodal benzene cage. Chinese Chemical Letters, 2024, 35(8): 109362-. doi: 10.1016/j.cclet.2023.109362
16. [16]
  Cheng-Da Zhao , Huan Yao , Shi-Yao Li , Fangfang Du , Li-Li Wang , Liu-Pan Yang . Amide naphthotubes: Biomimetic macrocycles for selective molecular recognition. Chinese Chemical Letters, 2024, 35(4): 108879-. doi: 10.1016/j.cclet.2023.108879
17. [17]
  Mengjia Luo , Yi Qiu , Zhengyang Zhou . Exploring temperature-driven phase dynamics of phosphate: The periodic to incommensurately modulated long-range ordered phase transition in CsCdPO4. Chinese Journal of Structural Chemistry, 2025, 44(1): 100446-100446. doi: 10.1016/j.cjsc.2024.100446
18. [18]
  Hanqing Zhang , Xiaoxia Wang , Chen Chen , Xianfeng Yang , Chungli Dong , Yucheng Huang , Xiaoliang Zhao , Dongjiang Yang . Selective CO2-to-formic acid electrochemical conversion by modulating electronic environment of copper phthalocyanine with defective graphene. Chinese Journal of Structural Chemistry, 2023, 42(10): 100089-100089. doi: 10.1016/j.cjsc.2023.100089
19. [19]
  Linshan Peng , Qihang Peng , Tianxiang Jin , Zhirong Liu , Yong Qian . Highly efficient capture of thorium ion by citric acid-modified chitosan gels from aqueous solution. Chinese Chemical Letters, 2024, 35(5): 108891-. doi: 10.1016/j.cclet.2023.108891
20. [20]
  Yingying Yan , Wanhe Jia , Rui Cai , Chun Liu . An AIPE-active fluorinated cationic Pt(Ⅱ) complex for efficient detection of picric acid in aqueous media. Chinese Chemical Letters, 2024, 35(5): 108819-. doi: 10.1016/j.cclet.2023.108819

Get Citation

PDF

XML

Metrics

PDF Downloads(5)
Abstract views(566)
HTML views(65)

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