Similar pyridinone compounds with different activities of anti-HIV-1 reverse transcriptase

doi:10.5246/jcps.2018.07.048

Journal of Chinese Pharmaceutical Sciences ›› 2018, Vol. 27 ›› Issue (7): 469-477.DOI: 10.5246/jcps.2018.07.048

• Original articles • Previous Articles Next Articles

Similar pyridinone compounds with different activities of anti-HIV-1 reverse transcriptase

Yunqi Liu, Xixi Li, Xiaodong Dou, Chao Tian, Zhili Zhang, Junyi Liu^*, Xiaowei Wang^*

Department of Chemical Biology, School of Pharmaceutical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China

Received:2018-04-22 Revised:2018-05-18 Online:2018-07-25 Published:2018-05-30
Contact: Tel.: +86-010-82805203, E-mail: xiaoweiwang@bjmu.edu.cn
Supported by:
The National Natural Science Foundation of China (Grant No. 21172014, 20972011 and 21042009).

Abstract

Abstract:

Among the structurally diverse NNRTIs, pyridinone scaffolds demonstrate high potency against HIV-1 wild type and drug-resistant strains. During the optimization of our pyridinone compound 1 (LAM-trans),we found that the introduction of the N atoms in the C-4 position could dramatically improve the water solubility (7b), whereas protonation of the piperidine N atom resulted in a decrease in its hydrophobic interaction with the binding pocket. In particular, protonation altered the orientation of the alicyclic rings in the hydrophobic pocket, thus impeding the formation of key halogen bond and eventually leading to a huge change in anti-HIV-1 RT activity. These results provided theoretical and experimental basis for the subsequent structural modification of pyridinone compounds.

Key words: Pyridinone derivatives, HIV-1 Reverse transcriptase, Halogen bond, Molecular docking study

CLC Number:

R916

Supporting:

Yunqi Liu, Xixi Li, Xiaodong Dou, Chao Tian, Zhili Zhang, Junyi Liu, Xiaowei Wang. Similar pyridinone compounds with different activities of anti-HIV-1 reverse transcriptase[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(7): 469-477.

References

[1] Cohen, M.S.; Chen, Y.Q.; McCauley, M.; Gamble, T.; Hosseinipour, M.C.; Kumarasamy, N.; Hakim, J.G.; Kumwenda, J.; Grinsztejn, B.; Pilotto, J. H.; Godbole, S.V.; Mehendale, S.; Chariyalertsak, S.; Santos, B.R.; Mayer, K.H.; Hoffman, I.F.; Eshleman, S.H.; Piwowar-Manning, E.; Wang, L.; Makhema, J.; Mills, L.A.; De Bruyn, G.; Sanne, I.; Eron, J.; Gallant, J.; Havlir, D.; Swindells, S.; Ribaudo, H.; Elharrar, V.; Burns, D.; Taha, T.E.; Nielsen-Saines, K.; Celentano, D.; Essex, M.; Fleming, T.R. Prevention of HIV-1 infection with early antiretroviral therapy. N. Engl. J. Med. 2011, 365, 493−505.

[2] De Clercq, E. The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res. 1998, 38, 153-179.

[3] De Bethune, M.P. 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). Antiviral Res. 2010, 85, 75-90.

[4] Zhan, P.; Pannecouque, C.; De Clercq, E.; Liu, X.Y. Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends. J. Med. Chem., 2016, 59, 2849-2878.

[5] Menendez-Arias, L. Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases. Prog. Nucleic Acid Res. Mol. Biol. 2002, 71, 91-147.

[6] Ren, J.; Stammers, D.K. Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Res. 2008, 134, 157-170.

[7] Benjahad, A.; Croisy, M.; Monneret, C.; Bisagni, E.; Mabire, D.; Coupa, S.; Poncelet, A.; Csoka, I.; Guillemont, J.; Meyer, C.; Andries, K.; Pauwels, R.; De Bethune, M.P.; Himmel, D.M.; Das, K.; Arnold, E.; Nguyen, C.H.; Grierson, D.S. 4-benzyl and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones: In vitro evaluation of new c-3-amino-substituted and c-5,6-alkyl-substituted analogues against clinically important HIV mutant strains. J. Med. Chem. 2005, 48, 1948-1964.

[8] Vite-Caritin, V.; Mendez-Lucio, O.; Reyes, H.; Cabrera, A.; Chavez, D.; Medina-Franco, J.L. Advances in the development of pyridinone derivatives as non-nucleoside reverse transcriptase inhibitors. RSC Adv. 2016, 6, 2119-2130.

[9] Li, A.M.; Ouyang, Y.B.; Wang, Z.Y.; Cao, Y.Y.; Liu, X.Y.; Ran, L.; Li, C.; Li, L.; Zhang, L.; Qiao, K.; Xu, W.S.; Huang, Y.; Zhang, Z.L.; Tian, C.; Liu, Z.M.; Jiang, S.B.; Shao, Y.M.; Du, Y.S.; Ma, L.Y.; Wang, X.W.; Liu, J.Y. Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains. J. Med. Chem. 2013, 56, 2593-2608.

[10] Wu, S.T.; Yin, Q.Q.; Zhao, L.; Fan, N.N.; Tang, X.W.; Zhao, J.X.; Sheng, T.; Guo, Y.; Tian, C.; Zhang, Z.L.; Xu, W.S.; Liu, Z.M.; Jiang, S.B.; Ma, L.Y.; Liu, J.Y.; Wang, X.W. A stereo configuration-activity study of 3-iodo-4-(2-methylcycl ohexyloxy)-6-phenethylpyridin-2(2H)-ones as potency inhibitors of HIV-1 variants. Org. Biomol. Chem. 2016, 14, 1413-1420.

[11] Zhan, P.; Chen, X.W.; Li, D.Y.; Fang, Z.J.; De Clercq, E.; Liu, X.Y. HIV-1 NNRTIs: structural diversity, pharmacophore similarity, and implications for drug design. Med. Res. Rev. 2013, 33, E1-E72.

[12] Cao, Y.Y.; Zhang, Y.; Wu, S.T.; Yang, Q.Z.; Sun, X.; Zhao, J.X.; Pei, F.; Guo, Y.; Tian, C.; Zhang, Z.L.; Wang, H.N.; Ma, L.Y.; Liu, J.Y.; Wang, X.W. Synthesis and biological evaluation of pyridinone analogues as novel potent HIV-1 NNRTIs. Bioorg. Med. Chem. 2015, 23, 149-159.

[13] Qin, H.; Liu, C.; Guo, Y.; Wang, R. P.; Zhang, J.F.; Ma, L.Y.; Zhang, Z.L.; Wang, X.W.; Cui, Y.X.; Liu, J.Y. Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. 2010, 18, 3231-3237.

[14] Malla, P.; Kumar, R.; Kumar, M. Validation of Formylchromane Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors by Pharmacophore Modeling, Atom-Based 3D-QSAR and Docking Studies. Chem. Biol. Drug Des. 2013, 82, 71-80.
[15] Gross, G.; Tardio, J.; Kuhlmann, O. Solubility and stability of dalcetrapib in vehicles and biological media. Int. J. Pharm. 2012, 437, 103-109.

Similar pyridinone compounds with different activities of anti-HIV-1 reverse transcriptase

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 6

Recommended Articles

Metrics

Comments

[1]	Xixi Li, Qian Liu, Tao Sheng, Junyi Liu, Xiaowei Wang. Pyridin-2(1H)-ones as HIV-1 NNRTIs: a combinatorial optimization strategy [J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(2): 79-89.
[2]	Ningning Fan, Zhenming Liu, Xiaowei Wang, Junyi Liu. Docking and field-based QSAR studies of S-DABOs as HIV-1 reverse transcriptase inhibitors [J]. Journal of Chinese Pharmaceutical Sciences, 2017, 26(7): 512-520.
[3]	Quanzhi Yang, Tao Sheng, Ningning Fan, Yameng Hao, Yuanyuan Cao, Ying Guo, Zhili Zhang, Chao Tian, Junyi Liu, Xiaowei Wang. Design, synthesis and activity evaluation of novel pyridinone derivatives as anti-HIV-1 dual (RT/IN) inhibitors [J]. Journal of Chinese Pharmaceutical Sciences, 2017, 26(1): 31-44.
[4]	Han Yan, Xiao-Wei Wang^, Ying Guo, Zhi-Li Zhang, Jun-Yi Liu^ . Synthesis and anti-HIV-1 activity evaluation of N-1-alkyl-5-halogeno-6-alkylamino uracils as novel non-nucleoside HIV-1 reverse transcriptase inhibitors [J]. , 2011, 20(2): 146-153.
[5]	Wei Wang, Li Li, Chang Liu, Liang Zhang, Han Yan, Zhi-Li Zhang, Xiao-Wei Wang, Jun-Yi Liu^*. Synthesis and biological evaluation of novel 1-aryl-5-iodo-6-benzyluracils as potent HIV-1 non-nucleoside reverse transcriptase inhibitors [J]. , 2010, 19(4): 312-317.
[6]	Xiao-Yan Ma, Zhi-Jian Cheng, Yan-Li Chen, A-Min Li, Zhi-Li Zhang, Xiao-Wei Wang, Jun-Yi Liu^* . A convenient synthesis of 1-alkyl-5-amino-6-phenylethyluracils as potential non-nucleoside HIV-1RT inhibitors [J]. , 2008, 17(4): 281-284.