Original articles
Kaijun Jin, Minjie Liu, Chunlin Zhuang, Erik De Clercq, Christophe Pannecouque, Ge Meng, Fener Chen. Improving the positional adaptability: structurebased design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 344-357

Improving the positional adaptability: structurebased design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors
Kaijun Jina,b, Minjie Liua,b, Chunlin Zhuanga,b, Erik De Clercqc, Christophe Pannecouquec, Ge Menga,b, Fener Chena,b
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 Rega Institute for Medical Research, KU Leuven, Leuven B-3000, Belgium
Abstract:
In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structureeactivity relationship and PK profiles were also discussed.
Key words:    HIV-1    NNRTIs    NP-DATAs    BP-DATAs    Positional adaptability    Molecular modeling   
Received: 2019-02-08     Revised: 2019-07-08
DOI: 10.1016/j.apsb.2019.09.007
Funds: This research work was financially supported by National Natural Science Foundation of China under Grant Nos. 21871055 and 21372050 as well as Shanghai Municipal Natural Science Foundation under Grant No. 13ZR1402200 (China). We would like to thank the technical assistance of Mr. Kris Uyttersprot, Mrs. Kristien Erven, and Mrs. Cindy Heens from the RegaInstititute of Leuven University for the HIVexperiments and HIV RT polymerase assays.
Corresponding author: Ge Meng, Fener Chen     Email:mgfudan@fudan.edu.cn;rfchen@fudan.edu.cn
Author description:
Service
PDF(KB) Free
Print
0
Authors
Kaijun Jin
Minjie Liu
Chunlin Zhuang
Erik De Clercq
Christophe Pannecouque
Ge Meng
Fener Chen

References:
1. de Clercq E. New anti-HIV agents and targets. Med Res Rev 2002;22:531-65.
2. Zhang X. Anti-retroviral drugs:current state and development in the next decade. Acta Pharm Sin B 2018;8:131-6.
3. Song Y, Fang Z, Zhan P, Liu X. Recent advances in the discovery and development of novel HIV-1 NNRTI platforms (Part II):2009-2013 update. Curr Med Chem 2013;21:329-55.
4. de Béthune M. 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 2010;85:75-90.
5. Bec G, Meyer B, Gerard MA, Steger J, Fauster K, Wolff P, et al. Thermodynamics of HIV-1 reverse transcriptase in action elucidates the mechanism of action of non-nucleoside inhibitors. J Am Chem Soc 2013;135:9743-52.
6. Rawal RK, Murugesan V, Katti SB. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs. Curr Med Chem 2012; 19:5364-80.
7. Wang J, Morin P, Wang W, Kollman PA. Use of MM-PBSA in reproducing the binding free energies to HIV-1 RTof TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA. J Am Chem Soc 2001;123:5221-30.
8. Tantillo C, Ding J, Jacobo-Molina A, Nanni RG, Boyer PL, Hughes SH, et al. Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. J Mol Biol 1994;243:369-87.
9. Dodda LS, Tirado-Rives J, Jorgensen WL. Unbinding dynamics of non-nucleoside inhibitors from HIV-1 reverse transcriptase. J Phys Chem B 2019;123:1741-8.
10. Ekkati AR, Bollini M, Domaoal RA, Spasov KA, Anderson KS, Jorgensen WL. Discovery of dimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 2012;22:1565-8.
11. Bollini M, Frey KM, Cisneros JA, Spasov KA, Das K, Bauman JD, et al. Extension into the entrance channel of HIV-1 reverse transcriptasedcrystallography and enhanced solubility. Bioorg Med Chem Lett 2013;23:5209-12.
12. Meng G, Chen F, de Clercq E, Balzarini J, Pannecouque C. Nonnucleoside HIV-1 reverse transcriptase inhibitors:part i. synthesis and structureeactivity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogues. Chem Pharm Bull 2003; 51:779-89.
13. Das K, Clark Jr AD, Lewi PJ, Heeres J, de Jonge MR, Koymans LM, et al. Roles of conformational and positional adaptability in structurebased design of TMC125-R165335(etravirine) and related nonnucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 2004;47:2550-60.
14. Das K, Bauman JD, Rim AS, Dharia C, Clark Jr AD, Camarasa MJ, et al. Crystal structure of tert-butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket. J Med Chem 2011;54:2727-37.
15. Paris KA, Haq O, Felts AK, Das K, Arnold E, Levy RM. Conformational landscape of the human immunodeficiency virus type 1 reverse transcriptase non-nucleoside inhibitor binding pocket:lessons for inhibitor design from a cluster analysis of many crystal structures. J Med Chem 2009;52:6413-20.
16. Ariën KK, Venkatraj M, Michiels J, Joossens J, Vereecken K, Van der Veken P, et al. Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission. J Antimicrob Chemother 2013; 68:2038-47.
17. Chen X, Zhan P, Li D, de Clercq E, Liu X. Recent advances in dapys and related analogues as HIV-1 NNRTIs. Curr Med Chem 2011;18:359-76.
18. Zhan P, Chen X, Li D, Fang Z, de Clercq E, Liu X. HIV-1 NNRTIs:structural diversity, pharmacophore similarity, and impliations for drug design. Med Res Rev 2013;33:E1-72.
19. Janssen PA, Lewi PJ, Arnold E, Daeyaert F, de Jonge M, Heeres J, et al. In search of a novel anti-HIV drug:multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 2005;48:1901-9.
20. Ludovici DW, Kavash RW, Kukla MJ, Ho CY, Ye H, de Corte BL, et al. Evolution of anti-HIV drug candidates. Part 2:diaryltriazine (DATA) analogues. Bioorg Med Chem Lett 2001;11:2229-34.
21. Lansdon EB, Brendza KM, Hung M, Wang R, Mukund S, Jin D, et al. Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278):implications for drug design. J Med Chem 2010;53:4295-9.
22. Wainberg MA, Zaharatos GJ, Brenner BG. Development of antiretroviral drug resistance. N Engl J Med 2011;365:637-46.
23. Lai MT, Feng M, Falgueyret JP, Tawa P, Witmer M, DiStefano D, et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother 2014;58:1652-63.
24. Xiong Y, Chen F, Balzarini J, de Clercq E, Pannecouque C. Nonnucleoside HIV-1 reverse transcriptase inhibitors. Part 11:structural modulations of diaryltriazines with potent anti-HIV activity. Eur J Med Chem 2008;43:1230-6.
25. Xiong Y, Chen F, Balzarini J, de Clercq E, Pannecouque C. Nonnucleoside HIV-1 reverse transcriptase inhibitors. Part 13:synthesis of fluorine-containing diaryltriazine derivatives for in vitro anti-HIV evaluation against wild-type strain. Chem Biodivers 2009;6:561-8.
26. Li Z, Han J, Chen H. Revealing interaction mode between HIV-1 reverse transcriptase and diaryltriazine analog inhibitor. Chem Biol Drug Des 2008;72:350-9.
27. Jin K, Yin H, de Clercq E, Pannecouque C, Meng G, Chen F. Discovery of biphenyl-substituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1. Eur J Med Chem 2018;145:726-34.
28. Sang Y, Han S, Pannecouque C, de Clercq E, Zhuang C, Chen F. Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors. Eur J Med Chem 2019;182:111603.
29. Sang Y, Han S, Han S, Pannecouque C, de Clercq E, Zhuang C, et al. Follow on-based optimization of the biphenyl-DAPYs as HIV-1 nonnucleoside reverse transcriptase inhibitors against the wild-type and mutant strains. Bioorg Chem 2019;89:102974.
30. Gu S, Xiao T, Zhu Y, Liu G, Chen F. Recent progress in HIV-1 inhibitors targeting the entrance channel of HIV-1 non-nucleoside reverse transcriptase inhibitor binding pocket. Eur J Med Chem 2019; 174:277-91.
31. Du Z, Zhou W, Wang F, Wang J. In situ generation of palladium nanoparticles:ligand-free palladium catalyzed ultrafast SuzukieMiyaura cross-coupling reaction in aqueous phase at room temperature. Tetrahedron 2011;67:4914-8.
32. Lu D, Chambers P, Wipf P, Xie X, Englert D, Weber S. Lipophilicity screening of novel drug-like compounds and comparison to clogP. J Chromatogr A 2012;1258:161-7.
33. Namasivayam V, Vanangamudi M, Kramer VG, Kurup S, Zhan P, Liu X, et al. The journey of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) from lab to clinic. J Med Chem 2019;62:4851-83.
34. Liu X, Wright M, Hop CE. Rational use of plasma protein and tissue binding data in drug design. J Med Chem 2014;57:8238-48.
35. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS:high performance molecular simulations through multilevel parallelism from laptops to supercomputers. Software 2015;1-2:19-25.