Login Register Cart 0
Generic placeholder image

Current Organic Chemistry

Editor-in-Chief

ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Advances in the Synthesis of Diarylpyrimidine as Potent Non-nucleoside Reverse Transcriptase Inhibitors: Biological Activities, Molecular Docking Studies and Structure-activity Relationship: A Critical Review

Author(s): Mustapha Suleiman, Aso Hameed Hasan, Sankaranarayanan Murugesan, Syazwani Itri Amran and Joazaizulfazli Jamalis*

Volume 27, Issue 8, 2023

Published on: 01 August, 2023

Page: [661 - 691] Pages: 31

DOI: 10.2174/1385272827666230711173329

Price: $65

Abstract

Acquired immunodeficiency syndrome (AIDS) is an ailment that is caused primarily by the Human immunodeficiency virus (HIV), which is the main agent responsible for this deadly disease. Of all the different inhibitors employed to curtail the menace caused by this deadly virus, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been cutting edge in the fight against AIDS. Over the past few years, the diaryl pyrimidine family and its derivatives have shown promising NNRTI properties attributed to their characteristic flexibility, targeting of conserved residues of reverse transcriptase, positional adaptability and, importantly, the formation of hydrogen bonds, which altogether led to the generation of secondgeneration NNRTIs. This breakthrough in the DAPY derivatives led to the development of TMC278 (rilpivirine) and TMC125 (etravirine), the two most recently approved NNRTIs by the FDA because of their low cytotoxicity, superior activities against mutant strains and WT HIV-1, excellent potency and high specificity. However, new challenges loom on the DAPY derivatives: the disappointing pharmacokinetic properties and accelerated emergence of resistance (particularly, K1013N and Y181C mutations, which are the two most important HIV-1 mutations that persist in most of the FDA-approved regimens), which implores further research to develop novel HIV-1 NNRTIs. In this review, we detail the reported different synthetic pathways for diaryl pyrimidine modification from published articles from 2010 to 2022, their biological activities, in addition to molecular docking studies and structure-activity relationships to uncover the possible molecular contributions that improved or reduced the NNRTIs properties. In a nutshell, the research findings provide valuable insights into the various modifications of the DAPY derivatives to develop novel NNRTIs.

« Previous Next »
Graphical Abstract

[1]
Giami, A.; Janssen, E. Abstracts for the 24th Congress of the World Association for Sexual Health (WAS). Int. J. Sex. Health, 2019, 31(sup1), 1-627.
[http://dx.doi.org/10.1080/19317611.2019.1661941]
[2]
Lederman, MM AIDS in the heartland-hemophilia was the harbinger of things to come. 2021.
[http://dx.doi.org/10.1097/QAI.0000000000002602]
[3]
Zhuang, C.; Pannecouque, C.; De Clercq, E.; Chen, F. Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): Our past twenty years. Acta Pharm. Sin. B, 2020, 10(6), 961-978.
[http://dx.doi.org/10.1016/j.apsb.2019.11.010] [PMID: 32642405]
[4]
Jin, K.; Sang, Y.; De Clercq, E.; Pannecouque, C.; Meng, G. Design and synthesis of a novel series of non-nucleoside HIV-1 inhibitors bearing pyrimidine and N-substituted aromatic piperazine. Bioorg. Med. Chem. Lett., 2018, 28(22), 3491-3495.
[http://dx.doi.org/10.1016/j.bmcl.2018.10.010] [PMID: 30318436]
[5]
Huang, B.; Li, X.; Zhan, P.; De Clercq, E.; Daelemans, D.; Pannecouque, C.; Liu, X. Design, synthesis, and biological evaluation of novel 2‐(pyridin‐3‐yloxy)acetamide derivatives as potential Anti‐HIV‐1 agents. Chem. Biol. Drug Des., 2016, 87(2), 283-289.
[http://dx.doi.org/10.1111/cbdd.12657] [PMID: 26347922]
[6]
Jin, X.; Piao, H.R.; Pannecouque, C.; De Clercq, E.; Zhuang, C.; Chen, F.E. Design of the naphthyl-diarylpyrimidines as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) via structure-based extension into the entrance channel. Eur. J. Med. Chem., 2021, 226, 113868.
[http://dx.doi.org/10.1016/j.ejmech.2021.113868] [PMID: 34583311]
[7]
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, 726-734.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.016] [PMID: 29353724]
[8]
Chidambaram, S.K.; Ali, D.; Alarifi, S.; Radhakrishnan, S.; Akbar, I. In silico molecular docking: Evaluation of coumarin based derivatives against SARS-CoV-2. J. Infect. Public Health, 2020, 13(11), 1671-1677.
[http://dx.doi.org/10.1016/j.jiph.2020.09.002] [PMID: 33008777]
[9]
Smith, S.J.; Pauly, G.T.; Hewlett, K.; Schneider, J.P.; Hughes, S.H. Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants. Chem. Biol. Drug Des., 2021, 97(1), 4-17.
[http://dx.doi.org/10.1111/cbdd.13766] [PMID: 32743937]
[10]
Chander, S.; Penta, A.; Murugesan, S. Structure-based virtual screening and docking studies for the identification of novel inhibitors against wild and drug resistance strains of HIV-1 RT. Med. Chem. Res., 2015, 24(5), 1869-1883.
[http://dx.doi.org/10.1007/s00044-014-1251-2]
[11]
De Luca, A.; Sidumo, Z.J.; Zanelli, G.; Magid, N.A.; Luhanga, R.; Brambilla, D.; Liotta, G.; Mancinelli, S.; Marazzi, M.C.; Palombi, L.; Ceffa, S. Accumulation of HIV-1 drug resistance in patients on a standard thymidine analogue-based first line antiretroviral therapy after virological failure: Implications for the activity of next-line regimens from a longitudinal study in Mozambique. BMC Infect. Dis., 2017, 17(1), 605.
[http://dx.doi.org/10.1186/s12879-017-2709-x] [PMID: 28870148]
[12]
Hofstra, L.M.; Sánchez Rivas, E.; Nijhuis, M.; Bank, L.E.A.; Wilkinson, E.; Kelly, K.; Mudrikova, T.; Schuurman, R.; de Oliveira, T.; de Kort, J.; Wensing, A.M.J. High rates of transmission of drug-resistant HIV in Aruba resulting in reduced susceptibility to the WHO recommended first-line regimen in nearly half of newly diagnosed HIV-infected patients. Clin. Infect. Dis., 2017, 64(8), 1092-1097.
[http://dx.doi.org/10.1093/cid/cix056] [PMID: 28329390]
[13]
Gu, S.X.; Xiao, T.; Zhu, Y.Y.; Liu, G.Y.; Chen, F.E. 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, 277-291.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.054] [PMID: 31051402]
[14]
Liu, G.; Wang, W.; Wan, Y.; Ju, X.; Gu, S. Application of 3D-QSAR, pharmacophore, and molecular docking in the molecular design of diarylpyrimidine derivatives as HIV-1 nonnucleoside reverse transcriptase inhibitors. Int. J. Mol. Sci., 2018, 19(5), 1436.
[http://dx.doi.org/10.3390/ijms19051436] [PMID: 29751616]
[15]
Gu, S.X.; Lu, H.H.; Liu, G.Y.; Ju, X.L.; Zhu, Y.Y. Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors. Eur. J. Med. Chem., 2018, 158, 371-392.
[http://dx.doi.org/10.1016/j.ejmech.2018.09.013] [PMID: 30223123]
[16]
Xue, P.; Lu, H.H.; Zhu, Y.Y.; Ju, X.L.; Pannecouque, C.; Zheng, X.J.; Liu, G.Y.; Zhang, X.L.; Gu, S.X. Design and synthesis of hybrids of diarylpyrimidines and diketo acids as HIV-1 inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(8), 1640-1643.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.009] [PMID: 28314598]
[17]
Battini, L.; Bollini, M. Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors. Med. Res. Rev., 2019, 39(4), 1235-1273.
[http://dx.doi.org/10.1002/med.21544] [PMID: 30417402]
[18]
Himmel, D.M.; Arnold, E. Non-nucleoside reverse transcriptase inhibitors join forces with integrase inhibitors to combat HIV. Pharmaceuticals (Basel), 2020, 13(6), 122.
[http://dx.doi.org/10.3390/ph13060122] [PMID: 32545407]
[19]
Shirvani, P.; Fassihi, A.; Saghaie, L. Recent advances in the design and development of non‐nucleoside reverse transcriptase inhibitor scaffolds. ChemMedChem, 2019, 14(1), 52-77.
[http://dx.doi.org/10.1002/cmdc.201800577] [PMID: 30417561]
[20]
Havens, J.P.; Podany, A.T.; Scarsi, K.K.; Fletcher, C.V. Clinical pharmacokinetics and pharmacodynamics of etravirine: An updated review. Clin. Pharmacokinet., 2020, 59(2), 137-154.
[http://dx.doi.org/10.1007/s40262-019-00830-9] [PMID: 31679131]
[21]
Vanangamudi, M.; Kurup, S.; Namasivayam, V. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): A brief overview of clinically approved drugs and combination regimens. Curr. Opin. Pharmacol., 2020, 54, 179-187.
[http://dx.doi.org/10.1016/j.coph.2020.10.009] [PMID: 33202360]
[22]
Fulco, P.P.; McNicholl, I.R. Etravirine and rilpivirine: Nonnucleoside reverse transcriptase inhibitors with activity against human immunodeficiency virus type 1 strains resistant to previous nonnucleoside agents. Pharmacotherapy, 2009, 29(3), 281-294.
[http://dx.doi.org/10.1592/phco.29.3.281] [PMID: 19249947]
[23]
Matamoros, T.; Alvarez, M.; Barrioluengo, V.; Betancor, G.; Menendez-Arias, L. Reverse transcriptase and retroviral replication; DNA Replication and Related Cellular Process, InTech: Rijeka, Croatia, 2011, pp. 111-142.
[http://dx.doi.org/10.5772/21660]
[24]
Olmedo, D.; Sancho, R.; Bedoya, L.M.; López-Pérez, J.L.; del Olmo, E.; Muñoz, E.; Alcamí, J.; Gupta, M.P.; San Feliciano, A. 3-Phenylcoumarins as inhibitors of HIV-1 replication. Molecules, 2012, 17(8), 9245-9257.
[http://dx.doi.org/10.3390/molecules17089245] [PMID: 22858844]
[25]
Dharmaratne, H.R.W.; Tan, G.T.; Marasinghe, G.P.K.; Pezzuto, J.M. Inhibition of HIV-1 reverse transcriptase and HIV-1 replication by Calophyllum coumarins and xanthones. Planta Med., 2002, 68(1), 86-87.
[http://dx.doi.org/10.1055/s-2002-20058] [PMID: 11842340]
[26]
Abram, M.E.; Ferris, A.L.; Das, K.; Quinoñes, O.; Shao, W.; Tuske, S.; Alvord, W.G.; Arnold, E.; Hughes, S.H. Mutations in HIV-1 reverse transcriptase affect the errors made in a single cycle of viral replication. J. Virol., 2014, 88(13), 7589-7601.
[http://dx.doi.org/10.1128/JVI.00302-14] [PMID: 24760888]
[27]
Kudo, E.; Taura, M.; Matsuda, K.; Shimamoto, M.; Kariya, R.; Goto, H.; Hattori, S.; Kimura, S.; Okada, S. Inhibition of HIV-1 replication by a tricyclic coumarin GUT-70 in acutely and chronically infected cells. Bioorg. Med. Chem. Lett., 2013, 23(3), 606-609.
[http://dx.doi.org/10.1016/j.bmcl.2012.12.034] [PMID: 23290051]
[28]
Monforte, A.M.; De Luca, L.; Buemi, M.R.; Agharbaoui, F.E.; Pannecouque, C.; Ferro, S. Structural optimization of N1-aryl-benzimidazoles for the discovery of new non-nucleoside reverse transcriptase inhibitors active against wild-type and mutant HIV-1 strains. Bioorg. Med. Chem., 2018, 26(3), 661-674.
[http://dx.doi.org/10.1016/j.bmc.2017.12.033] [PMID: 29291935]
[29]
Ferro, S.; Buemi, M.R.; De Luca, L.; Agharbaoui, F.E.; Pannecouque, C.; Monforte, A.M. Searching for novel N 1 -substituted benzimidazol-2-ones as non-nucleoside HIV-1 RT inhibitors. Bioorg. Med. Chem., 2017, 25(14), 3861-3870.
[http://dx.doi.org/10.1016/j.bmc.2017.05.040] [PMID: 28559060]
[30]
Lei, Y.; Han, S.; Yang, Y.; Pannecouque, C.; De Clercq, E.; Zhuang, C.; Chen, F.E. Design of biphenyl-substituted diarylpyrimidines with a cyanomethyl linker as HIV-1 NNRTIs via a molecular hybridization strategy. Molecules, 2020, 25(5), 1050.
[http://dx.doi.org/10.3390/molecules25051050] [PMID: 32111013]
[31]
Gu, S.X.; Zhu, Y.Y.; Chen, F.E.; De Clercq, E.; Balzarini, J.; Pannecouque, C. Structural modification of diarylpyrimidine derivatives as HIV-1 reverse transcriptase inhibitors. Med. Chem. Res., 2015, 24(1), 220-225.
[http://dx.doi.org/10.1007/s00044-014-1119-5]
[32]
Chen, W.; Zhan, P.; Daelemans, D.; Yang, J.; Huang, B.; De Clercq, E.; Pannecouque, C.; Liu, X. Structural optimization of pyridine-type DAPY derivatives to exploit the tolerant regions of the NNRTI binding pocket. Eur. J. Med. Chem., 2016, 121, 352-363.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.054] [PMID: 27267005]
[33]
Liu, Y.; Meng, G.; Zheng, A.; Chen, F.; Chen, W.; Clercq, E.D.; Pannecouque, C.; Balzarini, J. Design and synthesis of a new series of cyclopropylamino-linking diarylpyrimidines as HIV non-nucleoside reverse transcriptase inhibitors. Eur. J. Pharm. Sci., 2014, 62, 334-341.
[http://dx.doi.org/10.1016/j.ejps.2014.06.003] [PMID: 24956462]
[34]
Gao, P.; Song, S.; Wang, Z.; Sun, L.; Zhang, J.; Pannecouque, C.; De Clercq, E.; Zhan, P.; Liu, X. Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs. Bioorg. Med. Chem., 2021, 40, 116195.
[http://dx.doi.org/10.1016/j.bmc.2021.116195] [PMID: 33979774]
[35]
Li, W.; Li, X.; De Clercq, E.; Zhan, P.; Liu, X. Discovery of potent HIV-1 non-nucleoside reverse transcriptase inhibitors from arylthioacetanilide structural motif. Eur. J. Med. Chem., 2015, 102, 167-179.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.043] [PMID: 26276432]
[36]
Wan, Z.Y.; Tao, Y.; Wang, Y.F.; Mao, T.Q.; Yin, H.; Chen, F.E.; Piao, H.R.; De Clercq, E.; Daelemans, D.; Pannecouque, C. Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2015, 23(15), 4248-4255.
[http://dx.doi.org/10.1016/j.bmc.2015.06.048] [PMID: 26162497]
[37]
Minuto, J.J.; Haubrich, R. Etravirine: A second-generation NNRTI for treatment-experienced adults with resistant HIV-1 infection. Future HIV Ther., 2008, 2(6), 525-537.
[http://dx.doi.org/10.2217/17469600.2.6.525] [PMID: 19881888]
[38]
Kabbara, W.K.; Ramadan, W.H. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate for the treatment of HIV-1 infection in adults. J. Infect. Public Health, 2015, 8(5), 409-417.
[http://dx.doi.org/10.1016/j.jiph.2015.04.020] [PMID: 26001757]
[39]
Lansdon, E.B.; Brendza, K.M.; Hung, M.; Wang, R.; Mukund, S.; Jin, D.; Birkus, G.; Kutty, N.; Liu, X. Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): Implications for drug design. J. Med. Chem., 2010, 53(10), 4295-4299.
[http://dx.doi.org/10.1021/jm1002233] [PMID: 20438081]
[40]
Howe, Z.W.; Norman, S.; Lueken, A.F.; Huesgen, E.; Farmer, E.K.; Jarrell, K.; Mathis, J.E.; Bonham, K.W.; Hahn, J. Therapeutic review of cabotegravir/rilpivirine long‐acting antiretroviral injectable and implementation considerations at an HIV specialty clinic. Pharmacotherapy, 2021, 41(8), 686-699.
[http://dx.doi.org/10.1002/phar.2605] [PMID: 34130357]
[41]
Pasquau, J.; de Jesus, S.E.; Arazo, P.; Crusells, M.J.; Ríos, M.J.; Lozano, F.; de la Torre, J.; Galindo, M.J.; Carmena, J.; Santos, J.; Tornero, C.; Verdejo, G.; Samperiz, G.; Palacios, Z.; Hidalgo-Tenorio, C. Effectiveness and safety of dual therapy with rilpivirine and boosted darunavir in treatment-experienced patients with advanced HIV infection: A preliminary 24 week analysis (RIDAR study). BMC Infect. Dis., 2019, 19(1), 207-215.
[http://dx.doi.org/10.1186/s12879-019-3817-6] [PMID: 30819101]
[42]
Mills, A.; Richmond, G.J.; Newman, C.; Osiyemi, O.; Cade, J.; Brinson, C.; De Vente, J.; Margolis, D.A.; Sutton, K.C.; Wilches, V.; Hatch, S.; Roberts, J.; McCoig, C.; Garris, C.; Vandermeulen, K.; Spreen, W.R. Long-acting cabotegravir and rilpivirine for HIV-1 suppression: Switch to 2-monthly dosing after 5 years of daily oral therapy. AIDS, 2022, 36(2), 195-203.
[http://dx.doi.org/10.1097/QAD.0000000000003085] [PMID: 34652287]
[43]
Babkov, D.A.; Valuev-Elliston, V.T.; Paramonova, M.P.; Ozerov, A.A.; Ivanov, A.V.; Chizhov, A.O.; Khandazhinskaya, A.L.; Kochetkov, S.N.; Balzarini, J.; Daelemans, D.; Pannecouque, C.; Seley-Radtke, K.L.; Novikov, M.S. Scaffold hopping: Exploration of acetanilide-containing uracil analogues as potential NNRTIs. Bioorg. Med. Chem., 2015, 23(5), 1069-1081.
[http://dx.doi.org/10.1016/j.bmc.2015.01.002] [PMID: 25638501]
[44]
Li, X.; Chen, W.; Tian, Y.; Liu, H.; Zhan, P.; De Clercq, E.; Pannecouque, C.; Balzarini, J.; Liu, X. Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach. Eur. J. Med. Chem., 2014, 80, 112-121.
[http://dx.doi.org/10.1016/j.ejmech.2014.04.036] [PMID: 24769349]
[45]
Wu, H.Q.; Yao, J.; He, Q.Q.; Chen, W.X.; Chen, F.E.; Pannecouque, C.; De Clercq, E.; Daelemans, D. Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem., 2015, 23(3), 624-631.
[http://dx.doi.org/10.1016/j.bmc.2014.11.032] [PMID: 25537532]
[46]
Huang, B.; Wang, X.; Liu, X.; Chen, Z.; Li, W.; Sun, S.; Liu, H.; Daelemans, D.; De Clercq, E.; Pannecouque, C.; Zhan, P.; Liu, X. Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays. Bioorg. Med. Chem., 2017, 25(16), 4397-4406.
[http://dx.doi.org/10.1016/j.bmc.2017.06.022] [PMID: 28659246]
[47]
Lu, H.H.; Xue, P.; Zhu, Y.Y.; Ju, X.L.; Zheng, X.J.; Zhang, X.; Xiao, T.; Pannecouque, C.; Li, T.T.; Gu, S.X. Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR. Bioorg. Med. Chem., 2017, 25(8), 2491-2497.
[http://dx.doi.org/10.1016/j.bmc.2017.03.009] [PMID: 28314514]
[48]
Zeng, Z.; Liang, Y.H.; Feng, X.Q. Lead optimization of diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. ChemMedChem, 2010, 49, 3315-3321.
[http://dx.doi.org/10.1002/cmdc.201000045]
[49]
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49(11), 3315-3321.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[50]
Das, K.; Clark, A.D., Jr; Lewi, P.J.; Heeres, J.; de Jonge, M.R.; Koymans, L.M.H.; Vinkers, H.M.; Daeyaert, F.; Ludovici, D.W.; Kukla, M.J.; De Corte, B.; Kavash, R.W.; Ho, C.Y.; Ye, H.; Lichtenstein, M.A.; Andries, K.; Pauwels, R.; de Béthune, M.P.; Boyer, P.L.; Clark, P.; Hughes, S.H.; Janssen, P.A.J.; Arnold, E. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem., 2004, 47(10), 2550-2560.
[http://dx.doi.org/10.1021/jm030558s] [PMID: 15115397]
[51]
Hassam, M.; Basson, A.E.; Liotta, D.C.; Morris, L.; van Otterlo, W.A.L.; Pelly, S.C. Novel cyclopropyl-indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors. ACS Med. Chem. Lett., 2012, 3(6), 470-475.
[http://dx.doi.org/10.1021/ml3000462] [PMID: 24900496]
[52]
Gu, S.X.; Qiao, H.; Zhu, Y.Y.; Shu, Q.C.; Liu, H.; Ju, X.L.; De Clercq, E.; Balzarini, J.; Pannecouque, C. A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities. Bioorg. Med. Chem., 2015, 23(20), 6587-6593.
[http://dx.doi.org/10.1016/j.bmc.2015.09.020] [PMID: 26385446]
[53]
Yan, Z.H.; Wu, H.Q.; Chen, W.X.; Wu, Y.; Piao, H.R.; He, Q.Q.; Chen, F.E.; De Clercq, E.; Pannecouque, C. Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2014, 22(12), 3220-3226.
[http://dx.doi.org/10.1016/j.bmc.2014.03.020] [PMID: 24794751]
[54]
Pannecouque, C.; Daelemans, D.; De Clercq, E. Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: Revisited 20 years later. Nat. Protoc., 2008, 3(3), 427-434.
[http://dx.doi.org/10.1038/nprot.2007.517] [PMID: 18323814]
[55]
Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods, 1988, 20(4), 309-321.
[http://dx.doi.org/10.1016/0166-0934(88)90134-6] [PMID: 2460479]
[56]
Yang, J.; Wang, L.J.; Liu, J.J.; Zhong, L.; Zheng, R.L.; Xu, Y.; Ji, P.; Zhang, C.H.; Wang, W.J.; Lin, X.D.; Li, L.L.; Wei, Y.Q.; Yang, S.Y. Structural optimization and structure-activity relationships of N2-(4-(4-Methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine derivatives, a new class of reversible kinase inhibitors targeting both EGFR-activating and resistance mutations. J. Med. Chem., 2012, 55(23), 10685-10699.
[http://dx.doi.org/10.1021/jm301365e] [PMID: 23116168]
[57]
Shao, Y.; Cole, A.G.; Brescia, M.R.; Qin, L.Y.; Duo, J.; Stauffer, T.M.; Rokosz, L.L.; McGuinness, B.F.; Henderson, I. Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists. Bioorg. Med. Chem. Lett., 2009, 19(5), 1399-1402.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.042] [PMID: 19181527]
[58]
Tian, X.; Qin, B.; Wu, Z.; Wang, X.; Lu, H.; Morris-Natschke, S.L.; Chen, C.H.; Jiang, S.; Lee, K.H.; Xie, L. Design, synthesis, and evaluation of diarylpyridines and diarylanilines as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. J. Med. Chem., 2010, 53(23), 8287-8297.
[http://dx.doi.org/10.1021/jm100738d] [PMID: 21049929]
[59]
Stockmann, V.; Bakke, J.M.; Bruheim, P.; Fiksdahl, A. Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides. Tetrahedron, 2009, 65(18), 3668-3672.
[http://dx.doi.org/10.1016/j.tet.2009.02.072]
[60]
Meng, Q.; Liu, N.; Huang, B.; Zhan, P.; Liu, X. Novel fluorine-containing DAPY derivatives as potent HIV-1 NNRTIs: A patent evaluation of WO2014072419. Expert Opin. Ther. Pat., 2015, 25(12), 1477-1486.
[http://dx.doi.org/10.1517/13543776.2016.1088832] [PMID: 26415039]
[61]
Murugesan, V.; Tiwari, V.S.; Saxena, R.; Tripathi, R.; Paranjape, R.; Kulkarni, S.; Makwana, N.; Suryawanshi, R.; Katti, S.B. Lead optimization at C-2 and N-3 positions of thiazolidin-4-ones as HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2011, 19(22), 6919-6926.
[http://dx.doi.org/10.1016/j.bmc.2011.09.018] [PMID: 21982685]
[62]
Samuele, A.; Kataropoulou, A.; Viola, M.; Zanoli, S.; La Regina, G.; Piscitelli, F.; Silvestri, R.; Maga, G. Non-nucleoside HIV-1 reverse transcriptase inhibitors di-halo-indolyl aryl sulfones achieve tight binding to drug-resistant mutants by targeting the enzyme-substrate complex. Antiviral Res., 2009, 81(1), 47-55.
[http://dx.doi.org/10.1016/j.antiviral.2008.09.008] [PMID: 18984007]
[63]
Shah, P.; Westwell, A.D. The role of fluorine in medicinal chemistry. J. Enzyme Inhib. Med. Chem., 2007, 22(5), 527-540.
[http://dx.doi.org/10.1080/14756360701425014] [PMID: 18035820]
[64]
Chen, W.; Zhan, P.; Rai, D.; De Clercq, E.; Pannecouque, C.; Balzarini, J.; Zhou, Z.; Liu, H.; Liu, X. Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays. Bioorg. Med. Chem., 2014, 22(6), 1863-1872.
[http://dx.doi.org/10.1016/j.bmc.2014.01.054] [PMID: 24581546]
[65]
Meng, G.; Liu, Y.; Zheng, A.; Chen, F.; Chen, W.; De Clercq, E.; Pannecouque, C.; Balzarini, J. Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors. Eur. J. Med. Chem., 2014, 82, 600-611.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.059] [PMID: 24952305]
[66]
Lorenz, J.C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y. A novel class of tunable zinc reagents (RXZnCH2Y) for efficient cyclopropanation of olefins. J. Org. Chem., 2004, 69(2), 327-334.
[http://dx.doi.org/10.1021/jo030312v] [PMID: 14725443]
[67]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[68]
Parry, C.M.; Kohli, A.; Boinett, C.J.; Towers, G.J.; McCormick, A.L.; Pillay, D. Gag determinants of fitness and drug susceptibility in protease inhibitor-resistant human immunodeficiency virus type 1. J. Virol., 2009, 83(18), 9094-9101.
[http://dx.doi.org/10.1128/JVI.02356-08] [PMID: 19587031]
[69]
Gupta, R.K.; Kohli, A.; McCormick, A.L.; Towers, G.J.; Pillay, D.; Parry, C.M. Full-length HIV-1 Gag determines protease inhibitor susceptibility within in-vitro assays. AIDS, 2010, 24(11), 1651-1655.
[http://dx.doi.org/10.1097/QAD.0b013e3283398216] [PMID: 20597164]
[70]
Liang, Y.H.; Feng, X.Q.; Zeng, Z.S.; Chen, F.E.; Balzarini, J.; Pannecouque, C.; De Clercq, E. Design, synthesis, and SAR of naphthyl-substituted Diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. ChemMedChem, 2009, 4(9), 1537-1545.
[http://dx.doi.org/10.1002/cmdc.200900212] [PMID: 19591191]
[71]
Fyfe, J.W.B.; Fazakerley, N.J.; Watson, A.J.B. Chemoselective suzuki-miyaura cross‐coupling via kinetic transmetallation. Angew. Chem. Int. Ed., 2017, 56(5), 1249-1253.
[http://dx.doi.org/10.1002/anie.201610797] [PMID: 27982480]
[72]
Guillemont, J.; Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P.J.; Heeres, J.; de Jonge, M.R.; Koymans, L.M.H.; Daeyaert, F.F.D.; Vinkers, M.H.; Arnold, E.; Das, K.; Pauwels, R.; Andries, K.; de Béthune, M.P.; Bettens, E.; Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P.A.J. Synthesis of novel diarylpyrimidine analogues and their antiviral activity against human immunodeficiency virus type 1. J. Med. Chem., 2005, 48(6), 2072-2079.
[http://dx.doi.org/10.1021/jm040838n] [PMID: 15771449]
[73]
Du, Z.; Zhou, W.; Wang, F.; Wang, J.X. In situ generation of palladium nanoparticles: Ligand-free palladium catalyzed ultrafast Suzuki-Miyaura cross-coupling reaction in aqueous phase at room temperature. Tetrahedron, 2011, 67(26), 4914-4918.
[http://dx.doi.org/10.1016/j.tet.2011.04.093]
[74]
Jain, A.N. Surflex-Dock 2.1: Robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search. J. Comput. Aided Mol. Des., 2007, 21(5), 281-306.
[http://dx.doi.org/10.1007/s10822-007-9114-2] [PMID: 17387436]
[75]
Du, J.; Guo, J.; Kang, D.; Li, Z.; Wang, G.; Wu, J.; Zhang, Z.; Fang, H.; Hou, X.; Huang, Z.; Li, G.; Lu, X.; Liu, X.; Ouyang, L.; Rao, L.; Zhan, P.; Zhang, X.; Zhang, Y. New techniques and strategies in drug discovery. Chin. Chem. Lett., 2020, 31(7), 1695-1708.
[http://dx.doi.org/10.1016/j.cclet.2020.03.028]
[76]
Huo, Z.; Zhang, H.; Kang, D.; Zhou, Z.; Wu, G.; Desta, S.; Zuo, X.; Wang, Z.; Jing, L.; Ding, X.; Daelemans, D.; De Clercq, E.; Pannecouque, C.; Zhan, P.; Liu, X. Discovery of novel diarylpyrimidine derivatives as potent HIV-1 NNRTIs targeting the “NNRTI adjacent” binding site. ACS Med. Chem. Lett., 2018, 9(4), 334-338.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00524] [PMID: 29670696]
[77]
Liang, Y.H.; He, Q.Q.; Zeng, Z.S.; Liu, Z.Q.; Feng, X.Q.; Chen, F.E.; Balzarini, J.; Pannecouque, C.; Clercq, E.D. Synthesis and anti-HIV activity of 2-naphthyl substituted DAPY analogues as non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem., 2010, 18(13), 4601-4605.
[http://dx.doi.org/10.1016/j.bmc.2010.05.036] [PMID: 20570527]
[78]
Rotili, D.; Tarantino, D.; Artico, M.; Nawrozkij, M.B.; Gonzalez-Ortega, E.; Clotet, B.; Samuele, A.; Esté, J.A.; Maga, G.; Mai, A. Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: New, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level. J. Med. Chem., 2011, 54(8), 3091-3096.
[http://dx.doi.org/10.1021/jm101626c] [PMID: 21438533]
[79]
Janssen, P.A.J.; Lewi, P.J.; Arnold, E.; Daeyaert, F.; de Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.; Andries, K.; de Béthune, M.P.; Pauwels, R.; Das, K.; Clark, A.D., Jr; Frenkel, Y.V.; Hughes, S.H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams, P.; Stoffels, P. 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]benzonitr-ile (R278474, rilpivirine). J. Med. Chem., 2005, 48(6), 1901-1909.
[http://dx.doi.org/10.1021/jm040840e] [PMID: 15771434]
[80]
Rotili, D.; Samuele, A.; Tarantino, D.; Ragno, R.; Musmuca, I.; Ballante, F.; Botta, G.; Morera, L.; Pierini, M.; Cirilli, R.; Nawrozkij, M.B.; Gonzalez, E.; Clotet, B.; Artico, M.; Esté, J.A.; Maga, G.; Mai, A. 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: Enantioselectivity studies. J. Med. Chem., 2012, 55(7), 3558-3562.
[http://dx.doi.org/10.1021/jm201308v] [PMID: 22428851]
[81]
Feng, X.Q.; Zeng, Z.S.; Liang, Y.H.; Chen, F.E.; Pannecouque, C.; Balzarini, J.; Clercq, E.D. Synthesis and biological evaluation of 4-(hydroxyimino)arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV. Bioorg. Med. Chem., 2010, 18(7), 2370-2374.
[http://dx.doi.org/10.1016/j.bmc.2010.03.007] [PMID: 20307984]
[82]
Mordant, C.; Schmitt, B.; Pasquier, E.; Demestre, C.; Queguiner, L.; Masungi, C.; Peeters, A.; Smeulders, L.; Bettens, E.; Hertogs, K.; Heeres, J.; Lewi, P.; Guillemont, J. Synthesis of novel diarylpyrimidine analogues of TMC278 and their antiviral activity against HIV-1 wild-type and mutant strains. Eur. J. Med. Chem., 2007, 42(5), 567-579.
[http://dx.doi.org/10.1016/j.ejmech.2006.11.014] [PMID: 17223230]
[83]
Ludovici, D.W.; De Corte, B.L.; Kukla, M.J.; Ye, H.; Ho, C.Y.; Lichtenstein, M.A.; Kavash, R.W.; Andries, K.; de Béthune, M.P.; Azijn, H.; Pauwels, R.; Lewi, P.J.; Heeres, J.; Koymans, L.M.H.; de Jonge, M.R.; Van Aken, K.J.A.; Daeyaert, F.F.D.; Das, K.; Arnold, E.; Janssen, P.A.J. Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. Bioorg. Med. Chem. Lett., 2001, 11(17), 2235-2239. Available from: https://doi.org/10.1016/S0960-894X(01)00412-7
[http://dx.doi.org/10.1016/S0960-894X(01)00412-7] [PMID: 11527705]
[84]
Li, D.; Zhan, P.; Liu, H.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Liu, X. Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs. Bioorg. Med. Chem., 2013, 21(7), 2128-2134.
[http://dx.doi.org/10.1016/j.bmc.2012.12.049] [PMID: 23415090]
[85]
Loizidou, E.Z.; Zeinalipour-Yazdi, C.D.; Christofides, T.; Kostrikis, L.G. Analysis of binding parameters of HIV-1 integrase inhibitors: Correlates of drug inhibition and resistance. Bioorg. Med. Chem., 2009, 17(13), 4806-4818.
[http://dx.doi.org/10.1016/j.bmc.2009.04.058] [PMID: 19450984]
[86]
Xiao, T.; Tang, J.F.; Meng, G.; Pannecouque, C.; Zhu, Y.Y.; Liu, G.Y.; Xu, Z.Q.; Wu, F.S.; Gu, S.X.; Chen, F.E. Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities. Eur. J. Med. Chem., 2020, 186, 111864.
[http://dx.doi.org/10.1016/j.ejmech.2019.111864] [PMID: 31767136]
[87]
Guo, S.; Wang, Y.; Sun, C.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Efficient synthesis of 2-arylamino substituted pyridinyl nitriles by Buchwald-Hartwig amination. Tetrahedron Lett., 2013, 54(25), 3233-3237.
[http://dx.doi.org/10.1016/j.tetlet.2013.03.085]
[88]
Tian, X.; Qin, B.; Lu, H.; Lai, W.; Jiang, S.; Lee, K.H.; Chen, C.H.; Xie, L. Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Bioorg. Med. Chem. Lett., 2009, 19(18), 5482-5485.
[http://dx.doi.org/10.1016/j.bmcl.2009.07.080] [PMID: 19666220]
[89]
Freitag, A.; Prajwal, P.; Shymanets, A.; Harteneck, C.; Nürnberg, B.; Schächtele, C.; Kubbutat, M.; Totzke, F.; Laufer, S.A. Development of first lead structures for phosphoinositide 3-kinase-C2γ inhibitors. J. Med. Chem., 2015, 58(1), 212-221.
[http://dx.doi.org/10.1021/jm5006034] [PMID: 24983663]
[90]
Romines, K.R.; Freeman, G.A.; Schaller, L.T.; Cowan, J.R.; Gonzales, S.S.; Tidwell, J.H.; Andrews, C.W., III; Stammers, D.K.; Hazen, R.J.; Ferris, R.G.; Short, S.A.; Chan, J.H.; Boone, L.R. Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor. J. Med. Chem., 2006, 49(2), 727-739.
[http://dx.doi.org/10.1021/jm050670l] [PMID: 16420058]
[91]
Spychała, J. A facile preparation of n2-arylisocytosines. Synth. Commun., 1997, 27(11), 1943-1949.
[http://dx.doi.org/10.1080/00397919708006796]
[92]
Zhan, P.; Pannecouque, C.; De Clercq, E.; Liu, X. Anti-HIV drug discovery and development: Current innovations and future trends. J. Med. Chem., 2016, 59(7), 2849-2878.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00497] [PMID: 26509831]
[93]
Liu, G.; Wan, Y.; Wang, W.; Fang, S.; Gu, S.; Ju, X. Docking-based 3D-QSAR and pharmacophore studies on diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Mol. Divers., 2019, 23(1), 107-121.
[http://dx.doi.org/10.1007/s11030-018-9860-1] [PMID: 30051344]
[94]
Kang, D.; Fang, Z.; Li, Z.; Huang, B.; Zhang, H.; Lu, X.; Xu, H.; Zhou, Z.; Ding, X.; Daelemans, D.; De Clercq, E.; Pannecouque, C.; Zhan, P.; Liu, X. Design, synthesis, and evaluation of thiophene[3,2- d]pyrimidine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors with significantly improved drug resistance profiles. J. Med. Chem., 2016, 59(17), 7991-8007.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00738] [PMID: 27541578]
[95]
Kang, D.; Wang, Z.; Zhang, H.; Wu, G.; Zhao, T.; Zhou, Z.; Huo, Z.; Huang, B.; Feng, D.; Ding, X.; Zhang, J.; Zuo, X.; Jing, L.; Luo, W.; Guma, S.; Daelemans, D.; Clercq, E.D.; Pannecouque, C.; Zhan, P.; Liu, X. Further exploring solvent-exposed tolerant regions of allosteric binding pocket for novel HIV-1 NNRTIs discovery. ACS Med. Chem. Lett., 2018, 9(4), 370-375.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00054] [PMID: 29670703]
[96]
Chan, A.H.; Lee, W.G.; Spasov, K.A.; Cisneros, J.A.; Kudalkar, S.N.; Petrova, Z.O.; Buckingham, A.B.; Anderson, K.S.; Jorgensen, W.L. Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography. Proc. Natl. Acad. Sci. USA, 2017, 114(36), 9725-9730.
[http://dx.doi.org/10.1073/pnas.1711463114] [PMID: 28827354]
[97]
Zhang, H.; Tian, Y.; Kang, D.; Huo, Z.; Zhou, Z.; Liu, H.; De Clercq, E.; Pannecouque, C.; Zhan, P.; Liu, X. Discovery of uracil-bearing DAPYs derivatives as novel HIV-1 NNRTIs via crystallographic overlay-based molecular hybridization. Eur. J. Med. Chem., 2017, 130, 209-222.
[http://dx.doi.org/10.1016/j.ejmech.2017.02.047] [PMID: 28254696]
[98]
Kang, D.; Fang, Z.; Huang, B.; Lu, X.; Zhang, H.; Xu, H.; Huo, Z.; Zhou, Z.; Yu, Z.; Meng, Q.; Wu, G.; Ding, X.; Tian, Y.; Daelemans, D.; De Clercq, E.; Pannecouque, C.; Zhan, P.; Liu, X. Structure-based optimization of thiophene[3,2- d]pyrimidine derivatives as potent HIV-1 Non-nucleoside reverse transcriptase inhibitors with improved potency against resistance-associated variants. J. Med. Chem., 2017, 60(10), 4424-4443.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00332] [PMID: 28481112]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy