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In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, F2-7f exhibited moderate anti-HIV-1 activity with an EC50 value of 5.89 \u03bcM, which was slightly weaker than the lead compound PF74 (EC50 = 0.75 \u03bcM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by 7f with an HIV-2 EC50 value of 4.52 \u03bcM and nearly 5-fold increased potency over anti-HIV-1 (EC50 = 21.81 \u03bcM), equivalent to PF74 (EC50 = 4.16 \u03bcM). Furthermore, F2-7f preferred to bind to the CA hexamer rather than to the monomer, similar to PF74, according to surface plasmon resonance results. Molecular dynamics simulation indicated that F2-7f and PF74 bound at the same site. Additionally, we computationally analyzed the ADMET properties for 7f and F2-7f. Based on this analysis, 7f and F2-7f were predicted to have improved drug-like properties and metabolic stability over PF74, and no toxicities were predicted based on the chemotype of 7f and F2-7f. Finally, the experimental metabolic stability results of F2-7f in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that F2-7f is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.<\/jats:p>","DOI":"10.3390\/molecules27238415","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T03:00:36Z","timestamp":1669950036000},"page":"8415","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators"],"prefix":"10.3390","volume":"27","author":[{"given":"Shujing","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, China"},{"name":"Department of Pharmacy, Qilu Hospital of Shandong University, Jinan 250012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleed","family":"Zalloum","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O. 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Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Pannecouque","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, K.U. 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Med. Chem."},{"key":"ref_2","unstructured":"(2022, October 12). Available online: https:\/\/www.who.int\/health-topics\/hiv-aids#tab=tab_1."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1021\/acs.jmedchem.1c01758","article-title":"Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors","volume":"65","author":"Wang","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12174","DOI":"10.1038\/s41598-020-68806-5","article-title":"HIV-1 and HIV-2 Prevalence, Risk Factors and Birth Outcomes Among Pregnant Women in Bissau, Guinea-Bissau: A Retrospective Cross-sectional Hospital Study","volume":"10","author":"Rasmussen","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"850","DOI":"10.2174\/1573409916666201006143007","article-title":"A Review on Pharmacokinetics Properties of Antiretroviral Drugs to Treat HIV-1 Infections","volume":"17","author":"Khan","year":"2021","journal-title":"Curr. Comput. Aid. Drug Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tips.2021.10.004","article-title":"Update and Latest Advances in Antiretroviral Therapy","volume":"43","author":"Delgado","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.cclet.2020.03.028","article-title":"New Techniques and Strategies in Drug Discovery","volume":"31","author":"Du","year":"2020","journal-title":"Chin. Chem. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113380","DOI":"10.1016\/j.ejmech.2021.113380","article-title":"An Insight on Medicinal Aspects of Novel HIV-1 Capsid Protein Inhibitors","volume":"217","author":"Sun","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rossi, E., Meuser, M.E., Cunanan, C.J., and Cocklin, S. (2021). Structure, Function, and Interactions of the HIV-1 Capsid Protein. Life, 11.","DOI":"10.3390\/life11020100"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12977-021-00566-0","article-title":"The HIV-1 Capsid and Reverse Transcription","volume":"18","author":"Aiken","year":"2021","journal-title":"Retrovirology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s12250-019-00095-3","article-title":"Multiple Roles of HIV-1 Capsid during the Virus Replication Cycle","volume":"34","author":"Novikova","year":"2019","journal-title":"Virol. Sin."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.apsb.2020.07.016","article-title":"Novel PF74-like Small Molecules Targeting the HIV-1 Capsid Protein: Balance of Potency and Metabolic Stability","volume":"11","author":"Wang","year":"2021","journal-title":"Acta. Pharm. Sin. B"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nrmicro3503","article-title":"HIV-1 Capsid: The Multifaceted Key Player in HIV-1 Infection","volume":"13","author":"Campbell","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1126\/science.aah4972","article-title":"The Structure and Flexibility of Conical HIV-1 Capsids Determined within Intact Virions","volume":"354","author":"Mattei","year":"2016","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"658","DOI":"10.2174\/13892037113146660084","article-title":"The HIV-1 Capsid Protein as a Drug Target: Recent Advances and Future Prospects","volume":"14","author":"Domenech","year":"2013","journal-title":"Curr. Prot. Pept. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1742-4690-10-29","article-title":"The NTD-CTD Intersubunit Interface Plays a Critical Role in Assembly and Stabilization of the HIV-1 Capsid","volume":"10","author":"Yufenyuy","year":"2013","journal-title":"Retrovirology"},{"key":"ref_17","first-page":"39","article-title":"Capsid-CPSF6 Interaction: Master Regulator of Nuclear HIV-1 Positioning and Integration","volume":"1","author":"Achuthan","year":"2019","journal-title":"J. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e0031022","DOI":"10.1128\/msphere.00310-22","article-title":"Defining the HIV Capsid Binding Site of Nucleoporin 153","volume":"7","author":"Li","year":"2022","journal-title":"mSphere"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41564-021-00868-1","article-title":"Sec24C is an HIV-1 Host Dependency Factor Crucial for Virus Replication","volume":"6","author":"Rebensburg","year":"2021","journal-title":"Nat. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1021\/acs.biochem.6b00159","article-title":"HIV Capsid Assembly, Mechanism, and Structure","volume":"55","author":"Chen","year":"2016","journal-title":"Biochemistry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113903","DOI":"10.1016\/j.ejmech.2021.113903","article-title":"Design, Synthesis, and Mechanistic Investigations of Phenylalanine Derivatives Containing a Benzothiazole Moiety as HIV-1 Capsid Inhibitors with Improved Metabolic Stability","volume":"227","author":"Xu","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Blair, W.S., Pickford, C., Irving, S.L., Brown, D.G., Anderson, M., Bazin, R., Cao, J., Ciaramella, G., Isaacson, J., and Jackson, L. (2010). HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001220"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113848","DOI":"10.1016\/j.ejmech.2021.113848","article-title":"Design, Synthesis, and Mechanism Study of Dimerized Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors","volume":"226","author":"Zhang","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1126\/science.aaa5936","article-title":"STRUCTURAL VIROLOGY. X-ray Crystal Structures of Native HIV-1 Capsid Protein Reveal Conformational Variability","volume":"349","author":"Gres","year":"2015","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"112085","DOI":"10.1016\/j.ejmech.2020.112085","article-title":"Design, Synthesis and Structure-activity Relationships of 4-phenyl-1H-1,2,3-triazole Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Promising Antiviral Activities","volume":"190","author":"Sun","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Xu, S., Sun, L., Ding, D., Zhang, X., Liu, X., and Zhan, P. (2022). Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes. Metabolites, 12.","DOI":"10.3390\/metabo12080752"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/s41586-020-2443-1","article-title":"Clinical Targeting of HIV Capsid Protein with a Long-acting Small Molecule","volume":"584","author":"Link","year":"2020","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Margot, N.A., Naik, V., Vander, V.L., Anoshchenko, O., Singh, R., Dvory-Sobol, H., Rhee, M.S., and Callebaut, C. (2022). Resistance Analyses in Highly Treatment-Experienced People with HIV Treated with the Novel Capsid HIV Inhibitor Lenacapavir. J. Infect. Dis., ahead of print.","DOI":"10.1093\/infdis\/jiac364"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1021\/acs.jmedchem.0c00015","article-title":"Design, Synthesis, and Mechanism Study of Benzenesulfonamide-Containing Phenylalanine Derivatives as Novel HIV-1 Capsid Inhibitors with Improved Antiviral Activities","volume":"63","author":"Sun","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Xu, S., Sun, L., Zalloum, W.A., Zhang, X., Huang, T., Ding, D., Tao, Y., Zhao, F., Gao, S., and Kang, D. (2022). From Design to Biological Mechanism Evaluation of Phenylalanine-bearing HIV-1 Capsid Inhibitors Targeting a Vital Assembly Interface. Chin. Chem. Lett., in press.","DOI":"10.1016\/j.cclet.2022.06.034"},{"key":"ref_31","first-page":"1070","article-title":"Exploring Modifications of an HIV-1 Capsid Inhibitor: Design, Synthesis, and Mechanism of Action","volume":"5","author":"Xu","year":"2018","journal-title":"J. Drug Des. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1002\/cbdv.200900148","article-title":"Beyond Profiling: Using ADMET Models to Guide Decisions","volume":"6","author":"Segall","year":"2009","journal-title":"Chem. Biodivers."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5439","DOI":"10.1016\/j.bmcl.2014.10.027","article-title":"Discovery and Optimization of Novel Small-molecule HIV-1 Entry Inhibitors Using Field-based Virtual Screening and Bioisosteric Replacement","volume":"24","author":"Tuyishime","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Karadsheh, R., Meuser, M.E., and Cocklin, S. (2020). Composition and Orientation of the Core Region of Novel HIV-1 Entry Inhibitors Influences Metabolic Stability. Molecules, 25.","DOI":"10.3390\/molecules25061430"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1021\/acs.jmedchem.0c01810","article-title":"Rapid Optimization of the Metabolic Stability of a Human Immunodeficiency Virus Type-1 Capsid Inhibitor Using a Multistep Computational Workflow","volume":"64","author":"Meuser","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1021\/acs.jcim.6b00233","article-title":"Predicting Regioselectivity and Lability of Cytochrome P450 Metabolism Using Quantum Mechanical Simulations","volume":"56","author":"Tyzack","year":"2016","journal-title":"J. Chem. Inf. Model"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s10822-018-0107-0","article-title":"WhichP450: A Multi-class Categorical Model to Predict the Major Metabolising CYP450 Isoform for a Compound","volume":"32","author":"Hunt","year":"2018","journal-title":"J. Comput. Aid. Mol. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1002\/cmdc.200700319","article-title":"Towards an Integrated Description of Hydrogen Bonding and Dehydration: Decreasing False Positives in Virtual Screening with the HYDE Scoring Function","volume":"3","author":"Reulecke","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.1021\/acs.jmedchem.5b01146","article-title":"Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model","volume":"59","author":"Kaur","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0165-1110(84)90007-1","article-title":"A Review of The Genetic Effects of Ethyl Methanesulfonate","volume":"134","author":"Sega","year":"1984","journal-title":"Mutat. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1111\/j.1440-1746.2011.07036.x","article-title":"Severe Acute Liver Injury Associated with Lumiracoxib","volume":"27","author":"Pillans","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8472","DOI":"10.1128\/JVI.05006-11","article-title":"Inhibiting Early-stage Events in HIV-1 Replication by Small-molecule Targeting of the HIV-1 Capsid","volume":"86","author":"Kortagere","year":"2012","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.pep.2005.01.016","article-title":"Protein production by auto-induction in high-density shaking cultures","volume":"41","author":"Studier","year":"2005","journal-title":"Protein Expr. Purif."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature19098","article-title":"HIV-1 Uses Dynamic Capsid Pores to Import Nucleotides and Fuel Encapsidated DNA Synthesis","volume":"536","author":"Jacques","year":"2016","journal-title":"Nature"},{"key":"ref_45","unstructured":"Simoudis, E., Han, J., and Fayyad, U. A Density-Based Algorithm for Discovering Clusters in Large Spatial Databases with Noise. Proceedings of the 2nd International Conference on Knowledge Discovery and Data Mining."},{"key":"ref_46","unstructured":"Hawkins, P.C.D., Skillman, A.G., Warren, G.L., Ellingson, B.A., and Stahl, M.T. (2010). OMEGA, Version 3.0.0.1, OpenEye Scientific."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1021\/ci100031x","article-title":"Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and the Cambridge Structural Database","volume":"50","author":"Hawkins","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_48","unstructured":"(2022, October 12). OEDOCKING 3.0.1: OpenEye Scientific Software, Santa Fe, NM. Available online: http:\/\/www.eyesopen.com."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1021\/acs.jcim.5b00142","article-title":"POSIT: Flexible Shape-Guided Docking for Pose Prediction","volume":"55","author":"Kelley","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1021\/ci100436p","article-title":"FRED Pose Prediction and Virtual Screening Accuracy","volume":"51","author":"McGann","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s10822-012-9584-8","article-title":"FRED and HYBRID Docking Performance on Standardized Datasets","volume":"26","author":"McGann","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_52","unstructured":"Case, D.A., Betz, R.M., Botello-Smith, W., Cerutti, D.S., Cheatham, T.E., Darden, T.A., Duke, R.E., Giese, T.J., Gohlke, H., and Goetz, A.W. (2016). Amber 2016, University of California."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1021\/ct700119m","article-title":"Clustering molecular Dynamics Trajectories: 1. Characterizing the Performance of Different Clustering Algorithms","volume":"3","author":"Shao","year":"2007","journal-title":"J. Chem. Theory Comput."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/jcc.20634","article-title":"A Semiempirical Free Energy Force Field with Charge-based Desolvation","volume":"28","author":"Huey","year":"2007","journal-title":"J. Comput. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/0471250953.bi0814s24","article-title":"Using AutoDock for Ligand-receptor Docking","volume":"24","author":"Morris","year":"2008","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1758-2946-1-15","article-title":"Application of the PM6 Semi-empirical Method to Modeling Proteins Enhances Docking Accuracy of AutoDock","volume":"1","author":"Bikadi","year":"2009","journal-title":"J. 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