Abstract
Background: Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have resulted in a global health threat. Meanwhile, due to the emergence of drugresistant HIV-1 strains, the discovery of potent compounds for antiretroviral therapy success is highly desirable.
Objective: This study aimed to develop anti-HIV-1 candidates which can be effectively applied for the treatment of HIV infection.
Methods: Based upon our previous results, a series of E isomers of C15-imines of matrine (3a-l) were semi-synthesized from a natural quinolizidine alkaloid matrine. Their anti-HIV-1 activities were evaluated against HIV-1ⅢB replication in acutely infected C8166 cells in vitro.
Results: Derivatives 3c, 3h and 3j showed good anti-HIV-1 activities with EC50 and therapeutic index (TI) values of 0.0089/0.012/0.0091 mM, and 23.71/32.49/27.43, respectively.
Conclusion: The substituents and their corresponding positions on the phenyl ring of C15-imine derivatives of matrine were vital for anti-HIV-1 activities. Compounds 3c, 3h and 3j can be used as leads for further structural modification as HIV-1 inhibitors.
Graphical Abstract
[1]
Cohen, J. Halting HIV/AIDS Epidemics. Science, 2011, 334(6061), 1338-1340.
[http://dx.doi.org/10.1126/science.334.6061.1338] [PMID: 22158796]
[http://dx.doi.org/10.1126/science.334.6061.1338] [PMID: 22158796]
[2]
Han, D.; Tan, J.; Men, J.; Li, C.; Zhang, X. Quantitative structure activity/pharmacokinetics relationship studies of HIV-1 protease inhibitors using three modelling methods. Med. Chem., 2021, 17(4), 396-406.
[http://dx.doi.org/10.2174/1573406415666190826154505] [PMID: 31448716]
[http://dx.doi.org/10.2174/1573406415666190826154505] [PMID: 31448716]
[3]
Pillai, G.G.; Mederos, L.; Panda, C.S.; Gronski, A.; Burk, P.; Hall, C.D.; Katritzky, A.R.; Tämm, K.; Karelson, M. Robust modeling and scaffold hopping: Case study based on HIV reverse transcriptase inhibitors type-1 data. Med. Chem., 2016, 12(6), 513-526.
[http://dx.doi.org/10.2174/1573406411666151005110141] [PMID: 26434799]
[http://dx.doi.org/10.2174/1573406411666151005110141] [PMID: 26434799]
[4]
Waheed, A.A.; Tachedjian, G. Why do we need new drug classes for HIV treatment and prevention? Curr. Top. Med. Chem., 2016, 16(12), 1343-1349.
[http://dx.doi.org/10.2174/1568026616999151013124606] [PMID: 26459806]
[http://dx.doi.org/10.2174/1568026616999151013124606] [PMID: 26459806]
[5]
Weinstein, E.R.; Lee, J.S.; Mendez, N.A.; Harkness, A.; Safren, S.A.; El-Sadr, W. HIV/AIDS and aging: The new frontier for HIV/AIDS research and care. AIDS, 2021, 35(12), 2043-2045.
[http://dx.doi.org/10.1097/QAD.0000000000003000] [PMID: 34471073]
[http://dx.doi.org/10.1097/QAD.0000000000003000] [PMID: 34471073]
[6]
Chávez-Hernández, A.L.; Juárez-Mercado, K.E.; Saldívar-González, F.I.; Medina-Franco, J.L. Towards the de novo design of HIV-1 protease inhibitors based on natural products. Biomolecules, 2021, 11(12), 1805.
[http://dx.doi.org/10.3390/biom11121805] [PMID: 34944448]
[http://dx.doi.org/10.3390/biom11121805] [PMID: 34944448]
[7]
Lv, M.; Xu, H. Dipyridodiazepinone analogs as human immunodeficiency virus type 1-specific non-nucleoside reverse transcriptase inhibitors: An overview. Curr. Med. Chem., 2010, 17(18), 1874-1898.
[http://dx.doi.org/10.2174/092986710791163902] [PMID: 20377515]
[http://dx.doi.org/10.2174/092986710791163902] [PMID: 20377515]
[8]
Wodarz, D.; Nowak, M.A. HIV therapy: Managing resistance. Proc. Natl. Acad. Sci. , 2000, 97(15), 8193-8195.
[http://dx.doi.org/10.1073/pnas.97.15.8193] [PMID: 10899988]
[http://dx.doi.org/10.1073/pnas.97.15.8193] [PMID: 10899988]
[9]
Giatsou, E.; Abdi, B.; Plu, I.; Desire, N.; Palich, R.; Calvez, V.; Seilhean, D.; Marcelin, A.G.; Jary, A. Ultradeep sequencing reveals HIV-1 diversity and resistance compartmentalization during HIV-encephalopathy. AIDS, 2020, 34(11), 1609-1614.
[http://dx.doi.org/10.1097/QAD.0000000000002616] [PMID: 32701585]
[http://dx.doi.org/10.1097/QAD.0000000000002616] [PMID: 32701585]
[10]
van Zyl, G.U.; Dorfman, J.R.; Kearney, M.F. HIV drug resistance in various body compartments. Curr. Opin. HIV AIDS, 2022, 17(4), 205-212.
[http://dx.doi.org/10.1097/COH.0000000000000741] [PMID: 35762375]
[http://dx.doi.org/10.1097/COH.0000000000000741] [PMID: 35762375]
[11]
Safakish, M.; Hajimahdi, Z.; Vahabpour, R.; Zabihollahi, R.; Zarghi, A. Novel benzoxazin-3-one derivatives: Design, synthesis, molecular modeling, anti-HIV-1 and integrase inhibitory assay. Med. Chem., 2020, 16(7), 938-946.
[http://dx.doi.org/10.2174/1573406415666190826161123] [PMID: 31448713]
[http://dx.doi.org/10.2174/1573406415666190826161123] [PMID: 31448713]
[12]
Singh, A.; Kumar, V.; Mishra, A.; Singh, V.K. Targeting the HIV-1 Tat and human Tat protein complex through natural products: An in silico docking and molecular dynamics simulation approach. Lett. Drug Des. Discov., 2022, 19(11), 982-995.
[http://dx.doi.org/10.2174/1570180819666220330122542]
[http://dx.doi.org/10.2174/1570180819666220330122542]
[13]
Dumond, J.; Tronchet, J.M.J.; Kirkiacharian, S.; Seman, M.; Reboud-Ravaux, M. Insights into biophysical methods to study interactions between HIV-1 reverse transcriptase and non-nucleoside reverse transcriptase inhibitors. Lett. Drug Des. Discov., 2020, 17(6), 818-825.
[http://dx.doi.org/10.2174/1570180816666190723121845]
[http://dx.doi.org/10.2174/1570180816666190723121845]
[14]
Gochfeld, D.; El Sayed, K.; Yousaf, M.; Hu, J.; Bartyzel, P.; Dunbar, D.; Wilkins, S.; Zjawiony, J.; Schinazi, R.; Wirtz, S.; Tharnish, P.M.; Hamann, M.T. Marine natural products as lead anti-HIV agents. Mini Rev. Med. Chem., 2003, 3(5), 401-424.
[http://dx.doi.org/10.2174/1389557033487962] [PMID: 12769693]
[http://dx.doi.org/10.2174/1389557033487962] [PMID: 12769693]
[15]
Ran, J.Q.; Huang, N.; Xu, H.; Yang, L.M.; Lv, M.; Zheng, Y.T. Anti HIV-1 agents 5: Synthesis and anti-HIV-1 activity of some N-arylsulfonyl-3-acetylindoles in vitro. Bioorg. Med. Chem. Lett., 2010, 20(12), 3534-3536.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.132] [PMID: 20488700]
[http://dx.doi.org/10.1016/j.bmcl.2010.04.132] [PMID: 20488700]
[16]
Cary, D.C.; Peterlin, B.M. Natural products and HIV/AIDS. AIDS Res. Hum. Retroviruses, 2018, 34(1), 31-38.
[http://dx.doi.org/10.1089/aid.2017.0232] [PMID: 29226706]
[http://dx.doi.org/10.1089/aid.2017.0232] [PMID: 29226706]
[17]
Sparks, E.; Zorzela, L.; Necyk, C.; Hughes, C.; Vohra, S. Study of natural product adverse events in adult HIV-infected patients in Canada. HIV Med., 2022, 23(1), 29-38.
[http://dx.doi.org/10.1111/hiv.13155] [PMID: 34432937]
[http://dx.doi.org/10.1111/hiv.13155] [PMID: 34432937]
[18]
Huang, J.; Xiang, S.Y.; Lv, M.; Yang, L.M.; Zhang, Y.; Zheng, Y.T.; Xu, H. 14-Formyl-15-aryloxy/methoxymatrine and 14-aryloxymethylidenylmatrine derivatives as anti-HIV-1 agents. Med. Chem., 2018, 14(3), 249-252.
[http://dx.doi.org/10.2174/1573406413666171002120310] [PMID: 28969577]
[http://dx.doi.org/10.2174/1573406413666171002120310] [PMID: 28969577]
[19]
Lv, M.; Ma, Q.; Zhang, S.; Xu, H. Agrochemical properties evaluation of some imines alkaloids of matrine/oxymatrine. Bioorg. Med. Chem. Lett., 2021, 48, 128246.
[http://dx.doi.org/10.1016/j.bmcl.2021.128246] [PMID: 34233221]
[http://dx.doi.org/10.1016/j.bmcl.2021.128246] [PMID: 34233221]
[20]
Huang, N.; Wang, Q.; Yang, L.M.; Xu, H.; Zheng, Y.T. Anti HIV-1 agents 7. Discovery of 1-hydroxy-4-chloro-9,10-anthraquinone derivatives as new HIV-1 inhibitors in vitro. Lett. Drug Des. Discov., 2011, 8(7), 602-605.
[http://dx.doi.org/10.2174/157018011796235185]
[http://dx.doi.org/10.2174/157018011796235185]
