Abstract
A series of thirty-one new compounds were synthesized and evaluated for their anti-HIV-1 and cytotoxicity activity. Of these, twelve were found to be inhibitors of HIV replications in primary human lymphocytes with median effective concentration (EC50) values < 20 µM. However, most of the compounds demonstrated cytotoxicity in different cells. Our structure activity relationship study identified different patterns. In the series of 2-aryl pyrrolidines, comparing the activity of the compounds containing 2-aryl substituents we observed that compounds 1c, 1f–j, 2f,g with benzyloxyphenyl and isopropoxy groups were more potent. Compounds 1g–j, 2f,g, in which the 1-aryl moiety contained a methyl group in 3,5- or 4-positions also showed high activity. In the series of compounds containing the amide, aminomethyl and nitrile groups we observed an increase in activity with C(O)NH2 < CH2NH2 < CN. In the series of 2-pyrimidinyl pyrrolidines, the best results were demonstrated with derivatives 5e and 5f, in which the presence of a benzyl fragment in 1st and aniline fragment in 6th positions of pyrimidine ring we observed an increase in anti-HIV activity. Molecular docking studies of synthesized compounds with HIV-1 reverse transcriptase enzyme were performed. Binding energies of ligands were estimated, and the interacting amino acids of HIV-1 reverse transcriptase protein were shown. Based on corroborative results of the molecular docking studies and in vitro experiments, we suggest that three groups of synthesized ligands (1c, 1f–i), (2f,g), (5e,f, 7) are of high interest for further research on new drugs against HIV.
Graphic abstract
General structure of synthesized 2-aryl and 2-pyrimidinyl pyrrolidines.
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Prajapati DG, Ramajayam R, Yadav MR, Giridhar R (2009) The search for potent, small molecule NNRTIs. Bioorg Med Chem 17:5744–5762. https://doi.org/10.1016/j.bmc.2009.06.060
De Corte BL (2005) From 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk](1,4)benzodiazepin-2(1H)-one (TIBO) to Etravirine (TMC125): fifteen years of research on non-nucleoside inhibitors of HIV-1 reverse transcriptase. J Med Chem 48:1689–1696. https://doi.org/10.1021/jm040127p
Pauwels R, Andries K, Debyser Z, Van Daele P, Schols D, Stoffels P, De Vreese K, Woestenborghs R, Vandamme AM, Janssen CGM, Anne J, Cauwenbergh G, Desmyter J, Heykants J, Janssen MAC, De Clercq E, Janssen PAJ (1993) Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of a-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc Natl Acad Sci USA 90:1711–1715. https://doi.org/10.1073/pnas.90.5.1711
Schinazi RF, Sommadossi JP, Saalmann V, Cannon DL, **e M-W, Hart GC, Smith GA, Hahn EF (1990) Activities of 3′-azido-3′-deoxythymidine nucleotide dimers in primary lymphocytes infected with human immunodeficiency virus type 1. Antimicrob Agents Chemother 34(6):1061–1067. https://doi.org/10.1128/aac.34.6.1061
Stuyver LJ, Lostia S, Adams M, Mathew J, Pai BS, Grier J, Tharnish P, Choi Y, Chong Y, Choo H, Chu CK, Otto MJ, Schinazi RF (2002) Antiviral activities and cellular toxicities of modified 2′,3′-dideoxy-2′,3′-didehydrocytidine analogues. Antimicrob Agents Chemother 46(12):3854–3860. https://doi.org/10.1128/AAC.46.12.3854-3860.2002
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28(1):235–242. https://doi.org/10.1093/nar/28.1.235
Das K, Bauman JD, Clark AD, Frenkel YV, Lewi PJ, Shatkin AJ, Arnold E (2008) High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci USA 105(5):1466–1471. https://doi.org/10.1073/pnas.0711209105
Yang Y, Kang D, Nguyen LA, Smithline ZB, Pannecouque C, Zhan P, Steitz TA (2018) Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors. Elife. https://doi.org/10.7554/eLife.36340
Kuroda DG, Bauman JD, Challa JR, Patel D, Troxler T, Das K, Hochstrasser RM (2013) Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase. Nat Chem 5(3):174–181. https://doi.org/10.1038/nchem.1559
Bollini M, Frey KM, Cisneros JA, Spasov KA, Das K, Bauman JD, Jorgensen WL (2013) Extension into the entrance channel of HIV-1 reverse transcriptase–crystallography and enhanced solubility. Bioorg Med Chem Lett 23(18):5209–5212. https://doi.org/10.1016/j.bmcl.2013.06.093
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791. https://doi.org/10.1002/jcc.21256
Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR (2012) Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform. https://doi.org/10.1186/1758-2946-4-17
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461. https://doi.org/10.1002/jcc.21334
Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 51(10):2778–2786. https://doi.org/10.1021/ci200227u
Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW, Tang Y (2012) AdmetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 52(11):3099–3105. https://doi.org/10.1021/ci300367a
Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717. https://doi.org/10.1038/srep42717
Gasparyan SP (2011) Synthesis of new analogs of 2-arylpyrrolidinecarbonitriles. Chem J Armenia 64(1):117–122
Gasparyan SP, Alexanyan MV, Harutyunyan GK, Hovhannesyan VE, Martirosyan VV, Paronikyan RV, Stepanyan HM, Martirosyan AH (2012) Synthesis and biological properties of new analogs of 2-arylpyrrolidinecarbonitriles and pyrrolidinecarboxamides. Pharm Chem J 46(6):331–333. https://doi.org/10.1007/s11094-012-0792-2
Gasparyan SP, Alexanyan MV, Harutyunyan GK, Hovhannesyan VE, Martirosyan AH, Panosyan HA (2014) Metal-complex reduction of nitrile groupe in substituted pyrrolidinecarbonitriles. Chem J Armenia 67(2–3):239–246
Gasparyan SP (2016) Synthesis of new derivatives of 2-arylpyrrolidinecarbonitriles and pyrrolidinecarboxamides. Chem J Armenia 69(3):333–340
Martirosyan AH, Gasparyan SP, Alexanyan MV, Harutyunyan GK, Panosyan HA, Schinazi RF (2017) Anti-human immunodeficiency activity of novel 2-arylpyrrolidine analogs. Med Chem Res 26(1):101–108. https://doi.org/10.1007/s00044-016-1731-7
Martirosyan A, Tamazyan R, Gasparyan S, Alexanyan M, Panosyan H, Martirosyan V, Schinazi R (2010) Synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides. Tetrahedron Lett 51(2):231–233. https://doi.org/10.1016/j.tetlet.2009.11.01
Gasparyan SP, Alexanyan MV, Harutyunyan GK, Kocharov SL, Martirosyan AH, Tamazyan RA, Ayvazyan AG, Panosyan HA, Danagulyan GG (2016) Synthesis of new derivatives of 5-(3,4-dihydro-2H-pyrrol-5-yl)pyrimidine. Russ J Org Chem 52(11):1646–1653. https://doi.org/10.1134/S1070428016110166
Acknowledgements
The authors are grateful to the Civilian Research and Development Foundation (CRDF) (Grant No. ARB2-2701-YE-05). This work was also facilitated in part by the NIH Grant P30-AI-050409 (to RFS). This paper is dedicated to the memory of our friend and colleague Dr. Ashot H. Martirosyan who had a huge role in implementation of this work.
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Gasparyan, S.P., Martirosyan, A.H., Alexanyan, M.V. et al. Design, antihuman immunodeficiency activity and molecular docking studies of synthesized 2-aryl and 2-pyrimidinyl pyrrolidines. Mol Divers 25, 2045–2052 (2021). https://doi.org/10.1007/s11030-020-10095-1
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DOI: https://doi.org/10.1007/s11030-020-10095-1