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Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues

Russian Journal of Bioorganic Chemistry volume 46, pages 822–836 (2020)Cite this article

Abstract—

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains by development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of pregnenolone analogues, 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones, were synthesized. Further, treatment of 3-((4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-ones with thiosemicarbazide in ethanolic KOH or hydrazine hydrate in HOAc gave 5-(4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline, respectively. Analogously, treatment of 3-((4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one with hydroxylamine afforded the Z/E isomers of 3-(4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one oxime. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 3-(thiophene-2-yl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline were the most active in inhibiting HIV-1 and HIV-2 with IC50 = 60.5 μM (SI > 2, against HIV-2 and SI < I against HIV-1), and > 0.29 μM (SI < I), respectively, suggesting to be new leads in the development of antiviral agents. QSAR of 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones and 5-(substituted phenyl)-3-(5-preg-5-3β-ol-17-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamides has been studied. The conformational analysis of 5-(4-trifluoromethylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamide and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline as well as the molecular docking study of the latter compound have been investigated.

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REFERENCES

  1. Ambrosy, A.P., Butler, J., Ahmed, A., Vaduganathan, M., van Veldhuisen, D.J., Colucci,

  2. W.S., and Gheorghiade, M., J. Am. Coll. Cardiol., 2014, vol. 63, pp. 1823–1832. https://doi.org/10.1016/j.jacc.2014.01.051

    CAS  Article  Google Scholar 

  3. Latham, K.A., Zamora, A., Drought, H., Subramanian, S., Matejuk, A., Offner, H., and Rosloniec, E.F., J. Immunol., 2003, vol. 171, pp. 5820–5827. https://doi.org/10.4049/jimmunol.171.11.5820

    CAS  Article  PubMed  Google Scholar 

  4. Dietrich, J., Rao, K., S. Pastorino, and Kesari, S., Expert. Rev. Clin. Pharmacol., 2011, vol. 4, pp. 233–242.https://doi.org/10.1586/ecp.11.1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Rassokhina, I.V., Volkova, Y.A., Kozlov, A.S., Scherbakov, A.M., Andreeva, O.M., Shirinian, V.Z., and Zavarzin, I.V., Steroids, 2016, vol. 113, pp. 29–37. https://doi.org/10.1016/j.steroids. 2016.06.001

  6. Spadari, A., Romagnoli, N., Predieri, P.G., Borghetti, P., Cantoni, A.M., Corradi, A., Res. Veter. Sci., 2013, vol. 94, pp. 379–387. https://doi.org/10.1016/j.rvsc.2012.11.020

    CAS  Article  Google Scholar 

  7. Moreira, V.M., Vasaitis, T.S., Njar, V., and Salvador, J.A.R., Steroids, 2007, vol. 72, pp. 939–948. https://doi.org/10.1016/j.steroids.2007.08.004

    CAS  Article  PubMed  Google Scholar 

  8. Banday, A.H., Shameem, S.A., Gupta, B.D., and Kumar, H.M.S., Steroids, 2010, vol. 75, pp. 801–804.https://doi.org/10.1016/j.steroids.2010.02.015

    CAS  Article  PubMed  Google Scholar 

  9. de Bono, J.S., Logothetis, C.J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K.N., Jones, R.J., and Goodman, O.B., Saad, F., Staffurth, J.N., Mainwaring, P., Harland, S., Flaig, T.W., Huston, T.E., Cheg, T., Patterson, H., Hainsworth, J.D., Ryan, C.J., Sternberg, C.N., Ellard, S.L., Fléchon, A., Saleh, M., Scholz, M., Efstathiou, E., Zivi, A., Bianchini, D., Loriot, Y., Chieffo, N., Kheoh, N., Haqq, C.M., and Scher, H., N. Engl. J. Med., 2001, vol. 364, pp. 1995–2005. https://doi.org/10.1056/NEJMoa1014618

    Article  Google Scholar 

  10. Bryce, A. and Ryan, C.J., Clin. Pharmacol. Ther., 2012, vol. 91, pp. 101–108. https://doi.org/10.1038/clpt.2011.275

    CAS  Article  PubMed  Google Scholar 

  11. Handratta, V.D., Vasaitis, T.S., Njar, V.C., Gediya, L.K., Kataria, R., Chopra, P., Newman, D., Farquhar, R., Guo, Z., Qiu, Y., and Brodie, A.M., J. Med. Chem., 2005, vol. 48, pp. 2972–2984. https://doi.org/10.1021/jm040202w

    CAS  Article  PubMed  Google Scholar 

  12. Banday, A.H., Zargar, and M.I., Ganaie, B.A., Steroids, 2011, vol. 76, pp. 1358–1362. https://doi.org/10.1016/j.steroids.2011.07.001

  13. Lone, I.H., Khan, K.Z., Fozdar, B.I., and Hussain, F., Steroids, 2013, vol. 78, pp. 945–950. https://doi.org/10.1016/j.steroids.2013.05.015

  14. Banday, A.H., Akram, S.S.M., and Shameem, S.A., Steroids, 2014, vol. 84, pp. 64–69. https://doi.org/10.1016/j.steroids.2014.03.010

    CAS  Article  PubMed  Google Scholar 

  15. Sisodia, B.S., Negi, S.A., Darokar, M.P., Dwivedi, U.N., and Khanuja, S.P., Chem. Biol. Drug Des., 2012, vol. 79, pp. 610–615. https://doi.org/10.1111/j.1747-0285.2012.01323.x

    CAS  Article  PubMed  Google Scholar 

  16. Banday, A.H., Shameem, S.A., and Jeelani, S., Steroids, 2014, vol. 92, pp. 13–19. https://doi.org/10.1016/j.steroids.2014.09.004

    CAS  Article  PubMed  Google Scholar 

  17. Choudhary, M.I., Alam, M.S., Atta-ur-Rahman, Yousuf, S., Wu, Y.-C., Lin, A.-S., and Shaheen, F., Steroids, 2011, vol. 76, pp. 1554–1559. https://doi.org/10.1016/j.steroids. 2011.09.006

  18. Pinto-Bazurco M.M.A., Negri, M., Jagusch, C., Müller-Vieira, U., Lauterbach, T., and Hartmann, R.W., J. Med. Chem., 2018, vol. 51, pp. 5009–5018. https://doi.org/10.1021/jm800355c

    CAS  Article  Google Scholar 

  19. Salvador, J.A.R., Moreira, V.M., and Silvestre, S.M., Steroidal CYP17 inhibitors for prostate cancer treatment: from concept to clinic, in Advances in Prostate Cancer, Hamilton, G., Ed., Rijeka, Croatia: InTech, 2013, chapter 12, pp. 275–304.https://doi.org/10.5772/45948

    Book  Google Scholar 

  20. Haidar, S., Ehmer, P.B., Barassin, S., Batzl-Hartmann, C., Hartmann, R.W., J. Steroid. Biochem. Mol. Biol., 2003, vol. 84, pp. 555–562.https://doi.org/10.1016/S0960-0760(03)00070-0

  21. Al-Masoudi, N.A., Ali, D.S., Saeed, B., Hartmann, R.W., Engel, M., and Rashid, S., Arch. Pharm. Chem. Life Sci., 2014, vol. 374, pp. 896–907. https://doi.org/10.1002/ardp.201400255

    CAS  Article  Google Scholar 

  22. Al-Masoudi, N.A., Mahdi, K.M., Abdul-Rida, N.A., Saeed, B.A., and Engel, M., Steroids, 2015, vol. pp. 52–59.https://doi.org/10.1016/j.steroids.2015.05.002

  23. Al-Masoudi, N.A., Kadhim, R.A., Abdul-Rida, N.A., Saeed, B.A., and Engel, M., Steroids, 2015, vol. 101, pp. 43–50. https://doi.org/10.1016/j.steroids.2015.05.011

    CAS  Article  PubMed  Google Scholar 

  24. Mahdi, K.M., N Abdul-Rida, N.A., and Al-Masoudi, N.A., Eur. J. Chem., 2015, vol. 6, pp. 1–7. https://doi.org/10.5155/eurjchem.6.1.1-7.1139

  25. Karthikeyan, C., Moorthy, N.S.H.N., Ramasamy, S., Vanam, U., Manivannan, E., Karunagaran, D., and Trivedi, P., Recent Pat. Anticancer Drug Discov., 2015, vol. 10, pp. 97–115. https://doi.org/10.2174/1574892809666140819153902

    CAS  Article  PubMed  Google Scholar 

  26. Dominguez, J.N., León, C., Rodrigues, J., de Dominguez, N.G., Gut, J., and Rosenthal, P.J., J. Med. Chem., 2005, vol. 48, pp. 3654–3658. https://doi.org/10.1021/jm058208o

    CAS  Article  PubMed  Google Scholar 

  27. Lee, S.H., Seo, G.S., Kim, J.Y., Jin, X.Y., Kim, H.D., and Sohn, D.H., Eur. J. Pharmacol., 2006, vol. 532, pp. 178–186. https://doi.org/10.1016/j.ejphar.2006.01.005

    CAS  Article  PubMed  Google Scholar 

  28. Al-Hazam, H.A., Al-Shamkani, Z.A., Al-Masoudi, N.A., Saeed, B.A., and Pannecouque, C., Z. Naturforsch., 2017, vol. 72, pp. 249–256. https://doi.org/10.1016/j.ejphar.2006.01.005

    CAS  Article  Google Scholar 

  29. Rizvi, S.U.F., Siddiqui, H.L., Johns, M., Detorio, M., and Schinazi, R.F., Med. Chem. Res., 2012, vol. 21, pp. 3741–3749. https://doi.org/10.1007/s00044-011-9912-x

    CAS  Article  Google Scholar 

  30. Svetaz, L., Tapia, A., Lopez, S.N., Furlan, R.L.E., Petenatti, E., Pioli, R., Schmeda-Hirschmann, G., and Zacchino, S.A., J. Agric. Food Chem., 2004, vol. 52, pp. 3297–3300. https://doi.org/10.1021/jf0352 13x

  31. Willker, W., Leibfritz, D., Kerssebaum, R., and Bermel, W., Magn. Reson. Chem., 1993, vol. 31, pp. 287–292. https://doi.org/10.1002/mrc.1260310315

    CAS  Article  Google Scholar 

  32. Pannecouque, C., Daelemans, D., and De Clercq, E., Nat. Protoc., 2008, vol. 3, pp. 427–434. https://doi.org/10.1038/nprot.2007.517

    CAS  Article  PubMed  Google Scholar 

  33. Hargrave, K.D., Proudfoot, J.R., Grozinger, K.G., Cullen, E., Kapadia, S.R., Patel, U.R., Fuchs, V.U., Mauldin, S.C., Vitous, J., Behnke, M.L., Klunder, J.M., Pal, K., Skiles, J.W., McNieil, D.W., Rose, J.M., Chow, G.C., Skoog, M.T., Wu, J.C., Schmidt, G., Engel, W.E., Eberlein, W.G., Saboe, T.D., Rosenthal, A.S., and Adams, J., J. Med. Chem., 1991, vol. 34, pp. 2231–2241. https://doi.org/10.1021/jm00111a045

    CAS  Article  PubMed  Google Scholar 

  34. Mitsuya, H., Weinhold, K.J., Furman, P.A., St. Clair, M.H., Lehrmann, H.N., Gallo, R.C., Bolognesi, D., Barry, D.W., and Broder, S., Proc. Natl. Acad. Sci. U. S. A., 1985, vol. 82, pp. 7096–7100. https://doi.org/10.1073/pnas.82.20.7096

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Ducki, S., Forrest, R., Hadfield, J.A., Kendall, A., Lawrence, N.J., McGown, A.T., David, D., and Rennison, D., Bioorg. Med. Chem. Lett., 1998, vol. 8, pp. 1051–1056. https://doi.org/10.1016/S0960-894X (98)00162-0

  36. Becke, A.D., J. Chem. Phys., 1993, vol. 98, pp. 5648–5652. https://doi.org/10.1063/1.464913

    CAS  Article  Google Scholar 

  37. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., et al., Gaussian, Inc., Wallingford CT, 2016.

  38. Molecular Operating Enviroment (MOE), 2013.08, Chemical Computing Group ULC, 1010 Sherbooks St. West, Suit #910, Montreal, QC, Canada, H3A 2R7, 2018.

  39. Ren, J., Chamberlain, P.P., Stamp, A., Short, S.A., Weaver, K.L., Romines, K.R., Hazen, R., Freeman, A., Ferris, R.G., Andrews, C.W., Boone, L., Chan, H.H., and Stammers, D.K., J. Med. Chem., 2008, vol. 51, pp. 5000–50 008. https://doi.org/10.1021/jm8004493

    CAS  Article  PubMed  Google Scholar 

  40. Sahu, V.K., Khan, A.K.R., Singh, R.K., and Singh, P.P., Am. J. Immunol., 2008, vol. 4, pp. 33–42. https://doi.org/10.3844/ajisp.2008.33.42

    CAS  Article  Google Scholar 

  41. DMOL3User Guide, San Diego, CA, USA: Accelrys, Inc., 2003.

  42. Rogers, D., and Hopfinger, A.J., J. Chem. Inf. Comput. Sci., 1994, vol. 34, pp. 854–866. https://doi.org/10.1021/ci00020a020

    CAS  Article  Google Scholar 

  43. Popovic, M., Sarngadharan, M.G., Read, E., and Gallo, R.C., Science, 1984, vol. 224, pp. 497–500. https://doi.org/10.1126/science.6200935

    CAS  Article  PubMed  Google Scholar 

  44. Barré-Sinoussi, F., Chermann, J.C., Rey, F., Nugeyre. M.T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Vezinet-Brun, F., Rouzioux, C., Rozenbaum, W., and Montagnier, L., Science, 1983, vol. 220, pp. 868–871. https://doi.org/10.1126/science.6189183

    Article  PubMed  Google Scholar 

  45. Miyoshi, I., Taguchi, H., Kobonishi, I., Yoshimoto, S., Ohtsuki, Y., Shiraishi, Y., and Akagi, T., Gann. Monogr. Cancer Res., 1982, vol. 28, pp. 219–228.

    Google Scholar 

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ACKNOWLEDGMENTS

W. Al-Masoudi would like to thank College of Verterinary, Basrah University, Iraq, for the sabbatical leave. We thank Miss A. Friemel of the Chemistry, Department, Konstanz University, Germany, for the 2D NMR experiments.

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Authors and Affiliations

  1. Department of Physiology, Pharmacology and Chemistry, College of Veterinary, University of Basrah, 61001, Basrah, Iraq

    Wasfi A. Al-Masoudi

  2. Department of Chemistry, College of Science, University of Basrah, Basrah, 61001, Iraq

    Najim A. Al-Masoudi

  3. Department of Chemistry, College of Education, University of Basrah, 61001, Basrah, Iraq

    Bahjat A. Saeed

  4. Department of Chemistry, University of Konstanz, D-78464, P.O. Box 5560, Konstanz, Germany

    Rainer Winter

  5. Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000, Leuven, Belgium

    Christophe Pannecouque

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  1. Wasfi A. Al-Masoudi
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Correspondence to Najim A. Al-Masoudi.

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Wasfi A. Al-Masoudi, Al-Masoudi, N.A., Saeed, B.A. et al. Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues. Russ J Bioorg Chem 46, 822–836 (2020). https://doi.org/10.1134/S1068162020050039

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Keywords:

  • anti-HIV activity
  • α-unsaturated ketones
  • cytotoxicity
  • molecular docking study
  • QSAR
  • pregnenolone