Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

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Abstract

Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

About the authors

S. P. Korolev

Lomonosov Moscow State University; Belozersky Research Institute of Physicochemical Biology, Lomonosov Moscow State University

Author for correspondence.
Email: spkorolev@mail.ru
Россия

O. V. Kondrashina

Lomonosov Moscow State University; Belozersky Research Institute of Physicochemical Biology, Lomonosov Moscow State University

Email: spkorolev@mail.ru
Россия

D. S. Druzhilovsky

Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences

Email: spkorolev@mail.ru
Россия

A. M. Starosotnikov

Zelinsky Institute of Organic Chemistry, Russian Academy of Science

Email: spkorolev@mail.ru
Россия

M. D. Dutov

Zelinsky Institute of Organic Chemistry, Russian Academy of Science

Email: spkorolev@mail.ru
Россия

M. A. Bastrakov

Zelinsky Institute of Organic Chemistry, Russian Academy of Science

Email: spkorolev@mail.ru
Россия

I. L. Dalinger

Zelinsky Institute of Organic Chemistry, Russian Academy of Science

Email: spkorolev@mail.ru
Россия

D. A. Filimonov

Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences

Email: spkorolev@mail.ru
Россия

S. A. Shevelev

Zelinsky Institute of Organic Chemistry, Russian Academy of Science

Email: spkorolev@mail.ru
Россия

V. V. Poroikov

Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences

Email: spkorolev@mail.ru
Россия

Y. Y. Agapkina

Lomonosov Moscow State University; Belozersky Research Institute of Physicochemical Biology, Lomonosov Moscow State University

Email: spkorolev@mail.ru
Россия

M. B. Gottikh

Lomonosov Moscow State University; Belozersky Research Institute of Physicochemical Biology, Lomonosov Moscow State University

Email: spkorolev@mail.ru
Россия

References

  1. Cara A., Guarnaccia F., Reitz M.S. Jr., Gallo R.C., Lori F. // Virology. 1995. V. 208. P. 242-248.
  2. Marcelin A.G., Ceccherini-Silberstein F., Perno C.F., Calvez V. // Curr. Opin. HIV AIDS. 2009. V. 4. P. 531-537.
  3. FDA approves raltegravir tablets. // AIDS Patient Care STDS. 2007. V. 21. № 11. P. 889.
  4. Cooper D.A., Steigbigel R.T., Gatell J.M., Rockstroh J.K., Katlama C., Yeni P., Lazzarin A., Clotet B., Kumar P.N., Eron J.E., et al. // N. Engl. J. Med. 2008. V. 359. № 4. P. 355-365.
  5. Korolev S.P., Agapkina Y.Y., Gottikh M.B. // Acta Naturae. 2011. V. 3. № 3. P. 12-28.
  6. Kobayashi M., Nakahara K., Seki T., Miki S., Kawauchi S., Suyama A., Wakasa-Morimoto C., Kodama M., Endoh T., Oosugi E., et al. // Antiviral Res. 2008. V. 80. № 2. P. 213-222.
  7. Keseru G.M., Makara G.M. // Nature Reviews Drug Discovery. 2009. V. 8. P. 203-212.
  8. Johnson B.C., Metifiot M., Pommier Y., Highes S.H. Antimicrob. Agents Chemother. 2012. V. 56. P. 411-419.
  9. Ma K., Wang P., Fu W., Wan X., Zhou L., Chu Y., Ye D. Bioorg. Med. Chem. Lett. 2011. V. 21. № 22. P. 6724-6727.
  10. Ko G.M., Reddy A.S., Garg R., Kumar S., Hadaegh A.R. // Curr. Comput. Aided Drug Des. 2012. V. 8. № 4. P. 255-270.
  11. Filimonov D.A., Poroikov V.V. Probabilistic approach in activity prediction. In: Chemoinformatics Approaches to Virtual Screening. Eds. Alexandre Varnek and Alexander Tropsha. Cambridge (UK): RSC Publishing. 2008. P. 182-216.
  12. Filimonov D.A., Poroikov V.V. // Rus. Khim. Zhurn. 2006. V. 50. № 2. P. 66-75.
  13. Akimov D.V., Filimonov D.A., Prikazchikova T.A., Gottikh M.B., Poroikov V.V. // Biomed. Khim. 2005. V. 51. № 3. P. 335-340.
  14. Druzhilovsky D.S., Filimonov D.A., Liao C., Peach M., Nicklaus M., Poroikov V.V. Biochemistry (Moscow) Supplemental Series B. Biomedical Chemistry. 2010. V. 4. №1. P. 59-67.
  15. Summa V., Petrocchi A., Bonelli F., Crescenzi B., Donghi M., Ferrara M., Fiore F., Gardelli C., Gonzalez Paz O., Hazuda D.J., et al. // J. Med. Chem. 2008. V. 51. № 18. P. 5843-5855.
  16. http://www.schrodinger.com/products/14/17/
  17. Handzlik J., Bajda M., Zygmunt M., Maciąg D., Dybała M., Bednarski M., Filipek B., Malawska B., Kieć-Kononowicz K. // Bioorg. Med. Chem. 2012. V. 20. № 7. P. 2290-2303.
  18. Shukla S., Kumar P., Das N., Moorthy N.S., Shrivastava S.K., Trivedi P., Srivastava R.S. // Med Chem. 2012. V. 8. № 5. 834-845.
  19. Ghose A.K., Herbertz T., Hudkins R.L., Dorsey B.D., Mallamo J.P. // ACS Chem. Neurosci. 2012. V. 3. № 1. 50-68.
  20. Ghosh P.B., Whitehouse M.W. // J. Med. Chem. 1968. V. 11. P. 305-311.
  21. Ghosh P.B. // J. Chem. Soc. B. 1968. P. 334-338.
  22. Terrier F., Croisat D., Chatrousse A.-P., Pouet M.-J., Halle J.-C., Jacob G. // J. Org. Chem. 1992. V. 57. P. 3684-3689.
  23. Zatsepin T.S., Kachlova A.V., Romanova E.A., Stetsenko D.A., Gait M.J., Oretskaya T.S. Russian J. Bioorg. Chem. 2001. V. 27. №1. P. 39-44.
  24. Leh H., Brodin P., Bischerour J., Deprez E., Tauc P., Brochon J.-C., LeCam E., Coulaud D., Auclair C., Mouscadet J.-F. // Biochemistry. 2000. V. 39. P. 9285-9294.
  25. Malet I., Delelis O., Valantin M.A., Montes B., Soulie C., Wirden M., Tchertanov L., Peytavin G., Reynes J., Mouscadet J-F., et al. // Antimicrob. Agents. Chemother. 2008. V. 52. № 4. P. 1351-1358.
  26. FDA approves new 4-drug once-a-day HIV treatment // AIDS Policy Law. 2012. V. 27. № 11: 1.
  27. Delelis, O., Malet, I., Na, L., Tchertanov, L., Calvez, V., Marcelin, A.G., Subra, F., Deprez, E., Mouscadet, J.-F. // Nucleic Acids Res. 2009. V. 37. P. 1193-1201.
  28. Hare S., Vos A.M., Clayton R.F., Thuring J.W., Cummings M.D., Cherepanov P. // Proc. Natl. Acad. Sci. USA. 2010. V. 107. P. 20057-20062.
  29. Quashie P.K., Sloan R.D., Wainberg M.A. // BMC Med. 2012. V. 10:34
  30. Puras Lutzke R.A., Vink C., Plasterk R.H. // Nucleic Acids Res. 1994. V. 22. № 20. P. 4125-4131.
  31. Smolov M., Gottikh M., Tashlitskii V., Korolev S., Demidyuk I., Brochon J-C., Mouscadet J.-F., Deprez E. // FEBS J. 2006. V. 273. P. 1137-1151.
  32. Michel F., Crucifix C., Granger F., Eiler S., Mouscadet J.-F., Korolev S., Agapkina J., Ziganshin R., Gottikh M., Nazabal A., et al. // EMBO J. 2009. V. 28. P. 980-991.
  33. Krishnan L., Li X., Naraharisetty H.L., Hare S., Cherepanov P., Engelman A. // Proc. Natl. Acad. Sci. U S A. 2010. V. 107. № 36. P. 15910-15915.
  34. Johnson A.A., Marchand C., Patil S.S., Costi R., Di Santo R., Burke T.R.-Jr., Pommier Y. // Mol. Pharmacol. 2007. V. 71. № 3. P. 893-901.
  35. Korolev S.P., Tashlitskii V.N., Smolov M.A., Gromyko A.V., Zhuze A.L., Agapkina Yu.Yu., Gottikh M.B. HIV-1 integrase inhibition by dimeric bisbenzimidazoles with different spacers. // Russian J. Mol. Biol. 2010. V. 44. №4. P. 718-727.
  36. Neamati N., Lin Z., Karki R.G., Orr A., Cowansage K., Strumberg D., Pais G.C., Voigt J.H., Nicklaus M.C., Winslow H.E., et al. // J. Med. Chem. 2002. V. 45. №. 26. P. 5661-5670.
  37. http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf
  38. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000860/WC500037408.pdf

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Copyright (c) 2013 Korolev S.P., Kondrashina O.V., Druzhilovsky D.S., Starosotnikov A.M., Dutov M.D., Bastrakov M.A., Dalinger I.L., Filimonov D.A., Shevelev S.A., Poroikov V.V., Agapkina Y.Y., Gottikh M.B.

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