Sinan BAYINDIR, Adnan AYNA, Mehmet ÇİFTCİ, Yusuf TEMEL

The synthesis of new oxindoles as analogs of natural product 3,3′ -bis(indolyl)oxindole and in vitro evaluation of the enzyme activity of G6PDand 6PGD

Natural and synthetic derivatives that contain an indole core are being used in medical treatments and technological processes. Therefore, the development of new synthetic methods for the synthesis of indole derivatives is very popular. In this study, new oxindoles with reaction of 4,7-dihydro-1H -indole (2) and isatin (4) were synthesized as analogs of natural product 3,3′ -bis(indolyl)oxindole. The biological properties of the compounds obtained during this study were also studied, showing that compounds 5, 7, and 12 inhibited the activity of G6PD with an IC50 of 99 µM, 231 µM, and 304 µM respectively. The activity of rat erythrocyte 6PGD was increased in the presence of 5 and 7 and was inhibited in the presence of 12. As indole derivative 5 was an activator of 6PGD and inhibitor of G6PD, it was selected for docking studies to understand the mechanism of activation and inhibition.

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1. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875-2911.
2. Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-2920.
3. Kamal, A.; Srikanth, Y. V. V.; Khan, M. N. A.; Shaik, T. B.; Ashraf, M. Bioorg. Med. Chem. Lett. 2010, 20, 5229-5231.
4. Sayed, M. T.; Mahmoud, K.; Hilgeroth, A.; Fakhr, I. M. I. J. Heterocyclic Chem. 2016, 53, 188-196.
5. Huber, K.; Schemies, J.; Uciechowska, U.; Wagner, J. M.; Rumpf, T.; Lewrick, F.; Süss, R.; Sippl, W.; Jung, W.; Bracher, F. J. Med. Chem. 2010, 53, 1383-1386.
6. Giannini, G.; Marzi, M.; Marzo, M. D.; Battistuzzi, G.; Pezzi, R.; Brunetti, T. Bioorg. Med. Chem. Lett. 2009, 19, 2840-2844.
7. Gaisina, I. N.; Gallier, F.; Ougolkov, A. V.; Kim, K. H.; Kurome, T.; Guo, S.; Holzle, D.; Luchini, D. N.; Blond, S. Y.; Billadeau, D. D. et al. J. Med. Chem. 2009, 52, 1853-1863.
8. Paira, P.; Hazra, A.; Kumar, S.; Paira, R.; Sahu, K. B.; Naskar, S.; Saha, P.; Mondal, S.; Maity, A.; Banerjee, S. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4786-4789.
9. Shiri, M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250-2293.
10. Safe, S.; Papineni, S.; Chintharlapalli, S. Cancer Lett. 2008, 269, 326-338.
11. Lee, J. Y.; Lee, M. H.; Jeong, K. S. Supramol. Chem. 2007, 19, 257-263.
12. Chmielewski, M. J.; Charon, M.; Jurczak, J. Org. Lett. 2004, 6, 3501-3504.
13. Kilic, H.; Aydin, O.; Bayindir, S.; Saracoglu, N. J. Heterocyclic Chem. 2016, 53, 2096-2101.
14. Hong, L.; Liu, C.; Sun, W.; Wang, L.; Wong, K.; Wang, R. Org. Lett. 2009, 10, 2177-2180.
15. Gao, J.; Shao, Y.; Zhu, J.; Zhu, J.; Mao, H.; Wang, X.; Lv, J. Org. Chem. 2014, 79, 9000-9008.
16. Zhao, F.; Zhang, D.; Nian, Y.; Zhang, L.; Yang W.; Liu, H. Org. Lett. 2014, 16, 5124-5127.
17. Lu, B. Z.; Wei, H. X.; Zhang, Y.; Zhao, W.; Dufour, M.; Li, G.; Farina, V.; Senanayake, C. H. J. Org. Chem. 2013, 78, 4558-4562.
18. Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org. Lett. 2013, 15, 1802-1805.
19. Prasad, B.; Adepu, R.; Sandra, S.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Deora, G. S.; Misra, P.; Pal, M. Chem. Commun. 2012, 48, 10434-10436.
20. Bayindir, S.; Erdogan, E.; Kilic, H.; Saracoglu, N. Synlett 2010, 10, 1455-1458.
21. Kilic, H.; Bayindir, S.; Erdogan, E.; Saracoglu, N. Tetrahedron 2012, 68, 5619-5630.
22. Bayindir, S.; Erdogan, E.; Kilic, H.; Aydin, O.; Saracoglu, N. J. Heterocyclic Chem. 2015, 52, 1589-1594.
23. Aydin, O.; Kilic, H.; Bayindir, S.; Saracoglu, N. J. Heterocyclic Chem. 2016, 53, 1540-1553.
24. Kilic, H.; Bayindir, S.; Erdogan, E.; Agopcan, C. S.; Konuklar, F. A. S.; Bali, S. K.; Saracoglu, N.; Aviyente, V. New J. Chem. 2017, 41, 9674-9687.
25. Çavdar, H.; Saraçoğlu, N. Tetrahedron 2005, 61, 2401-2405.
26. Çavdar, H.; Saraçoğlu, N. J. Org. Chem. 2006, 71, 7793-7799.
27. Kilic, H.; Bayindir, S.; Saracoglu, N. Curr. Org. Chem. 2014, 11, 167-181.
28. Bayindir, S.; Saracoglu, N. RSC Adv. 2016, 6, 72959-72967.
29. Wang, L. T.; He, X. M.; Guo, Y.; Xu, J. A.; Shao, S. J. Org. Biomol. Chem. 2011, 9, 752-757.
30. Gale, P. A.; Garrido, S. E. G.; Garric, J. Chem. Soc. Rev. 2008, 37, 151-190.
31. Ghosh, K.; Kar, D.; Joardar, S.; Samander, A.; Bukhsh, A. R. K. RSC Adv. 2014, 4, 11590-11597.
32. Talaz, O.; Cavdar, H.; Durdagi, S.; Azak, H.; Ekinci, D. Bioorg. Med. Chem. 2013, 21, 1477-1482.
33. Gupte, S. A. Curr. Opin. Investig Drugs 2008, 9, 993-1000.
34. Beutler, E. N. Engl. J. Med. 1991, 324, 169-174.
35. Kovarova, J.; Barrett, M.P. Trends Parasitol. 2016, 32, 8, 622-634.
36. Krebs, H. A.; Eggleston, L. V. Adv. Enzyme Regul. 1978, 12, 421-433.
37. Zhang, C.; Zhang, Z.; Zhu, Y.; Qin, S. Anticancer Agents Med. Chem. 2014, 14, 280-289.
38. Park, J.; Rho, H. K.; Kim, K. H.; Choe, S. S.; Lee, Y. S.; Kim, J. B. Mol. Cell Biol. 2005, 25, 5146-5157.
39. Park, J.; Choe, S. S.; Choi, A. H.; Kim, K. H.; Yoon, M. J.; Suganami, T.; Ogawa, Y.; Kim, J. B. Diabetes 2006, 55, 2939-2949.
40. Lin, R.; Elf, S.; Shan, C.; Kang, H. B.; Ji, Q.; Zhou, L.; Hitosugi, T.; Zhang, L.; Zhang, S.; Seo, J. H. et al. Nat. Cell Biol. 2015, 17, 1484-1496.
41. Ozmen, I.; Kufrevioglu, O. I.; Gul, M. Drug Chem. Toxicol. 2005, 28, 433-445.
42. Temel, Y.; Kocyigit, U. M. J. Biochem Mol Toxicol. 2017, 31, 21927-21931.
43. Beydemir, S.; Ciftci, M.; Yılmaz, H.; Küfrevioglu, O. I. Turk. J. Vet. Anim. Sci. 2004, 28, 707-714.
44. Adams, M. J.; Ellis, G. H.; Gover, S.; Naylor, C. E.; Phillips, C. Structure 1994, 2, 651-668.
45. Zhang, L.; Chooback, L.; Cook, P. F. Biochem. J. 1999, 38, 11231-11238.
46. Karsten, W. E.; Chooback, L.; Cook, P. F. Biochem. J. 1998, 37, 15691-15697.
47. Kelley, L. A.; Mezulis, S.; Yates, C. M.; Wass, M. N.; Sternberg, M. J. Nat Protoc. 2015, 10, 845-858.
48. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. J. App. Cryst. 1993, 26, 283-291.
49. Grosdidier, A.; Zoete, V.; Michielin, O. Nucleic Acids Res. 2011, 39, 270-277.
50. Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. J Comput Chem. 2004, 25, 1605-1612.
51. Delano, W. L. The PyMOL Molecular Graphics System; Schr¨odinger: Cambridge, MA, USA, 2002.