Synthesis and MAO inhibitory activity of novel thiazole-hydrazones

A series of new thiazole-hydrazones (3a 3n) were synthesized, characterized, and screened for their hMAOA and hMAO-B inhibitory activity by an in vitro fluorometric method. Selectivity indexes (SIs) were expressed as IC50 (MAO-A) / IC50 (MAO-B). Compound 3f showed promising hMAO-A inhibition with an IC50 value of 1.20 µM and displayed a very significant SI of 0.04 towards hMAO-A. The mechanism of hMAO-A inhibition was investigated by enzyme kinetics using Lineweaver Burk graphics. Compound 3f was further screened for its cytotoxicity by using a healthy NIH/3T3 mouse embryonic fibroblast cell line (ATCC CRL1658) and was evaluated as nontoxic at its effective concentration against hMAO-A. The ADME prediction of the compounds revealed that they may have good pharmacokinetic profiles, which is necessary for drug candidates.

PDF

___

1. Salgın-G¨ok¸sen, U.; G¨okhan-Kelek¸ci, N.; Yabano˘glu-C¸ift¸ci, S.; Yelek¸ci, K.; U¸car, G. J. Neural. Transm. (Vienna) 2013, 120, 883-891.
2. Patil, P. O.; Sanjay, B. B. Arab. J. Chem. 2014, 7, 857-884.
3. Tripathi, R. K.; Ayyannan, S. R. ChemMedChem 2016, 11, 1551-1567.
4. Garcia-Miralles, M.; Ooi, J.; Ferrari Bardile, C.; Tan, L. J.; George, M.; Drum, C. L.; Lin, R. Y.; Hayden, M. R.; Pouladi, M. A. Exp. Neurol. 2016, 278, 4-10.
5. DAscenzio, M.; Chimenti, P.; Gidaro, M. C.; De Monte, C.; De Vita, D.; Granese, A.; Scipione, L.; Di Santo, R.; Costa, G.; Alcaro, S. et al. J. Enzyme Inhib. Med. Chem. 2015, 30, 908-919.
6. Harris, S.; Johnson, S.; Duncan, J. W.; Udemgba, C.; Meyer, J. H.; Albert, P. R.; Lomberk, G.; Urrutia, R.; Ou, X. M.; Stockmeier, C. A. et al. Neuropsychopharmacology 2015, 40, 1373-1382.
7. Kaya, B.; Sa˘glık, B. N.; Levent, S.; Ozkay, Y.; Kaplancıklı, Z. A. ¨ J. Enzyme Inhib. Med. Chem. 2016, 31, 1654-1661.
8. Chimenti, F.; Maccioni, E.; Secci, D.; Bolasco, A.; Chimenti, P.; Granese, A.; Carradori. S.; Alcaro, S.; Ortuso, F.; Y´anez, M. et al. J. Med. Chem. 2008, 51, 4874-4880.
9. Khattab, S. N.; Abdel Moneim, S. A.; Bekhit, A. A.; El Massry, A. M.; Hassan, S. Y.; El-Faham, A.; Ali Ahmed, H. E.; Amer, A. Eur. J. Med. Chem. 2015, 93, 308-320.
10. Kumar, B.; S, Sheetal.; Mantha, A. K.; Kumar, V. RSC Adv. 2016, 6, 42660-42683.
11. Finberg, J. P. Pharmacol Ther. 2014, 143, 133-152.
12. Badrey, M. G.; Gomha, S. M.; Arafa, W. A. A.; Abdulla, M. M. J. Heterocyclic Chem. 2017, 54, 1215-1227.
13. Chimenti, F.; Bolasco, A.; Secci, S; Chimenti, P.; Granese, A.; Carradori, S.; Y´anez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. Bioorg. Med. Chem. 2010, 18, 5715-5723.
14. Secci, D.; Bolasco, A.; Carradori, S.; DAscenzio, M.; Nescatelli, R.; Y´anez, M. Eur. J. Med. Chem. 2012, 58, 405-417.
15. Evranos-Aks¨oz, B.; Baysal, ˙I.; Yabano˘glu-C¸ift¸ci, S.; Djikic, T.; Yelek¸ci, K.; U¸car, G.; Ertan, R. Arch. Pharm. 2015, 348, 743-756.
16. Tripathi, R. K.; Ayyannan, S. R. ChemMedChem 2016, 11, 1551-1567.
17. Carradori, S.; Rotili, D.; De Monte, C.; Lenoci, A.; DAscenzio, M.; Rodriguez, V.; Filetici, P.; Miceli, M.; Nebbioso, A.; Altucci, L. et al. Eur. J. Med. Chem. 2014, 80, 569-578.
18. Chimenti, F.; Maccioni, E.; Secci, D.; Bolasco, A.; Chimenti, P.; Granese, A.; Befani, O.; Turini, P.; Alcaro, S.; Ortuso, F. et al. J. Med. Chem. 2007, 50, 707-712.
19. BioVision. Fluorometric Monoamine Oxidase A (MAO-A) Inhibitor Screening Kit, Catalog No: K796-100, Data Sheet; BioVision: Milpitas, CA, USA, 2015.
20. BioVision. Fluorometric Monoamine Oxidase B (MAO-B) Inhibitor Screening Kit, Catalog No: K797-100, Data Sheet; BioVision: Milpitas, CA, USA, 2015.
21. Lineweaver, H.; Burk, D. J. Am. Chem. Soc. 1934, 57, 658-666.
22. Pozzolini, M.; Scarfı, M. S.; Benatti, U.; Giovine, M. Anal. Biochem. 2003, 313, 338-341.
23. Mosmann, T. J. Immunol. Methods 1983, 65, 55-63.
24. International Organization for Standardization. Biological Evaluation of Medical Devices-Part 5: Tests for In Vitro Cytotoxicity ISO-10993-5, 3rd ed.; International Organization for Standardization: Geneva, Switzerland, 2009.
25. van de Waterbeemd, H.; Gifford, E. Nat. Rev. Drug Discov. 2003, 2, 192-204.
26. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Deliv. Rev. 2001, 46, 3-26.
27. Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43, 3714-3717.
28. Carpenter, T. S.; Kirshner, D. A.; Lau, E.Y.; Wong, S. E.; Nilmeier, J. P.; Lightstone, F. C. Biophysical J. 2014, 107, 630-641.
29. Lysek, R. Helv. Chim. Acta 2005, 88, 2788-2811.
30. Jampilek, J. Chem. Pap. 2005, 59, 182-186.
31. Bayer, GB Patent No: 694602, 1953.
32. Bradford, M. M. Anal. Biochem. 1976, 72, 248-254.
33. Demir Ozkay, ¨ U.; Can, ¨ O. D.; Sa˘glık, B. N.; Acar C¸ evik, U.; Levent, S.; ¨ Ozkay, Y.; Ilgın, S.; Atlı, ¨ O. ¨ Bioorg. Med. Chem. Lett. 2016, 26, 5387-5394.
34. Sa˘glık, B. N.; Ilgın, S.; Ozkay, Y. ¨ Eur. J. Med. Chem. 2016, 124, 1026-1040.
35. Patel, S.; Gheewala, N.; Suthar, A.; Shah, A. Int. J. Pharm. Sci. 2009, 1, 38-46.