DESIGN AND SYNTHESIS OF SOME ARYLHYDRAZONE DERIVATIVES AS POTENTIAL FAAH INHIBITORS

Year 2023, , 111 - 119, 20.01.2023

Zehra Tuğçe Gür Maz , Sümeyye Turanlı , H. Burak Calıskan

https://doi.org/10.33483/jfpau.1181948

Abstract

Objective: The aim was to design, synthesis and investigation of possible interactions in the enzyme active site of a series of arylhydrazone derivatives for the inhibition of the FAAH enzyme.”

Material and Method: Arylhydrazone derivatives were obtained through the reaction of nicotinic hydrazide or benzohydrazide with appropriate aldehyde derivatives, and the obtained crude product was recrystallized from ethanol. After elucidating chemical structures of the compounds via spectroscopic methods, the inhibitory activities against hFAAH were screened. The results were further supported with molecular modeling studies.

Result and Discussion: In this study, a new series of seven arylhydrazone derivatives were screened against hFAAH. 4-phenoxyphenyl bearing derivative 5 was found to inhibit hFAAH 40 % at 10 µM which indicates that newly developed inhibitor could serve as a starting point for improving inhibitory effect of the new series.

Keywords

Arylhydrazones, FAAH, heterocycles, inflammation

Supporting Institution

Gazi University Scientific Research Project Unit

Project Number

BAP: 02/2020-24

Thanks

The authors would like to thank Prof. Dr. Burcu Caliskan for providing her expertise in this research. This research is financially supported by Gazi University Scientific Research Project Unit (BAP: 02/2020-24).

POTANSİYEL FAAH İNHİBİTÖRÜ OLARAK BAZI ARİLHİDRAZON TÜREVİ BİLEŞİKLERİN TASARIMI VE SENTEZİ

Abstract

Amaç: FAAH enziminin inhibisyonu amacıyla bir seri arilhidrazon türevi bileşiğin tasarımı, sentezi ve enzim aktif bölgesinde olası etkileşimlerinin incelenmesidir.

Gereç ve Yöntem: Nikotinik hidrazit veya benzohidrazidin uygun aldehit türevleri ile reaksiyonu sonucu arilhidrazon türevleri elde edilmiş, elde edilen ham ürünler etanolden rekristalize edilmiştir. Bileşiklerin yapısı spektroskopik yöntemler ile aydınlatıldıktan sonra hFAAH enzimine karşı aktiviteleri taranmıştır. Elde edilen sonuçlar moleküler modelleme çalışmaları ile desteklenmiştir.

Sonuç ve Tartışma: Bu çalışmada, bir seri yedi arilhidrazon türevi hFAAH'a karşı taranmıştır. 4-fenoksifenil içeren türev olan Bileşik 5'in 10 uM'de hFAAH'ı % 40 oranında inhibe ettiği bulunmuş olup; ileri çalışmalarda potansiyel hFAAH inhibitörü olarak kullanılabilecek yeni bir arilhidrazon türevine ulaşılmıştır.

Keywords

Arilhidrazonlar, FAAH, heterosiklikler, inflamasyon

Project Number

BAP: 02/2020-24

References

• 1. Van Egmond, N., Straub, V.M., van der Stelt, M. (2021). Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors. Annual Review of Pharmacology and Toxicology, 61, 441-463. [CrossRef]
• 2. Mechoulam, R., Parker, L. A. (2013). The Endocannabinoid System and the Annual Review of Psychology, 64(1), 21-47. [CrossRef]
• 3. Lutz, B., Marsicano, G., Maldonado, R., Hillard, C.J. (2015). The endocannabinoid system in guarding against fear, anxiety and stress. Nature Reviews Neuroscience, 16(12), 705-718. [CrossRef]
• 4. Tuo, W., Leleu-Chavain, N., Spencer, J., Sansook, S., Millet, R., Chavatte, P. (2017). Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors. Journal of Medicinal Chemistry, 60(1), 4-46. [CrossRef]
• 5. Sachs, J., McGlade, E., Yurgelun-Todd, D. (2015). Safety and Toxicology of Cannabinoids. Neurotherapeutics, 12(4), 735-746. [CrossRef]
• 6. Bajaj, S., Jain, S., Vyas, P., Bawa, S., Vohora, D. (2021). The role of endocannabinoid pathway in the neuropathology of Alzheimer's disease: Can the inhibitors of MAGL and FAAH prove to be potential therapeutic targets against the cognitive impairment associated with Alzheimer's disease? Brain Research Bulletin, 174, 305-322. [CrossRef]
• 7. Bonifácio, M.J., Sousa, F., Aires, C., Loureiro, A.I., Fernandes-Lopes, C., Pires, N.M., Palma, P.N., Moser, P., Soares-da-Silva, P. (2020). Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10-2474. British Journal of Pharmacology, 177(9), 2123-2142. [CrossRef]
• 8. Ahn, K., Smith, S.E., Liimatta, M.B., Beidler, D., Sadagopan, N., Dudley, D.T., Young, T., Wren, P., Zhang, Y., Swaney, S., Van Becelaere, K., Blankman, J.L., Nomura, D.K., Bhattachar, S.N., Stiff, C., Nomanbhoy, T.K., Weerapana, E., Johnson, D.S., Cravatt, B.F. (2011). Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. The Journal of Pharmacology and Experimental Therapeutics, 338(1), 114-124. [CrossRef]
• 9. Ahn, K., Johnson, D.S., Mileni, M., Beidler, D., Long, J.Z., McKinney, M.K., Weerapana, E., Sadagopan, N., Liimatta, M., Smith, S. E., Lazerwith, S., Stiff, C., Kamtekar, S., Bhattacharya, K., Zhang, Y., Swaney, S., Van Becelaere, K., Stevens, R.C., Cravatt, B.F. (2009). Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chemistry & Biology, 16(4), 411-420. [CrossRef]
• 10. Rocha, J.F., Santos, A., Gama, H., Moser, P., Falcao, A., Pressman, P., Wallace Hayes, A., Soares-da-Silva, P. (2022). Safety, Tolerability, and Pharmacokinetics of FAAH Inhibitor BIA 10-2474: A Double-Blind, Randomized, Placebo-Controlled Study in Healthy Volunteers. Clinical Pharmacology & Therapeutics, 111(2), 391-403. [CrossRef]
• 11. Tripathi, R.K.P. (2020). A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents. European Journal of Medicinal Chemistry, 188, 111953. [CrossRef]
• 12. Fazio, D., Criscuolo, E., Piccoli, A., Barboni, B., Fezza, F., Maccarrone, M. (2020). Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold? Expert Opinion on Drug Discovery, 15(7), 765-778. [CrossRef]
• 13. Shang, Y., Hao, Q., Jiang, K., He, M., Wang, J. (2020). Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation. Bioorganic Medicinal Chemistry Letters, 30(10), 127118. [CrossRef]
• 14. Jaiswal, S., Ayyannan, S.R. (2022). Discovery of Isatin-Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase. ChemMedChem, 17(1), e202100559. [CrossRef]
• 15. Freitas, R., Barbosa, J.M.C., Bernardino, P., Sueth-Santiago, V., Wardell, S., Wardell, J.L., Decote-Ricardo, D., Melo, T. G., da Silva, E.F., Salomao, K., Fraga, C.A.M. (2020). Synthesis and trypanocidal activity of novel pyridinyl-1,3,4-thiadiazole derivatives. Biomedicine & Pharmacotherapy, 127, 110162. [CrossRef]
• 16. Fugard, A.J., Thompson, B.K., Slawin, A.M., Taylor, J.E., Smith, A.D. (2015). Organocatalytic Synthesis of Fused Bicyclic 2,3-Dihydro-1,3,4-oxadiazoles through an Intramolecular Cascade Cyclization. Organic Letters, 17(23), 5824-5827. [CrossRef]
• 17. Sarıgöl, D., Yüksel, D., Okay, G., Uzgören-Baran, A. (2015). Synthesis and structural studies of acyl hydrazone derivatives having tetrahydrocarbazole moiety. Journal of Molecular Structure, 1086, 146-152. [CrossRef]
• 18. Syakaev, V.V., Podyachev, S.N., Buzykin, B.I., Latypov, S.K., Habicher, W.D., Konovalov, A.I. (2006). NMR study of conformation and isomerization of aryl- and heteroarylaldehyde 4-tert-butylphenoxyacetylhydrazones. Journal of Molecular Structure, 788(1-3), 55-62. [CrossRef]
• 19. Alp, A.S., Kilcigil, G., Ozdamar, E.D., Coban, T., Eke, B. (2005). Synthesis and evaluation of antioxidant activities of novel 1,3,4-oxadiazole and imine containing 1H-benzimidazoles. Turkish Journal of Chemistry, 39, 42-53. [CrossRef]
• 20. Munir, R., Javid, N., Zia-Ur-Rehman, M., Zaheer, M., Huma, R., Roohi, A., Athar, M.M. (2021). Synthesis of Novel N-Acylhydrazones and Their C-N/N-N Bond Conformational Characterization by NMR Spectroscopy. Molecules, 26(16). [CrossRef]