Para-Aminobenzohydrazide Derivatives as Fatty Acid Amide Hydrolase Inhibitors: Design, Synthesis and Biological Evaluation

Document Type : Research article

Authors

1 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Centra Research Labretories, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Abstract

The endocannabinoid system plays an important neuromodulatory role in the periphery and central nervous system, which can regulate several physiological processes. The inhibition of enzymatic activities responsible for hydrolysis anandamide and other endogenous fatty acid amides, enhances cannabinoid receptors activity indirectly that may prove to be useful drugs for the treatment of range of ailments including pain, anxiety, and other central nervous system disorders. In this study, we designed, synthesized, and evaluated novel fatty acid amide hydrolase (FAAH) inhibitors based on 4-aminobenzohydrazide derivatives. Most of the synthesized compounds exhibited a proper affinity for the catalytic triad of FAAH in docking studies and had a considerable in-vitro FAAH inhibitory activity in comparison with JZL-195, a potent inhibitor of FAAH. Compound 2-(2-(4-(2-carboxybenzamido)benzoyl)hydrazine-1-carbonyl)benzoic acid, 12, was found to be the most potent inhibitor with IC50 value of 1.62 nM targeting FAAH enzyme.

Graphical Abstract

Para-Aminobenzohydrazide Derivatives as Fatty Acid Amide Hydrolase Inhibitors: Design, Synthesis and Biological Evaluation

Keywords

References

(1)      Río C del, Millán E, García V, Appendino G, DeMesa J and Muñoz E. The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders. Biochem. Pharmacol. (2018) 157: 122–33.
(2)      McPartland JM. The endocannabinoid system: an osteopathic perspective. J. Am. Osteopath. Assoc. (2008) 108: 586–600.
(3)      Fride E and Mechoulam R. Pharmacological activity of the cannabinoid receptor agonist, anandamide, a brain constituent. Eur. J. Pharmacol. (1993) 231: 313–14.
(4)      Devane WA, Hanuš L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A and Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (1992) 258: 1946–49.
(5)      Kerbrat A, Ferré JC, Fillatre P, Ronzière T, Vannier S, Carsin-Nicol B, Lavoué S, Vérin M, Gauvrit JY, Le Tulzo Y and Edan G. Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N. Engl. J. Med. (2016) 375: 1717–25.
(6)      Deplano A, Morgillo CM, Demurtas M, Björklund E, Cipriano M, Svensson M, Hashemian S, Smaldone G, Pedone E, Luque FJ, Cabiddu MG, Novellino E, Fowler CJ, Catalanotti B and Onnis V. Novel propanamides as fatty acid amide hydrolase inhibitors. Eur. J. Med. Chem. (2017) 136: 523–42.
(7)      Burman MA, Szolusha K, Bind R, Kerney K, Boger DL and Bilsky EJ. FAAH inhibitor OL-135 disrupts contextual, but not auditory, fear conditioning in rats. Behav. Brain Res. (2016) 308: 1–5.
(8)      Otrubova K, Ezzili C and Boger DL. The discovery and development of inhibitors of fatty acid amide hydrolase (FAAH). Bioorg. Med. Chem. Lett. (2011) 21: 4674–85.
(9)      Boger DL, Sato H, Lerner AE, Hedrick MP, Fecik RA, Miyauchi H, Wilkie GD, Austin BJ, Patricelli MP and Cravatt BF. Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide. Proc. Natl. Acad. Sci. U. S. A. (2000): 97: 5044–49.
(10)    Taylor RD, Maccoss M and Lawson ADG. Rings in drugs. J. Med. Chem. (2014) 57: 5845–59.
(11)    Tokumaru K and Johnston JN. A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions. Chem. Sci. (2017) 8: 3187–91.
(12)    Zavareh ER, Hedayati M, Rad LH, Shahhosseini S, Faizi M and Tabatabai SA. Design, synthesis and biological evaluation of 4-benzamidobenzoic acid hydrazide derivatives as novel soluble epoxide hydrolase inhibitors. Iran. J. Pharma. Res. (2014) 13: 51.
(13)    Demare P and Regla I. Synthesis of two local anesthetics from toluene: an organic multistep synthesis in a project-oriented laboratory course. J. Chem. Educ. (2012) 89: 147–49.
(14)    Dunetz JR, Magano J and Weisenburger GA. Large-scale applications of amide coupling reagents for the synthesis of pharmaceuticals. Org. Process Res. Dev. (2016) 20: 140–77
(15)    Soliman R and Darwish SAS. Antidiabetic activity of some 1-substituted 3,5-dimethylpyrazoles. J. Med. Chem. (1983) 26: 1659–63.
Iranian Journal of Pharmaceutical Research
Volume 19, Issue 4
Autumn 2020
Pages 103-112

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