Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies

Maleki, Mahdi Faal; Nadri, Hamid; Kianfar, Mostafa; Edraki, Najmeh; Eisvand, Farhad; Ghodsi, Razieh; Mohajeri, Seyed Ahmad; Hadizadeh, Farzin

doi:10.1016/j.bioorg.2021.104684

Cited by 20 publications

(11 citation statements)

References 49 publications

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“…Inhibition mechanism of the inhibitor 19 was evaluated using previously reported methods. [23,24] To evaluate the mechanism of inhibition, compound 19 was preincubated with the enzyme for 0, 15, 30, and 60 min before adding the substrate to initiate the reaction (Figure 3). Reversible inhibitors display a constant inhibitor potency regardless of preincubation time; in contrast, for irreversible inhibitors, the potency is enhanced when a longer preincubation time is employed.…”

Section: Preincubation Testmentioning

confidence: 99%

“…[25] The FAAH binding mode of the docked compounds was rationalized by taking into account the elemental amino acids in the active site of the enzyme as described for the substrate and inhibitor ligand. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] First, the docking method was validated by comparing the re-docked crystal ligand with the ligand in the co-crystal structure considering the covalent bond with S241 as well as H-bonding interactions with L142, I238, S241, and also π-π stacking with F381 (Figure S1). The substrate-binding site and the mechanism of hydrolysis for FAAH were previously elucidated as follows:…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

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Development and molecular modeling studies of new thiadiazole piperazine urea derivatives as potential fatty acid amide hydrolase inhibitors

Maz

Turanlı

Caliskan

et al. 2022

Archiv der Pharmazie

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A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). The urea derivatives possessing p-chlorophenylthiadiazole and benzylpiperazine fragments (19-22) were effective inhibitors of hFAAH. Notably, compounds with 4-chlorobenzyl ( 19) and 4-fluorobenzyl (20) tails at the piperazine side were identified as the most active inhibitors with IC 50 values of 0.13 and 0.22 µM, respectively. The preincubation test of 19 was in agreement with the irreversible binding mechanism. Molecular docking was performed to explore the potential binding interactions with key amino acid residues at the FAAH active site. These newly identified inhibitors could serve as leads for the further development of potent and selective FAAH inhibitors for FAAH-associated diseases.

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Section: Preincubation Testmentioning

confidence: 99%

Section: Molecular Docking Studiesmentioning

confidence: 99%

Development and molecular modeling studies of new thiadiazole piperazine urea derivatives as potential fatty acid amide hydrolase inhibitors

Maz

Turanlı

Caliskan

et al. 2022

Archiv der Pharmazie

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“…The cell cytotoxicity MTT assay was performed according to the reported literature procedure with slight modification. [80,81] The detailed procedure is summarized in Supporting Information Section SA.5.…”

Section: Cell Cytotoxicity Mtt Assaymentioning

confidence: 99%

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors

Jaiswal

Gupta

Ayyannan

2022

Archiv der Pharmazie

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Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH-MAGL inhibition properties. Phenyl [4-(piperidin-1-ylmethyl) phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC 50 = 19 nM), benzyl (1H-benzo[d]imidazol-2-yl)carbamate (3h) was the most potent FAAH inhibitor (IC 50 = 55 nM), and phenyl (6-fluorobenzo[d]thiazol-2-yl)carbamate (2i) egressed as a nonselective dual FAAH-MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent-reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood-brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug-likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.

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“…The cell cytotoxicity and neuroprotection studies were carried out according to the reported literature procedure with slight modification. [49,50] The detailed procedure is summarized in supporting information A.4.…”

Section: Cell Cytotoxicity and Neuroprotection Assaymentioning

confidence: 99%

Discovery of Isatin‐Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase

Jaiswal

Ayyannan

2021

ChemMedChem

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Using ligand-based design strategy, a set of isatin-3-carbohydrazones was designed, synthesized and evaluated for dual fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition properties. Compound 5-chloro-N'-(5-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 b) emerged as a potent MAGL inhibitor with nanomolar activity (IC 50 = 3.33 nM), while compound 5-chloro-N'-(1-(4-fluorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 j) was the most potent selective FAAH inhibitor (IC 50 = 37 nM). Compound 5-chloro-N'-(6-chloro-2-oxoindolin-3-ylidene)-2-hydroxybenzohydrazide (13 c) showed dual FAAH-MAGL inhibitory activity with an IC 50 of 31 and 29 nM respectively. Enzyme kinetics studies revealed that the isatin-based carbohydrazones are reversible inhibitors for both FAAH and MAGL. Further, blood-brain permeability assay confirmed that the lead compounds (13 b, 13 c, 13 g, 13 m and 13 q) are suitable as CNS candidates. Molecular dynamics simulation studies revealed the putative binding modes and key interactions of lead inhibitors within the enzyme active sites. The lead dual FAAH-MAGL inhibitor 13 c showed significant antioxidant activity and neuroprotection in the cell-based cytotoxicity assay. In summary, the study yielded three potent FAAH/MAGL inhibitor compounds (13 b, 13 c and 13 j) with acceptable pharmacokinetic profile and thus can be considered as promising candidates for treating neurological and mood disorders.

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Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies

Cited by 20 publications

References 49 publications

Development and molecular modeling studies of new thiadiazole piperazine urea derivatives as potential fatty acid amide hydrolase inhibitors

Development and molecular modeling studies of new thiadiazole piperazine urea derivatives as potential fatty acid amide hydrolase inhibitors

Synthesis and evaluation of carbamate derivatives as fatty acid amide hydrolase and monoacylglycerol lipase inhibitors

Discovery of Isatin‐Based Carbohydrazones as Potential Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase

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