New 2-Pyrazoline and Hydrazone Derivatives as Potent and Selective Monoamine Oxidase A Inhibitors

Abstract

Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N′-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)­acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 μM, Selectivity Index (SI): 9.70 × 10–4), 7 (0.009 μM, SI: 4.55 × 10–5), 14 (0.001 μM, SI: 8.00 × 10–4), 21 (0.009 μM, SI: 1.37 × 10–5), and 42 (0.010 μM, SI: 5.40 × 10–6), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood–brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21, and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.

Evaluation of antioxidant and cytotoxic properties of phenolic N -acylhydrazones: structure–activity relationship

“…Hydrazone nucleus, as a fusion of amide and imine subunits, possess hydrogen-bond donor and acceptor sites for interaction with amino acid residues [ 18 ]. Thus, compounds with hydrazone cores express inhibitory effects against numerous enzymes, such as cyclooxygenase (COX-1 and COX-2) [ 20 , 34 ], acetyl- and butyrylcholinesterase (AChE and BuChE) [ 35 ], monoamine oxidase A (MAO A) [ 36 ], as well as G-Protein-Coupled Receptor Kinase 2 (GRK2) involved in heart failure [ 37 ]. Particularly, the N -acylhydrazone group ( N AH ) is declared as a unique and versatile structural motif, suitable for synthetic transformations and the development of potential therapeutically useful compounds [ 38 ].…”

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

“…Moreover, single‐dose acute and subchronic administrations of compounds 146–148 showed significant antidepressant activity in FST, consistently displaying good BBB permeability and increased brain 5‐HT levels. [ 183 ]…”

Synthesis of 2‐Pyrazolines from Hydrazines: Mechanisms Explained

“…[34] Fazaeli et al also proposed tungstophosphoric acid supported on highly organosoluble polyamide (PW 12 /PA) as an efficient catalyst for the synthesis of 1,3,5-triaryl-2-pyrazoline derivatives and showed its generality for various chalcones. [61] Another acid-catalyzed synthesis of 2-pyrazolines was reported by Salgin-Goksen et al [35] In this approach, different chalcones 13 a were treated with hydrazines 13 b in DMF/npropanol solvent mixture in the presence of concentrated (con.) HCl as catalyst.…”

“…Another acid‐catalyzed synthesis of 2‐pyrazolines was reported by Salgin‐Goksen et al [35] In this approach, different chalcones 13 a were treated with hydrazines 13 b in DMF/ n ‐propanol solvent mixture in the presence of concentrated (con.) HCl as catalyst.…”