(S)-N-Benzyl-1-phenyl-3,4-dihydroisoqunoline-2(1H)-carboxamide Derivatives, Multi-Target Inhibitors of Monoamine Oxidase and Cholinesterase: Design, Synthesis, and Biological Activity

Abstract

A series of (S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives was synthesized and evaluated for inhibitory activity against monoamine oxidase (MAO)-A and-B, acetylcholine esterase (AChE), and butyrylcholine esterase (BChE). Four compounds (2i, 2p, 2t, and 2v) showed good inhibitory activity against both MAO-A and MAO-B, and two compounds (2d and 2j) showed selective inhibitory activity against MAO-A, with IC50 values of 1.38 and 2.48 µM, respectively. None of the compounds showed inhibitory activity against AChE; however, 12 compounds showed inhibitory activity against BChE. None of the active compounds showed cytotoxicity against L929cells. Molecular docking revealed several important interactions between the active analogs and amino acid residues of the protein receptors. This research paves the way for further study aimed at designing MAO and ChE inhibitors for the treatment of depression and neurodegenerative disorders.

Benzothiazole‐Propanamide Linker Pyrrolidine (Morpholine) as Monoamine Oxidase‐B and Butyrylcholinesterase Inhibitors

“…L929 cells in the logarithmic growth phase were selected, and the cell density was adjusted to 8×10 5 per well with a cell counter to inoculate in a 6-well plate, and the 6-well plate inoculated with cells was cultured in a 37 °C 5 % carbon dioxide cell incubator. After 24 h, 1 mL of medium containing 100 μM of the compound to be tested was added (medium without drug was added to the blank group), shaken gently, and cultured in a 37 °C 5 % carbon dioxide cell incubator.…”

“…In recent decades, several pathophy-siological mechanisms of AD have been studied and discovered. [5,6] The hypothetical factors in AD pathology including oxidative/nitrite stress, genetics, changes in cell apoptosis, mitochondrial damage, and enzymes such as cholinesterases (ChEs), monoamine oxidases (MAOs), and β-site amyloid precursor protein cleaving enzyme 1 etc. [7][8][9][10][11] ChEs and MAOs play important roles in the regulation of nerve conduction by catalyzing the degradation of neurotransmitters.…”

“…MTDL design strategy have been used for developing molecules capable of simultaneously regulate multiple pathways in neurodege‐nerative cascade. In recent decades, several pathophy‐siological mechanisms of AD have been studied and discovered [5,6] . The hypothetical factors in AD pathology including oxidative/nitrite stress, genetics, changes in cell apoptosis, mitochondrial damage, and enzymes such as cholinesterases (ChEs), monoamine oxidases (MAOs), and β‐site amyloid precursor protein cleaving enzyme 1 etc [7–11] …”

3-Phenethyl-2-phenylquinazolin-4(3H)-one isolated from marine-derived Acremonium sp. CNQ-049 as a dual- functional inhibitor of monoamine oxidases-B and butyrylcholinesterase

“…Dual-functional inhibitor is an inhibitor with two or more therapeutic effects and higher therapeutic ability can be expected than single functional inhibitor [21]. Recently, various dual-functional inhibitors have been developed and reported, such as dual-functional inhibitors for MAO, ChE, BACE1, antioxidant, and carbonic anhydrase VII [46][47][48][49][50][51]. However, compound 1 showed weak inhibitory activity against BACE1 as well as MAO-A and AChE.…”

Quinoline–sulfonamides as a multi-targeting neurotherapeutic for cognitive decline:in vitro,in silicostudies and ADME evaluation of monoamine oxidases and cholinesterases inhibitors

“…2). [28][29][30] Multitarget approaches can also reduce side effects and improve treatment outcomes. Few types of chemicals have been identi-ed as MAO and ChEs inhibitors.…”