Identification of New N-methyl-piperazine Chalcones as Dual MAO-B/AChE Inhibitors

Abstract

Monoamine oxidase-B (MAO-B), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) have been considered target enzymes of depression and neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, seventeen N-methyl-piperazine chalcones were synthesized, and their inhibitory activities were evaluated against the target enzymes. Compound 2k (3-trifluoromethyl-4-fluorinated derivative) showed the highest selective inhibition against MAO-B with an IC50 of 0.71 μM and selectivity index (SI) of 56.34, followed by 2n (2-fluoro-5-bromophenyl derivative) (IC50 = 1.11 μM, SI = 16.04). Compounds 2k and 2n were reversible competitive MAO-B inhibitors with Ki values of 0.21 and 0.28 μM, respectively. Moreover, 2k and 2n effectively inhibited AChE with IC50 of 8.10 and 4.32 μM, which underscored their multi-target inhibitory modes. Interestingly, compound 2o elicited remarkable inhibitions over MAO-B, AChE, and BChE with IC50 of 1.19–3.87 μM. A cell-based assay of compounds 2k and 2n against Vero normal cells pointed out their low cytotoxicity. In a docking simulation, 2k showed the lowest energy for MAO-B (−11.6 kcal/mol) with four hydrogen bonds and two π-π interactions. Furthermore, in silico studies were conducted, and disclosed that 2k and 2n are expected to possess favorable pharmacokinetic properties, such as the ability to penetrate the blood–brain barrier (BBB). In view of these findings, compounds 2k and 2n could serve as promising potential candidates for the treatment of neurodegenerative diseases.

Chalcones with N‐Methylpiperazine Moiety: Synthesis, Monoamine Oxidase Inhibition, Neuroprotective Effect and Computer Simulation Study

“…[20] In addition to the small bulky N-methyl, N-ethyl piperazine makes it possible to interact with several target enzymes through hydrophobic and charge transfer mechanisms. [21] Clozapine, Loxapine, Olanzapine, Trifluoroperazine, and Thiothixene (Figure 3) are just a few CNS-active medications that have the N-methyl piperazine moiety, which validates the druglike properties of piperazine derivatives. [22] The presence of the two basic nitrogen atoms in aryl piperazine is responsible for interacting with the active site of monoamine oxidase-B (MAO-B) through the establishment of ionic, hydrogen, and π-π interactions with amino acid residues.…”

“…[23] Some recent studies established that the incorporation of piperazine nucleus with other structural moieties is able to improve the interaction of the compounds with biological targets, and thereby improves the MAO inhibition properties. [14,21,[24][25][26][27][28][29][30] The unique class of enzymes known as monoamine oxidases (MAOs) is located in the mitochondria and is responsible for several biological processes. They are FAD-dependent and act as an essential catalyst in the oxidative deamination process for the metabolism of amine molecules.…”

“…One another research team established seventeen Nmethyl-piperazine chalcones (2 a-2 q) by modifying the structures of PC10 and PC11, which were evaluated for their potential to inhibit the MAO-B enzyme. [21] 2 k and 2 n were selected as the most potent in the series, with IC 50 values of 0.71 � 0.03 and 1.11 � 0.06 μM against MAO-B, respectively, and the selectivity index (SI) values were calculated as 6.34 and 16.04 respectively (Figure 5). The potent compounds were found to contain fluorine in their B ring of chalcone framework.…”

“…N‐methyl piperazine is a privileged framework of piperazine nucleus with improved lipophilic and steric properties, and making this motif with an appropriate structural factor in maintaining the proper balance of pharmacokinetic and pharmacodynamic features [20] . In addition to the small bulky N‐methyl, N‐ethyl piperazine makes it possible to interact with several target enzymes through hydrophobic and charge transfer mechanisms [21] . Clozapine, Loxapine, Olanzapine, Trifluoroperazine, and Thiothixene (Figure 3) are just a few CNS‐active medications that have the N‐methyl piperazine moiety, which validates the drug‐like properties of piperazine derivatives [22] …”

“…The presence of the two basic nitrogen atoms in aryl piperazine is responsible for interacting with the active site of monoamine oxidase‐B (MAO‐B) through the establishment of ionic, hydrogen, and π‐π interactions with amino acid residues [23] . Some recent studies established that the incorporation of piperazine nucleus with other structural moieties is able to improve the interaction of the compounds with biological targets, and thereby improves the MAO inhibition properties [14,21,24–30] …”