Synthesis and biological evaluation of new tetramethylpyrazine‐based chalcone derivatives as potential anti‐Alzheimer agents

Abstract

In the current study, a series of new ligustrazine-based chalcones was synthesized. For insertion of tetramethylpyrazine (TMP, also designated as ligustrazine) in chemical backbone of chalcone, a new ligustrazine-based aldehyde was prepared. New ketones were synthesized for inclusion of quinazolin-4-yl amino and pyrazin-2-yl amino moieties. The newly synthesized compounds were screened for acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases (MAO) inhibitory activities and also for in vitro cytotoxicity on PC12 cells. The effect of these compounds against amyloid β-induced cytotoxicity and aggregation was also investigated. The synthesized compounds effectively inhibited the related enzymes and also exhibited neuroprotective effects. Most of the compounds displayed better inhibitory potencies against Aβ aggregation than reference compounds. Some compounds such as 11e and 16b showed very potent effects on multiple targets exhibiting behavior as multifunctional anti-Alzheimer agents.

An Update of Synthetic Approaches and Structure‐Activity Relationships of Various Classes of Human MAO‐B Inhibitors

“…Various chalcone derivatives with anti‐MAO‐B enzyme activity have been synthesized. In this regard, a general method was opted to synthesize various chalcone derivatives using Claisen–Schmidt condensation, mostly between both the appropriately substituted acetophenones and benzaldehydes as shown in Scheme 1 [45–51] …”

“…Similarly, the imidazole‐chalcones having potent inhibition of MAO‐B, were designed and synthesized from imidazolylphenylethanone and substituted benzaldehydes by Sasidharan et al [54] . After five membered adduct, six membered heterocyclic (Pyrazinyl amino, quinazolinyl amino) moieties were also explored for MAO inhibition and synthesized from substituted Chloroquinazoline/chloropyrazine based aminoacetophenone and tetramethylpyrazine based aldehyde via Claisen‐Schmidt condensation [51,55] …”

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

“…Most compounds exhibited significant inhibition of ChEs, with compound 63a as the most promising selective AChEI with IC 50 values of 3.9 and 65.2 nM for eeAChE and hAChE, respectively, and IC 50 of 24.3 and 48.8 nM for eqBuChE and hBuChE, respectively. This compound also showed an effective ability to block self Aβ-aggregation and antioxidant activity against PC12 cell damage and very low hepatotoxicity in vitro and in vivo compared to tacrine [ 105 ].…”

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

“…More importantly, chalcones are appealing as key synthetic intermediates and frameworks in the design of therapeutic tools for the treatment of various ailments including antimicrobial, antibacterial, antimalarial, anticancer, anti-inflammatory, anti-HIV, anti-Alzheimer's, etc. [24][25][26][27][28][29][30][31][32]. The structural modification of chalcones where the B-ring ( Figure 2) is substituted with other bioactive fragments or units is a contemporary strategy that has been extensively utilized by various research groups involved in designing bioactive compounds for the treatment of different diseases [33].…”