Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

Abstract

Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives (1‐44), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty‐four compounds were evaluated on AChE and BChE enzymes at 10−3 and 10−4 concentrations. The inhibition concentrations were calculated as 0.268μM to 2.104μM for six compounds (4, 5, 16, 27, 37, and 38) on AChE. Compound 5 including the 4‐methoxy substituent (IC50: 0.268μM) and compound 38 containing the 4‐methoxy and 3‐methyl substituents (IC50: 0.286μM) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar‐Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed‐type kinetic mode.

Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

“…Compound 215 with the 4-methoxy group (IC 50 = 0.268 µM) and compound 216 with the 4-methoxy and 3-methyl substituents had the greatest AChE inhibitory action (IC 50 = 0.286 µM). Hydrogen bonding with Arg296 and Ar interactions with Trp286 were also investigated 256 ( Table 9 ).…”

Synthetic Access to Aromatic α-Haloketones

“…[ 12 , 13 , 14 ]. Other applications have demonstrated their utility as key synthetic intermediates for pharmaceutical blockbuster compounds ( Figure 1 ) [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Synthesis, anticholinesterase activity, molecular docking, and molecular dynamic simulation studies of 1,3,4‐oxadiazole derivatives

“…In the design of new AChEIs, studies on long-chain, unbranched molecular structures have been carried out, based on this approach. [20,21] Compounds containing nitrogen heterocyclic ring systems are of great importance and have an essential role as therapeutic agents in biological systems and are commonly used in many commercial drugs.…”

“…In the design of new AChEIs, studies on long‐chain, unbranched molecular structures have been carried out, based on this approach. [ 20,21 ]…”