Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Design and synthesis of some acridine-piperazine hybrids for the improvement of cognitive dysfunction

Design and synthesis of some acridine-piperazine hybrids for the improvement of cognitive dysfunction
Anuradha Sharma, Poonam Piplani
A novel series of hybrid molecules (5a–5m) was designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against cognitive dysfunction. Heterocyclic moieties acridine and piperazine were conjugated with suitable linkers in a single scaffold, and the structures of the target compounds were confirmed by IR, 1H NMR, 13C NMR, and LC-MS analysis. The pharmacological activity of synthesized compounds was evaluated using behavioral models of amnesia viz. step-down passive avoidance and elevated plus maze at a dose 0.5 mg/kg as compared to standard rivastigmine. In vitro acetylcholinesterase (AChE) inhibition studies using brain homogenate of mice as the enzyme source revealed that most of the compounds exhibited a significant ability to inhibit the enzyme cholinesterase with compound 5c being the most potent (IC50 0.33 μm). Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase, and glutathione has been carried out using the respective assays to see the effect of the synthesized compounds on the scopolamine-induced oxidative damage. The molecular docking studies indicated the binding mode of the compounds to the catalytic site, peripheral site, and mid-gorge of AChE simultaneously. The calculated absorption, distribution, metabolism and excretion properties ensured the drug-likeness of the target compounds. The synthesized compounds were found to be potential cognitive enhancers, which were able to interfere with the scopolamine-induced oxidative stress also. A series of acridine-piperazine hybrids was designed, synthesized and evaluated for cognitive potential using step down passive avoidance and elevated plus maze models supported by biochemical estimation for acetylcholinesterase. Biochemical estimation of oxidative stress markers viz. plasma nitrite, thiobarbituric acid reactive substances, catalase, superoxide dismutase and glutathione has been carried out. Further in silico studies of the target compounds 5a-5m were performed to explore the binding modes within the enzyme.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13017

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