مقالات پذیرفته شده در سومین کنگره بین المللی زیست پزشکی
Synthesis, molecular docking and acetylcholineesterase inhibitory evaluation of novel tacrine derivatives for the treatment of Alzheimer’s disease
Synthesis, molecular docking and acetylcholineesterase inhibitory evaluation of novel tacrine derivatives for the treatment of Alzheimer’s disease
Fatemeh Hajipour,1,*Maryam Eskandari,2Azar Mostoufi,3Masood Fereidoonnezhad,4
1. 1Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. 3. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 4. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Introduction: Alzheimer’s disease (AD), is a widespread and progressive disorder of the central nervous system in humans, which causes the loss of memory. The multi-factorial etiology of AD, necessitate the multi-target-directed ligand (MTDL) approach in seeking new drug candidates for its treatment. Inhibition of acetylcholinesterase (AChE) and butyryl cholinesterase (BuChE) are among the main strategy in the treatment of AD.
Methods: Here, a series of novel 2-hydroxyl-3-N-arylpropyl tacrine derivatives were synthesized in a few steps from tacrine and completely purified. These compounds were evaluated for enzyme activity against acetylcholinesterase and butyrylcholinesterase enzymes. The docking studies of the compounds on both of these targets well also acquired. The initial conformations of the hAChE, and hBuChE were taken from PDB ID: 4EY7 amd 4BDS, respectively. The Molecular docking simulations were carried out using AutoDock 4.2 and Vina.
Results: All of the synthesized compounds were fully characterized by 1HNMR, 13CNMR, IR, and Mass spectroscopy techniques. The anti-cholinesterase activity evaluation of synthesized compounds revealed that some of them had very potent inhibitory activity against AChE and BuChE superior to standard drug tacrine. Plausible π−π binding interactions was found in the catalytic cavity of the hAChE enzyme between pyridine groups of tacrine moiety with Trp84 and Phe333. The existence of hydrogen binding interactions was also found between the NH and OH groups of linker moiety with Tyr130 and Glu199, respectively. The binding site of compounds within the catalytic site of hBuChE was also explored.
Conclusion: The newly synthesized tacrine derivatives, especially one of them, had very potent inhibitory activity against AChE and BuchE, superior to standard drug tacrine. The binding of the compounds to the catalytic active site (CAS) and peripheral anionic site (PAS) of the targets were completely determined. These compounds have potential to become more prominent in Alzheimer's treatment