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Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease that is characterized by memory and cognitive impairments that predominantly affects the elderly and is the most common cause of dementia. As is known, the AChE enzyme consists of two parts. In this work, 10 new hydrazones ( 3a – 3j ) were designed and synthesized. Naphthalene, indole, benzofuran and benzothiophene rings were used to interact with the PAS region. 4-fluorophenyl and 4-fluorobenzyl structures were preferred for interaction with the CAS region. In biological activity studies, the AChE and BChE inhibitory potentials of all compounds were evaluated using the  in vitro  Ellman method. The biological evaluation showed that compounds  3i  and  3j  displayed significant activity against AChE. The compounds  3i  and  3j  displayed IC 50  values of 0.034 and 0.027 µM against AChE, respectively. The reference drug donepezil (IC 50  = 0.021 µM) also displayed a significant inhibition against AChE. In addition, the antioxidant activities of the compounds were also evaluated. Derivatives  3i  and  3j , which emerged active from both  in vitro  activity studies, were subjected to  in vitro  PAMPA tests to determine BBB permeability. Further docking simulation also revealed that these compounds ( 3i ,  3j  and donepezil) interacted with the enzyme active site in a similar manner to donepezil. A few parameters derived from MD simulation trajectories were computed and validated for the protein-ligand complex’s stability under the dynamic conditions. Communicated by Ramaswamy H. Sarma

Design, synthesis and molecular docking and ADME studies of novel hydrazone derivatives for AChE inhibitory, BBB permeability and antioxidant effects