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

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 (-) 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 Ellman method. The biological evaluation showed that compounds and displayed significant activity against AChE. The compounds and displayed IC values of 0.034 and 0.027 µM against AChE, respectively. The reference drug donepezil (IC = 0.021 µM) also displayed a significant inhibition against AChE. In addition, the antioxidant activities of the compounds were also evaluated. Derivatives and , which emerged active from both activity studies, were subjected to PAMPA tests to determine BBB permeability. Further docking simulation also revealed that these compounds (, 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.