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

Abstract

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 IC₅₀ values of 0.034 and 0.027 µM against AChE, respectively. The reference drug donepezil (IC₅₀ = 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

Keywords:

• Hydrazone
• acetylcholinesterase
• antioxidant
• PAMPA
• molecular docking

Acknowledgments

As the authors of this study, we thank Anadolu University Faculty of Pharmacy Central Research Laboratory (MERLAB), for their support and contributions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Authors’ contributions

D.O., Y.O. and Z.A.K. conceived and designed the experiments; D.O. performed the synthesis; S.L. performed analysis studies; B.N.S. performed the activity tests; D.O and B.N.S. performed the molecular docking studies; A.I., H.P. performed the molecular dynamic studies; D.O., B.N.S. and A.I., S.L. wrote the paper; Y.O and Z.A.K. reviewed the paper.