Computational design of new tacrine analogs: an in silico prediction of their cholinesterase inhibitory, antioxidant, and hepatotoxic activities

Abstract

Tacrine, the first drug approved for the treatment of Alzheimer's disease (AD), is a non-competitive cholinesterase inhibitor withdrawn due to its acute hepatotoxicity. However, new non-hepatotoxic forms of tacrine have been actively researched. Moreover, several recent reports have shown that oxidative stress is the cause of damage and plays a role in the pathogenesis of several neurodegenerative diseases including AD. The aim of the present study is the design of new easily synthesized tacrine analogs with less hepatotoxicity and potent antioxidant activity. In this context, a library of 34 novel tacrine analogs bearing an antioxidant fragment was designed and evaluated for its hepatotoxicity as well as anticholinesterase and antioxidant activities using computational methods. As a result, six new tacrine analogs have been proposed as potential inhibitors of cholinesterase with antioxidant activity and low or no hepatotoxicity. Furthermore, ADME calculations suggest that these compounds are promising oral drug candidates.

Communicated by Ramaswamy H. Sarma

Keywords:

• Tacrine analogs
• DFT calculations
• antiradical activity
• docking study
• hepatotoxicity

Acknowledgments

We would like to thank MESRS (Ministère de l’Enseignement Supérieur et de la Recherche Scientifique, Algeria) and DGRSDT (Direction Générale de la Recherche Scientifique et du développement Technologique, Algeria) for financial support, as well as the HPC resources of UCI-UFMC (unité de calcul intesif de l’universite Fréres Mentouri Constantine 1) for the computational resources used.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

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