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Review
. 2021 Oct 27;22(21):11584.
doi: 10.3390/ijms222111584.

Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders

Annia Galano  1 , Eduardo G Guzmán-López  1 , Russel J Reiter  2
Affiliations
Review

Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders

Annia Galano et al. Int J Mol Sci. .

Abstract

Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives.

Keywords: DNA repair; antioxidant; free radical scavengers; metal chelators; multifactorial diseases; multifunctional drugs; neuroprotection; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Melatonin (N-acetyl-5-methoxytryptamine).
Figure 1
Figure 1
Some factors that can trigger multifactorial diseases (MD).
Figure 2
Figure 2
Some events contributing to the multifactorial nature of neurodegenerative disorders (NDD).
Figure 3
Figure 3
Antioxidant protection exerted by melatonin and its metabolites. AOC: antioxidant activity; c3OHM: cyclic 3-hydroxymelatonin; 6OHM: 6-hydroxymelatonin; 4OHM: 4-hydroxymelatonin; AFMK: N1-acetyl-N2-formyl-5-methoxykynuramine; NAS: N-acetyl serotonin.
Figure 4
Figure 4
Multifunctionality of melatonin.
Scheme 2
Scheme 2
Melatonin and some related natural compounds.
Scheme 3
Scheme 3
Structures of some synthetic melatonin derivatives. BOC stands for the t-butyloxycarbonyl group.
Scheme 4
Scheme 4
Some computationally designed melatonin derivatives.
Scheme 5
Scheme 5
Other computationally designed melatonin derivatives.
See this image and copyright information in PMC

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