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Updated: Oct 25, 2025

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Biphenylpiperazine Based MAO Inhibitors: Synthesis, Biological Evaluation, Reversibility and Molecular Modeling
Lamiaa O El-Halaby1, Walaa M El-Husseiny1, Shahenda M El-Messery1
1Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt.
Abstract:
In this study, 21 new 1,4-biphenylpiperazine derivatives were designed, synthesized and evaluated as monoamine oxidase (MAO) inhibitors by in vitro fluorometric method. All these compounds exhibited inhibitory activity against hMAO enzymes, 17 analogues of them showed selectivity towards hMAO-B over hMAO-A enzyme. Compound 20 exhibited the best activity and selectivity towards hMAO-B with IC50 value of 53 nM and selectivity index of 1122 folds over MAO-A, compared to the reference drugs rasagiline (IC50 = 66 nM) and selegiline (IC50 = 40 nM). Kinetic study and reversibility test of the most potent compound (20) revealed that it is reversible and mixed competitive inhibitor (Ki value is 17 nM for the inhibition of hMAO-B). Compound 20 was evaluated against normal NIH/3T3 mouse embryonic fibroblast cell lines and it was found that it is non-cytotoxic at its effective concentration against hMAO-B. Moreover, compound 20 and the most potent compounds have acceptable ADME properties and good pharmacokinetics profiles. Molecular docking simulations were performed for explanation and elucidation for the biological activity of compounds 19 and 20. Accordingly, 1,4- biphenylpiperazine derivatives can be considered as a promising lead to produce more potent and safer MAO inhibitors for management of various neurological disorders.
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