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Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors

Author(s):

Naseer Maliyakkal*, Ipek Baysal, Anandkumar Tengli, Gulberk Ucar*, Mohammad Ali Abdullah Almoyad, Della Grace Thomas Parambi, Nicola Gambacorta, Orazio Nicolotti, Asmy Appadath Beeran and Bijo Mathew*  

Abstract:


Background: Chalcones with methoxy substituents are considered as a promising framework for the inhibition of monoamine oxidase (MAO) enzymes.

Methods: A series of nine trimethoxy substituted chalcones (TMa-TMi) was synthesized and evaluated as a multifunctional class of MAO inhibitors. All the synthesized compounds were investigated for their in vitro MAO inhibition, kinetics, reversibility, blood-brain barrier (BBB) permeation, and cytotoxicity and antioxidant potentials.

Results: In the present study, compound (2E)-3-(4-nitrophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (TMf) was provided with an MAO-A inhibition constant value equal to 3.47±0.09 μM and with a selectivity of 0.008. Thus, it was comparable to that of moclobemide, a well known potent hMAO-A inhibitor (SI=0.010). Compound (2E)-3-(4-bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (TMh) showed good MAO-B inhibition, with an inhibition constant of 0.46±0.009 μM. The PAMPA assay demonstrated that all the synthesized derivatives can cross the BBB successfully. The cytotoxicity studies revealed that TMf and TMh have 88.22 and 80.18 % cell viability at 25 µM. Compound TMf appeared as the most promising antioxidant molecule with IC50 values, relative to DPPH and H2O2 radical activities, equal to 6.02±0.17 and 7.25±0.07 μM. To shed light on the molecular interactions of TMf and TMh towards MAO-A and MAO-B, molecular docking simulations and MM/GBSA calculations have been carried out.

Conclusion: The lead molecules TMf and TMh with multi-functional nature can be further employed for the treatment of various neurodegenerative disorders and depressive states.

Keywords:

Chalcones, monoamine oxidase, reversibility, cytotoxicity, Blood-brain barrier, antioxidant

Affiliation:

Department of Basic Medical Sciences, College of Applied Medical Sciences in Khamis Mushyt, King Khalid University, Abha, Vocational School of Health Services, Pharmacy Services Programme, Hacettepe University, Ankara, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru, JSS Academy of Higher Education & Research, Mysuru-570015, Karnataka, Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Department of Basic Medical Sciences, College of Applied Medical Sciences in Khamis Mushyt, King Khalid University, Abha, Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf-2014, Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via E. Orabona, 4, I-70125 Bari, Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via E. Orabona, 4, I-70125 Bari, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Amrita Health Science Campus, Kochi-682 041



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