Trimethoxy Crown Chalcones as Multifunctional Class of Monoamine Oxidase Enzyme Inhibitors


Maliyakkal N., BAYSAL İ., Tengli A., UÇAR G., Almoyad M. A. A., Parambi D. G. T., ...More

COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING, vol.25, no.8, pp.1314-1326, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 25 Issue: 8
  • Publication Date: 2022
  • Doi Number: 10.2174/1386207324666210603125452
  • Journal Name: COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.1314-1326
  • Keywords: Chalcones, monoamine oxidase, reversibility, cytotoxicity, blood-brain barrier, antioxidant, DESIGN, ASSAY, MECHANISM
  • Hacettepe University Affiliated: Yes

Abstract

Background: Chalcones with methoxy substituent 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 a MAO-A inhibition constant value equal to 3.47 +/- 0.09 mu M with a selectivity of 0.008, thus 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) show good MAO-B inhibition with inhibition constant of 0.46 +/- 0.009 mu M. 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 mu M. 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 mu M. 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.