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., ...Daha Fazla

COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING, cilt.25, sa.8, ss.1314-1326, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 25 Sayı: 8
  • Basım Tarihi: 2022
  • Doi Numarası: 10.2174/1386207324666210603125452
  • Dergi Adı: COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1314-1326
  • Anahtar Kelimeler: Chalcones, monoamine oxidase, reversibility, cytotoxicity, blood-brain barrier, antioxidant, DESIGN, ASSAY, MECHANISM
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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.