Quinazolinone-based benzenesulfonamides with low toxicity and high affinity as monoamine oxidase-A inhibitors: Synthesis, biological evaluation and induced-fit docking studies

YAMALI C., GÜL H. İ., Sakarya M. T., SAĞLIK B. N., Ece A., DEMİREL G., ...Daha Fazla

BIOORGANIC CHEMISTRY, cilt.124, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 124
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.bioorg.2022.105822
  • Dergi Adı: BIOORGANIC CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, EMBASE, MEDLINE, Veterinary Science Database, Index Chemicus (IC)
  • Anahtar Kelimeler: Antidepressant, Monoamine oxidase, Quinazoline, Benzenesulfonamides, Docking, MOLECULAR DOCKING, HCA IX, DERIVATIVES, ANTIOXIDANT, DESIGN, IDENTIFICATION, SULFONAMIDES, PROTEIN, AGENTS
  • Anadolu Üniversitesi Adresli: Evet

Özet

The research in selective monoamine oxidases (MAO-A and MAO-B) inhibitors has been increased due to their therapeutic value for neurodegenerative diseases. In this study, 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino) benzenesulfonamides were synthesized and their MAOs inhibition potentials were investigated applying in vitro fluorometric technique. The most potent compounds 7 and 8 against MAO-A had IC50 values of 0.058 +/- 0.002 and 0.094 +/- 0.003 mu M, respectively, while the reference moclobemide had an IC50 value of 6.061 mu M. Compounds 7 (> 1724 times) and 8 (> 1063 times) more selective and reversible inhibitors of MAO-A rather than MAO-B. Toxicity studies of 7 (IC50 = 210.23 mu M) and 8 (IC50 = 259.27 mu M) showed that compounds can be considered as non-toxic towards SH-SY5Y cell line at their effective concentrations against MAO-A. In silico docking simulations successfully explained the observed activities and also highlighted structural water molecules to play a key role in the ligand-enzyme interactions. Calculated molecular descriptors are also obeying Lipinski's rule of five and brain/blood partition coefficients, a critical parameter in neurodegenerative diseases. These reversible inhibitors can have considerable advantages compared to irreversible inhibitors which may possess serious pharmacological side effects.