期刊
BIOORGANIC CHEMISTRY
卷 124, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105822
关键词
Antidepressant; Monoamine oxidase; Quinazoline; Benzenesulfonamides; Docking
资金
- Cukurova University BAP office
- Ataturk University BAP office
This study synthesized a series of 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino) benzenesulfonamides and investigated their inhibition potentials against MAOs. The most potent compounds 7 and 8 showed high selectivity and reversibility towards MAO-A, suggesting their potential as therapeutic agents for neurodegenerative diseases.
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.
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