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

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.

Journal

BIOORGANIC CHEMISTRY

Year

2022

Volume

124

ISSN

0045-2068

eISSN

1090-2120

DOI

10.1016/j.bioorg.2022.105822

WoS UID

WOS:000800387400002