화학공학소재연구정보센터
Process Biochemistry, Vol.99, 246-253, 2020
Inhibitions of monoamine oxidases and acetylcholinesterase by 1-methyl, 5-phenyl substituted thiosemicarbazones: Synthesis, biochemical, and computational investigations
A series of eleven 1-methyl, 5-phenyl substituted thiosemicarbazones (MT1-MT11) with the phenyl ring substitutions were prepared and investigated for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). [4-(dimethylamino) phenyl]methylidene}-N-methylhydrazine-1-carbothioamide (MT5) inhibited MAO-B potently with an IC50 of 8.77 mu M. Potencies for MAO-B increased in the order -N(CH3)(2) in MT5 > -OCH3 in MT3 > -Br in MT9. Most of the 11 compounds weakly inhibited AChE by < 30% at 10 mu M. MT5 competitively inhibited MAO-B and Ki value was 6.58 +/- 0.064 mu M. Reversibility experiments showed MT5 also reversibly inhibited MAO-B. MTT assays revealed that MT5 and MT3 were non-toxic to normal VERO cell lines with IC50 values of 191.96 and 187.04 mu g/mL, respectively. From the molecular docking, MT5 binding was found to be stabilized by hydrogen bonding to the non-bonding electron of the terminal N-methyl group with Cys172 (binding energy = -7.01 kcal/mol) of MAO-B. The molecular dynamics further predicted that MT5 had a major pi-pi hydrophobic interaction with Tyr326 of MAO-B, suggesting that it plays an important role in the stabilization of protein-ligand interaction.These results documents that MT5 is a moderately selective, reversible, and competitive inhibitor of MAO-B with low cytotoxic profile.