Development of methylthiosemicarbazones as new reversible monoamine oxidase-B inhibitors for the treatment of Parkinson's disease.
Selective monoamine oxidase-B (MAO-B) inhibition is an attractive subject for the treatment of Parkinson's disease (PD). In the current study, we synthesized some selected derivatives of methylthiosemicarbazones and investigated their MAOs and acetylcholinesterase (AChE) inhibitory activities. Among the series synthesized, compounds SM5, SM4, and SM9 most inhibited MAO-B with IC50 values of 5.48, 7.06, and 8.03 µM, respectively. All compounds tested weakly inhibited MAO-A at 10 µM with the residual activities of >50%. Compound SM5 had the highest selectivity index (SI) value for MAO-B (>7.30), followed by SM4 (>5.67). Kinetic experiments revealed that SM5 competitively inhibited MAO-B, with a mean K value of 2.39 ± 0.15 µM. Reversibility experiments showed that SM5 reversibly inhibited MAO-B, and 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that SM5 was not toxic to Vero cells (IC50 = 198.96 µg/mL). The SM5/MAO-B interaction was ascertained by molecular docking and dynamics studies. The study shows that SM5 competitively inhibits MAO-B in a reversible, moderate selective manner, and that it is non-toxic to Vero cells.Communicated by Ramaswamy H. Sarma.
['Mathew|Githa Elizabeth|GE|https://orcid.org/0000-0002-4237-9552', 'Oh|Jong Min|JM|', 'Mohan|Kumar|K|', 'Tengli|Anandkumar|A|', 'Mathew|Bijo|B|https://orcid.org/0000-0002-6658-4497', 'Kim|Hoon|H|https://orcid.org/0000-0002-7203-3712']
D000818:Animals D002522:Chlorocebus aethiops D007700:Kinetics D062105:Molecular Docking Simulation D008995:Monoamine Oxidase D008996:Monoamine Oxidase Inhibitors D010300:Parkinson Disease D013329:Structure-Activity Relationship D014709:Vero Cells
methylthiosemicarbazones reversibility Kinetics Parkinson’s disease molecular dynamics monoamine oxidase