Development of methylthiosemicarbazones as new reversible monoamine oxidase-B inhibitors for the treatment of Parkinson’s disease

Abstract

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_i 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

Keywords:

• Kinetics
• methylthiosemicarbazones
• molecular dynamics
• monoamine oxidase
• Parkinson’s disease
• reversibility

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Republic of Korea government (NRF-2019R1A2C1088967) (to H. Kim).