Assembling a Cinnamyl Pharmacophore in the C3-Position of Substituted Isatins via Microwave-Assisted Synthesis: Development of a New Class of Monoamine Oxidase-B Inhibitors for the Treatment of Parkinson’s Disease

Abstract

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 μM, followed by IHC2 (IC50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

Design, synthesis, and in vitro and in silico studies of morpholine derived thiazoles as bovine carbonic anhydrase-II inhibitors

“…A study of the protein–ligand interaction, Root Mean Square Deviation (RMSD), and Root Mean Square Fluctuation (RMSF) was carried out over all C α atoms throughout the 150 ns MD simulation to evaluate domain correlations. 39,40…”

Multireceptor Analysis for Evaluating the Antidiabetic Efficacy of Karanjin: A Computational Approach

“…The prior work contains more detailed information about the MD study, such as the solvent simulation box's size, shape, pressure control and temperature control parameters, as well as the treatment of long‐ and short‐range interactions [ 22 , 34 , 64 ]. To assess the correlations within the protein domains, Root Mean Square Deviation (RMSD) and RMSF analyses were conducted for each Cα atom for a 100 ns MD simulation [ 65 , 66 ]. MD simulations are conducted to understand the physical movements and interactions of atoms and molecules over time.…”