Brain permeable curcumin-based pyrazoline analogs: MAO inhibitory and antioxidant activity

Abstract

In continuation of our past efforts developing curcumin-based pyrazoline analogs for human monoamine oxidase (hMAO) inhibitory activity, we report a new series of pyrazoline derivatives with the chloro group (electron-withdrawing) located on the 5-phenyl ring replaced with a bioisostere methyl group (electron-donating). All the synthesized compounds (II, IIIa–IIId) were tested for hMAO inhibitory activity. Compounds IIIa–IIId were found to be potent and selective inhibitors of hMAO-A. Surprisingly, compound II exhibited a greater change in selectivity from hMAO-A (6550.00±74.80 µM) to hMAO-B (1098.50±36.70 µM) as compared to its chloro counterpart. Among all methyl-substituted derivates, compound IIIa was found potent and selective towards hMAO-A: IC50=48.00 ±2.41 µM; hMAO-B: IC50= >20000.00 µM). The molecular-level interaction between compounds II and IIIa and the hMAO isoforms that contributed to potency was observed in terms of the ability to form an “aromatic cage”. However, selectivity was investigated using molecular docking and molecular dynamics (MD) simulations, where the binding free energy indicates that the R isoform of compound IIIa has ∼ 5 kcal/mol of stronger affinity towards hMAO system in comparison to the S isoform. The brain permeability [Pe (x10−6 cm s−1): 15.22±0.34] and powerful antioxidant property (DPPH: IC50= 7.36±0.56 µM; H2O2: IC50= 8.13±0.40 µM) of compound (IIIa) might be useful in neutralizing the free radical generated during oxidative deamination of neurotransmitters and dietary amines, which may help treat depressive illness and neurodegenerative disorders without toxicity.