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

In continuation of our past effort s 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 mu M) to hMAO-B (1098.50 +/- 36.70 mu M) 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 mu M; hMAO-B: IC50= > 20 0 0 0.0 0 mu M). 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 investi-gated 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 an-tioxidant property (DPPH: IC50= 7.36 +/- 0.56 mu M; H2O2: IC50= 8.13 +/- 0.40 mu M) 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. (c) 2022 Published by Elsevier B.V.

Automated summary

In this study, a series of pyrazoline derivatives with a bioisostere methyl group replacing the chloro group on the 5-phenyl ring were synthesized and tested for hMAO inhibitory activity. Compound IIIa showed potent and selective inhibition of hMAO-A, along with strong antioxidant properties, indicating its potential in treating depressive illness and neurodegenerative disorders.