Design, synthesis and evaluation of sesamol-derived acetamides as dual inhibitors of monoamine oxidases and cholinesterases

Abstract

A set of sesamol-derived acetamides was designed, synthesized, and evaluated against monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) for targeting neurodegenerative diseases. Most of the tested compounds showed inhibition activity at micromolar to nanomolar ranges. The 3,4-dichoro derivative (compound 19) was the most potent MAO-A inhibitor (IC50 = 0.053 ± 0.001 µM) while the 4-methyl analog (compound 16) emerged as a lead MAO-B inhibitor (IC50 = 0.019 ± 0.001 µM) compared to the reference inhibitors clorgyline (MAO-A IC50 = 0.096 ± 0.003 µM) and selegyline (MAO B IC50 = 0.021 ± 0.002 µM). Further, the 2,4-dichloro analog (compound 20) emerged as a potent dual MAO (MAO-A IC50 = 0.160 ± 0.009 µM, MAO-B IC50 = 0.071 ± 0.002 µM) and ChE (AChE IC50 = 2.611 ± 0.086 µM and BChE IC50 = 4.22 ± 0.162 µM) inhibitor. Moreover, molecular simulation studies revealed that H-bonding and hydrophobic interactions stabilize the virtual lead inhibitor-protein complex. Selected MAO-ChE inhibitors showed significant antioxidant and iron-chelation properties, suggesting their potential in treating neurological disorders characterized by impaired iron homeostasis. In summary, the structural modification attempted in the present study yielded a few nanomolar MAO (MAO-B) inhibitors and, thus, provided new insights into the linker requirements for dual MAO/ChE inhibitory properties. (Figure presented.) © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.