Indole-based hydrazide-hydrazone and sulfonylhydrazone derivatives as MAO-B inhibitors with multitarget potential for neurodegenerative diseases

Given the complex, multifactorial nature of Parkinson’s and Alzheimer’s diseases (PD and AD), along with the limited effectiveness of single-target treatments, multi-target-directed ligands (MTDLs) present a promising alternative approach. Monoamine oxidases A and B (MAO-A, MAO-B), as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are key targets in the development of MTDLs. In our previous study, we developed melatonin–donepezil hybrids with hydrazone (3a–r) and sulfonylhydrazone (5a–l) scaffolds, which showed AChE/BChE inhibition, antioxidant activity, low neurotoxicity, blood–brain barrier permeability, and Aβ42 reduction. This study focused on their MAO-B inhibition. Compounds 3e, 3f, 3i, and 3r showed dual MAO-B/MAO-A inhibition, while 5a and 5c were selective for MAO-B. Docking confirmed strong binding, especially for 3e and 3f. Despite moderate CYP3A4 inhibition (~30–35%) by some compounds, 3e, 3f, 3i, 3r, 5a, and 5c exhibited promising multitarget activity and are strong candidates for further optimization to enhance MAO-B selectivity while minimizing drug–drug interaction risks.