Design, Synthesis, and Evaluation of Coumarin-Rasagiline Hybrids as Multifunctional Neuroprotective Agents

The design of hybrid molecules with multifunctional profiles has emerged as a promising strategy in medicinal chemistry, particularly for tackling complex disorders such as neurodegenerative diseases. There is an urgent need for therapeutic agents capable of acting on multiple pathological targets to both control neuronal death and support the recovery of already compromised neuronal populations. In this study, we synthesized and evaluated a series of hybrid compounds combining a coumarin scaffold with an alkynylamine moiety inspired by rasagiline. These molecules were studied for their potential as human monoamine oxidase (hMAO) inhibitors, antioxidants, and neuroprotective agents. Five compounds demonstrated inhibitory activity against hMAO-B in the micromolar range, along with significant neuroprotective effects against oxidative stress induced by Fe³⁺ (FeNTA), tert-butyl hydroperoxide (t-BHP), and hydrogen peroxide (H₂O₂). Additionally, all compounds exhibited the ability to scavenge free radicals (ABTS assay) and chelate Fe(II), further corroborating their antioxidant capacity. In addition, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were investigated. Docking studies and molecular dynamics simulations provide additional support for the experimental data. Collectively, these findings provide renewed evidence for the therapeutic potential of coumarin-rasagiline hybrids as multifunctional agents for the treatment of neurodegenerative diseases.