Chromone-deferiprone hybrids as novel MAO-B inhibitors and iron chelators for the treatment of Alzheimer's disease.

A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B ( h MAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards h MAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against h MAO-B with an IC 50 value of 1.58 μM and potent iron-chelating ability (pFe 3+ = 18.79) comparable to that of deferiprone (pFe 3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive h MAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with h MAO-B inhibitory, iron-chelating and anti-ferroptosis activities.