Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Abstract

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d , benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe 3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC 50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d . In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.

Novel druggable mechanism of Parkinson's disease: Potential therapeutics and underlying pathogenesis based on ferroptosis

“…The orally available iron chelator deferiprone (DFP, 4 ) has been employed in clinical studies to determine its impact on PD progression (Figure 7). 88,89 In a multicenter, unblinded, single‐arm pilot phase II clinical trial ( n = 20, NCT00907283), it was demonstrated that DFP reduced iron accumulation in the globus pallidus in two patients and improved motor symptoms in three patients 90 . Separately, in two randomized, double‐blind, placebo‐controlled phase II clinical trials, DFP reduced iron deposition in SN and progression of dyskinesia in early‐onset PD patients ( n = 19, NCT00943748; n = 22, NCT01539837) 91,92 .…”

Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer’s disease

“…Several pieces of evidence reported by our research group have revealed that coumarin/benzamide-based multi-target ligands with the iron-chelating ability and MAO-B inhibitory activity have an attractive anti-AD potential 20 , 22 . Aiming at identifying new multipotent ligands, in this work, a new series of chromone-hydroxypyridinone hybrids were rationally designed by linking chromone core and hydroxypyridinone moiety with the appropriate linkers ( Figure 2 ).…”

A recent update on huprine and its hybrids as a potential multifunctional agent for the treatment of Alzheimer's disease

“…It plays an important role in neural plasticity, synapse formation, antimicrobial activity, and iron export. APPs are mainly cleaved by two enzymes: (i) BACE1 and (ii) γ‐secretase, leads to the production of various Aβ‐peptides of different lengths (Aβ 1–40 , and Aβ 1–42 ; Jiang et al., 2021). The longest one is Aβ 1–42 , and the shortest one is Aβ 1–40 .…”