Abstract
Alzheimer's disease (AD) represents a considerable health and social problem. The pathogenesis of this multifactorial disease involves various events, among which amyloid beta (Aβ) protein brain accumulation and aggregation are crucial in triggering a cascade of neurotoxic events such as oxidative stress and neuroinflammation. The HYMBAD project focuses on the design and synthesis of new bio-hybrid molecules with a multi-target activity profile to tackle different Aβ-driven toxic events. In detail, scaffolds related to natural products namely chalcones and stilbenes, and polyoxometalates will be modified and conjugated with selected pharmacophores, among which are small peptide-like synthons and peptides containing the Aβ KLVFF motif. The biological evaluation of the hybrid bio-conjugates will assess their anti-inflammatory and antioxidant potentials (testing in vitro in microglial cells and in a Drosophila AD model), thereby enabling the development of novel agents for AD treatment.
Results achieved
The development of new therapeutic strategies against AD, a complex neurodegenerative disorder, currently poses a challenge in medicinal chemistry. The project HYMBAD, employing a multifunctional design strategy, aimed to develop bio-hybrid constructs that could simultaneously modulate different underlying features of the pathology, including oxidative stress, amyloid-β (Aβ) protein aggregation, and neuro-inflammatory processes. In particular, properly chosen pharmacophores were combined to develop multipotent agents in a disease-modifying therapeutic context. Efforts were also focused on bioactivity optimisation, preventing central nervous system toxicity, and improving BBB crossing. Through this integrated strategy, the project aimed to identify novel lead compounds and drug candidates with a multipotent bioactivity profile. Specifically, the research focused on the design and development of three main series of small molecules inspired by natural products, obtained by suitably modifying templates from the flavonoid family, such as chalcones and flavones, as well as from the stilbene class, regarded as privileged structures, endowed with a wide spectrum of beneficial effects. Their combination with selected pharmacophores enabled highlighting the anti-inflammatory, antioxidant, and neuroprotective effects of the developed hybrids. Regarding the chalcone-based set, various approaches were exploited, namely a) introducing an ester-linked 1,2,3-triazole moiety through an alkoxy spacer, by exploiting the click-chemistry approach, or b) incorporating an amino acid fragment via an acetoxy linker. An initial screening of the newly designed compounds focused on identifying anti-inflammatory and antioxidant lead compounds capable, at non-toxic concentrations, of effectively decreasing cytokine release from LPS-stimulated microglia and inducing Nuclear Factor Erythroid 2-related factor 2 (Nrf2) in SH-SY5Y cells, respectively. Exploiting the “scaffold hopping” approach, the flavone and flavanone templates, structurally related to the chalcone one, properly functionalized, were subjected to hybridisation by the insertion of the triazole-ester synthon. Moreover, the design of multipotent anti-AD agents involved the design of hybrids in which a methoxylated stilbene scaffold was connected to different amino and aminoacidic-related synthons through an alkyl-amido linker, capable of simultaneously activating the Nrf2 pathway, inhibiting the enzyme monoamino-oxidase-B (MAO-B) overexpression, thus mitigating oxidative stress and neuroinflammation, and ultimately providing neuroprotection. This study enabled the accomplishment of a SAR study and the identification of lead compounds, thus supporting their further optimisation to improve bioactivity. In this context, the conjugation of the discovered lead compounds with a synthon related to the KLVFF Aβ-recognition peptide would offer promise for obtaining a bio-hybrid with favourable bioactivities.Project details
Unibo Team Leader: Federica Belluti
Unibo involved Department/s:
Dipartimento di Farmacia e Biotecnologie
Coordinator:
Università degli Studi di PADOVA(Italy)
Total Unibo Contribution: Euro (EUR) 55.080,00
Project Duration in months: 24
Start Date:
16/10/2023
End Date:
28/02/2026
