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Secondary metabolites from plants and fungi have been frequently studied in the recent past for their possible use in the prevention and treatment of several pathologies, such as chronic and/or neurodegenerative diseases1. Particularly important seems to be their applications in the treatment of Alzheimer's disease (AD), the most common cause of dementia, accounting for millions of cases worldwide. AD is a recognized multifactorial pathology, and only symptomatic drugs are available for the therapy2. Natural compounds could be found as components of extracts but the possibility of isolation and characterization of the single molecules in the aglycone forms is a fascinating perspective: testing these chemical entities for their multi-functional activity on the main targets of AD is a big goal for worldwide researchers and industries3. In a recent work of our group, six natural compounds (five fungal secondary metabolites and one plant metabolite) were assayed for cholinesterases and beta-amyloid aggregation inhibition, antioxidant activity and metal chelation with promising results3. The identification of multiple biological properties of these natural scaffolds makes them also interesting for their potential in the design of nature-inspired structures. As an example of application of this strategy, one of the studied compounds, tenuazonic acid (TeA), a secondary metabolite produced by fungal Alternaria genera, was selected as a starting point for the design, synthesis and evaluation of a set of new hybrid derivatives containing a moiety that mimics donepezil, a commercial drug currently used for the treatment of AD4. In this communication, the results, development, and future perspective of this work will be discussed. References [1] Leuci R, Brunetti L, Poliseno V, Laghezza A, Loiodice F, Tortorella P, Piemontese L. 2021. Foods, 10: 29. [2] Piemontese L, Loiodice F, Chaves, Santos MA. 2019. Frontiers in Clinical Drug Research - Alzheimer Disorders, 8: 33-80. [3] Piemontese L, Vitucci G, Catto M, Laghezza A, Perna FM, Rullo M, Loiodice F, Capriati V, Solfrizzo M. 2018. Molecules, 23: 2182. [4] Poliseno V, Chaves S, Brunetti L, Loiodice F, Carrieri A, Laghezza A Tortorella P, Magalhães JD, Cardoso SM, Santos MA, Piemontese L. 2021. Biomolecules, 11: 111.

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a chemoinformatics search approach for new ligands that let us identify a novel PPAR pan-agonist with a very attractive activity profile being able to reduce lipid accumulation and improve insulin sensitivity. This compound represents, therefore, the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.