Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies’ brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.

Molecular hybrids obtained by connecting two or more bioactive molecules through a metabolizable linker are used as multi-target drugs for the therapy of multifactorial diseases. Ascorbic acid, as well as the ketone bodies acetoacetate and (R)-3-hydroxybutyrate, are bioactive molecules that have common fields of application in the treatment and prevention of neurodegenerative diseases and cardiac injuries as well. In spite of this, the preparation of ascorbic acid ketone body hybrids is uncovered by the literature. Herein, we report the lipase-catalyzed condensation of methyl acetoacetate with ascorbic acid, which affords the 6-O-acetoacetyl ascorbic acid in quantitative yield. The same approach, employing the methyl (R)-3-hydroxybutyrate in place of the methyl acetoacetate, allows the preparation of the 6-O-(R)-3-hydroxybutyryl ascorbic acid in 57% yield. A better result (90% overall yield) is achieved through the lipase-catalyzed coupling of ascorbic acid with methyl (R)-3-O-methoxymethyl-3-hydroxybutyrate followed by the cleavage of the MOM protecting group. The two novel products are fully characterized and additional information on the antioxidant activity of the new products is also given.