There is a need for innovation in plant-derived pharmaceuticals, food supplements and nutraceutical products regarding the use of more eco-sustainable solvents for their extraction. Furthermore, the poor oral bioavailability of several phytochemicals with health promoting effects stimulates the research in the field of pharmaceutical formulations. Natural Deep Eutectic Solvents (NADES) are formed by natural compounds, and can be considered as future solvents being especially useful for the preparation of nutraceuticals and food-grade extracts. In this paper various NADES were prepared using sugars, aminoacids and organic acids. Rutin (quercetin-3-O-α-L-rhamnopyranosyl-(1→6))-β-D-glucopyranose) was used as a model compound to study NADES. Moreover, the effect of various eutectic mixtures on rutin's water solubility was studied. Proline/glutamic acid (2:1) and proline/choline chloride (1:1) mixtures have a solubility comparable to ethanol. The proline/glutamic acid (2:1) eutectic containing rutin was used in a pharmacokinetic study in Balb/c mice while bioavailability was compared to oral dosing of water suspension. Plasmatic levels of rutin were measured by HPLC-MS/MS showing increased levels and longer period of rutin permanence in plasma of NADES treated animals. This paper reports the possible use of non-toxic NADES for pharmaceutical and nutraceutical preparations.

In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC-MS/MS method. The pharmacokinetic analysis revealed a 2–20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine.

"Nutraceuticals" are food-derived products largely used for their presumed healthpromoting or disease-preventing effects. In the recent years, many efforts have been aimed at assessing nutraceutical efficacy and safety, but these factors are difficult to address because of the complex chemical compositions and multiple mode of actions. Thus, the study of nutraceutical ingredients poses several challenges for the medicinal chemistry field, some of which are related to extraction and chemical characterization, some to in vitro and in vivo bioactivity evaluation, and some to the bioavailability and interaction of these natural mixtures with organs and microbiota. Furthermore, because of their nature as medicinal and food products, these nutraceuticals can also be considered as a valuable source of new "lead compounds", creating the opportunity to discover new classes of therapeutic agents. This review provides information on these themes, showing the new challenges that comprehensive medicinal chemistry research is called to answer in the field of nutraceuticals.

Larix decidua bark is a waste of the timber industry and is widely diffused in Northern Italy. This material can be considered a good source of antioxidants and phytoconstituents with possible use in cosmetic or nutraceutical products. In this study, simple extraction of larch bark was performed using mixtures of ethanol/water. Furthermore, the phytochemical composition of larch bark extract was studied using LC-MSn methods and the main constituents were identified as flavonoids, spiro-polyphenols, and procyanidins. To confirm the identification by LC-MS semi-preparative HPLC was performed in order to isolate the main constituents and verify the structures by 1H-NMR. Antioxidant properties were studied using an in vitro approach combining DPPH assay and LC-MS in order to establish different roles of the various classes of phytochemicasl of the extract. DPPH activity of some of the isolated compounds was also assessed. The overall results indicate this waste material as a good source of antioxidant compounds, mainly procyanidins, whichresulted the most active constituents in the DPPH assay.

Sesquiterpenes are natural products that have been extensively studied for their bioactivities, evidencing their potentiality as useful scaffolds for the development of drugs. Considering the different derivatives, the sesquiterpene lactones have been evaluated, especially on cancer cell and antineoplastic efficacy in in vivo studies. Their bioactivity is strictly related to the presence of the reactive α-methylene-γ-lactone group (αMγL). Nevertheless, several other sesquiterpenes lacking αMγL are known and have been studied for their biological effects and potential usefulness in the development of new drugs. In this review, we focused on several sesquiterpenes that are not presenting the αMγL moiety and may have future potential as scaffold for the development of new drugs, namely the bicyclic compounds belonging to the carotane type (daucanes) that present significant effects as antiproliferative and estrogenic agents. The monocyclic humulane derivatives correlated to zerumbone, and the bicyclic compound beta-caryophyllene and its derivatives that have been considered in the field of cancer and inflammation. It is noteworthy that published studies on sesquiterpenes, reported in this review, focus on pathologies of increasing importance, like estrogen, anti-proliferative, bone loss, immunity deficiency and anti-tumour activities. Some of the natural "old" sesquiterpenes can be considered for their possible role in drug discovery and in counteracting these "new" challenges.