Discovery of novel endocannabinoid level modulators by modification of old analgesic drugs

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysis of the fatty acid ethanolamide family of signaling lipids, which includes anandamide (AEA), an endogenous ligand for cannabinoid receptors. Endogenous FAAH substrates such as AEA serve key regulatory functions in the body and have been implicated in a variety of pathological conditions including pain, inflammation, sleep disorders, anxiety, depression, and vascular hypertension, and there has been an increasing interest in the development of inhibitors of this enzyme. Different structural classes of FAAH inhibitors have been reported including alpha-ketoheterocycles, (thio)hydantoins, piperidine/piperazine ureas, and carbamate derivatives. When tested, these compounds have been shown to be efficacious in models of inflammatory, visceral, and in some cases neuropathic pain without producing the central effects seen with directly acting cannabinoid receptor agonists. An intriguing aspect of FAAH inhibition is that some currently marketed nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to be weak inhibitors of FAAH, but can be used as a template for the design of more potent compounds. However, structure–activity relationships of analogues of clinically used NSAIDs with respect to FAAH inhibition have been examined scarcely in the literature. These findings led us to design and synthesis of new series of FAAH inhibitors derivable from conjugation of heterocyclic structures with NSAIDs as profens, fenamates, and new their correlate molecules. In this keynote we report on the synthetic pathways to transform old analgesic drugs into FAAH inhibitors and SAR studies on the new inhibitor series

Synthesis and evaluation of antioxidant and antiproliferative activity of 2-arylbenzimidazoles

Three series of arylbenzimidazole derivatives 3-40, 45 have been simply synthesized and tested for their antioxidant capacity. The 2-arylbenzimidazoles were tested against various radicals by the DPPH, FRAP and ORAC tests and showed different activity profiles. It has been observed that the number and position of the hydroxy groups on the 2-aryl portion and the presence of a diethylamino group or a 2-styryl group are related to a good antioxidant capacity. Furthermore, benzimidazoles showed satisfactory SPF values ​​in vitro compared to the commercial PBSA filter, proving to have a good photoprotective profile. In particular, 2-arylbenzimidazole-5-sulphonic acids 15 and 38, the 2-styryl-benzimidazole 45 showed broad spectrum solar protection against UVA and UVB rays. The antiproliferative effect of the benzimidazoles was tested on human skin melanoma Colo-38 cells. The styrylbenzimidazole 45 exhibited antiproliferative effect at low micromolar concentration against Colo-38 cells and very low antiproliferative activity on normal HaCat keratinocyte cells

Theoretical and Experimental Study of the Excess Thermodynamic Properties of Highly Nonideal Liquid Mixtures of Butanol Isomers + DBE

Binary alcohol + ether liquid mixtures are of significant importance as potential biofuels or additives for internal combustion engines and attract considerable fundamental interest as model systems containing one strongly H-bonded self-associating component (alcohol) and one that is unable to do so (ether), but that can interact strongly as a H-bond acceptor. In this context, the excess thermodynamic properties of these mixtures, specifically the excess molar enthalpies and volumes (HE and VE), have been extensively measured. Butanol isomer + di-n-butyl ether (DBE) mixtures received significant attention because of interesting differences in their VE, changing from negative (1- and isobutanol) to positive (2- and tert-butanol) with increasing alkyl group branching. With the aim of shedding light on the differences in alcohol self-association and cross-species H-bonding, considered responsible for the observed differences, we studied representative 1- and 2-butanol + DBE mixtures by molecular dynamics simulations and experimental excess property measurements. The simulations reveal marked differences in the self-association of the two isomers and, while supporting the existing interpretations of the HE and VE in a general sense, our results suggest, for the first time, that subtle changes in H-bonded topologies may contribute significantly to the anomalous volumetric properties of these mixtures

Cholinium-Based Ionic Liquids from Hydroxycinnamic Acids as New Promising Bioactive Agents: A Combined Experimental and Theoretical Investigation

Cholinium-based ionic liquids (Cho-ILs) are very attractive compounds for medicinal and pharmaceutical applications as bioavailability enhancers in drug formulations and active components in pharmaceutical ingredients. In this study, we synthesized six Cho-ILs from hydroxycinnamic acids (HCA) ([Cho][HCA] ILs), a group of bioactive compounds with poor water solubility. [Cho][HCA] ILs and their parent acids were evaluated for solubility, thermal stability, and antioxidant activity. Furthermore, [Cho][HCA] ILs were screened for their cytotoxicity. To rationalize the experimental antioxidant activities, density functional theory (DFT) calculations were performed. The theoretical approach allowed for identification of the most likely radical scavenging mechanisms involving HCAs and the corresponding ionic forms under the studied experimental conditions and to rationalize the observed activity differences between salts and acids. Overall, our results revealed a higher solubility and free-radical scavenging activity for [Cho][HCA] ILs than corresponding HCAs, a relatively high thermal stability (melting temperature > 100 °C) and negligible cytotoxicity activity. Furthermore, DFT calculations showed that both the hydrogen atom transfer and the sequential proton loss electron transfer mechanisms are likely to occur in aqueous and ethanolic solutions. The picture emerging from our results supports the increasingly expressed idea that [Cho][HCA]ILs are promising candidates for applications in pharmaceutical formulatio

L'Università dell'innovazione. L'ufficio di trasferimento tecnonolgico dell'Ateneo di Cagliari "Unica Laison Office"

Obiettivi ed organizzazzione dell'ufficio per il trasferimento tecnologico

Hydroxycinnamate-based Ionic liquids as bioactive compounds: physico-chemical characterization, biological activity and NMR insights into the effects on mutated cells metabolome

Nowadays, there is a strong collaboration between the research in drug discovery and drug delivery to improve pharmacokinetic and pharmacodynamic properties of new or use-consolidated drugs. With this purpose, several approaches have been proven to be fundamental for the developing of commercial drugs which are still in use. In this context, natural compounds such as Hydroxycinnamic acids (HCAs) are gaining increasing attention in pharmaceutical research due to their well-estabilished wide ranging benefits on health. HCAs are a group of phenolic products of plant secondary metabolism widely studied for their numerous biological properties, such as antioxidant, anti-inflammatory, anti-microbial, anti-collagenase, and anti-melanogenic activity. These features have made HCAs very attractive compounds for medicinal and pharmaceutical applications. However, their low water solubility represents a major drawback for their incorporation in hydrophilic topical formulations and thus, the search for new formulations with enhanced water solubility is of high priority in current research. The conversion of drugs or bioactive molecules into ionic liquids (ILs) rapresents a strategy to improve some issues related to solubility, polymorphism and bioavalibility. Indeed, by choosing an appropriate benign counterion, it is possible to obtain biocompatible and environmentally friendly ILs. In particular, ILs containing cholinium cation combined with hydroxycinnamic acid-based anion ([Cho][HCA] ILs) are promising compounds that are themselves components in active pharmaceutical ingredients (APIs) with potential applications in the formulation of pharmaceutical and cosmetic products due to the higher water solubility and antioxidant properties compared to their acidic precursors. In the present PhD thesis, I have synthesized six new derivatives of HCAs as [Cho][HCA] ILs. Several physico-chemical and biological properties of these compounds, considered important for their potential use in the pharmaceutical field, were studied: aqueous solubility, thermal stability, anti-oxidant activity, citotoxicity. To rationalize the experimental antioxidant activities, density functional theory (DFT) calculations were performed. Furthermore, some [Cho][HCA] ILs were also tested for their activity on mushroom tyrosinase, melanine production in human MNT 1 melanome cells and their impact of the cellular metabolome. Overall, this work successfully shows that [Cho][HCA] ILs may be good candidates as an alternative to HCAs in pharmaceutical field

Benzofuran hydrazones as potential scaffold in the development of multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity

New benzofuranhydrazones 3–12 were easily prepared and assayed for their radical-scavenging ability. Hydrazones 3–12 showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety. High antioxidant activity is showed by the 2-hydroxy-4-(diethylamino)benzylidene derivative 11. Furthermore, hydrazones 3–12 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The antiproliferative effects of the hydrazones 3–12 was tested on erythroleukemia K562 and Colo-38 melanoma human cells. All the compounds showed growth inhibition in the micromolar to sub micromolar concentration range. If taken together these results points to benzofuran hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 5, 7 and 11 correlated to their high antiproliferative activity

Nematicidal activity of acetophenones and chalcones against Meloidogyne incognita and structure-activity considerations

BACKGROUND: With the ultimate goal of identifying new compounds active against root-knot nematodes, a set of 14 substituted chalcones were synthesised, starting from acetophenones. These chalcones and various acetophenones were tested in vitro against Meloidogyne incognita. RESULTS: The most potent acetophenones were 4-nitroacetophenone and 4-iodoacetophenone, with EC50 /24 h values of 12 ± 5 and 15 ± 4 mg L-1 respectively, somewhat weaker than that of the chemical control fosthiazate in our previous experiments (EC50 /24 h 0.4 ± 0.3 mg L-1 ). When we converted the acetophenones to chalcones, the nematicidal activity differed, based on their substitution pattern. The condensation of 4-nitroacetophenone with 2,4,6-trihydroxybenzaldehyde to give the corresponding chalcone (E)-1-(4-nitrophenyl)-3-(2,4,6-trihydroxyphenyl)prop-2-en-1-one led to a slight reduction in activity (EC50 /24 h value 25 ± 17 mg L-1 ). Moreover, (E)-3-(2-hydroxy-5-iodophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one showed better activity (EC50 /24 h value 26 ± 15 mg L-1 ) than 4-methoxyacetophenone (EC50 /24 h value 43 ± 10 mg L-1 ). CONCLUSIONS: Acetophenones and chalcones may represent good leads in the discovery of new nematicidal compounds and may have potential use in crop management as active ingredients