Discovery of orexant and anorexant agents with indazole scaffold endowed with peripheral antiedema activity

CB1 receptors and endocannabinoids are integrated components of neuronal networks controlling different organism’s functions, such as appetite and food intake in the hypothalamus. A series of Rimonabant/Fubinaca hybrids have been synthesized in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied in cannabinoid receptor binding assay and functional receptor assay in vitro, the most active among them as agonist (LONI 11) and antagonist (LONI 4) were tested in vivo to evaluate their ability to stimulate or suppress the feeding behavior after i.p. administration. For LONI 11 formalin test and tail flick tests after s.c. and i.c.v. routes respectively, were also performed in vivo with the aim to investigate the antinociceptive effect at the central or peripheral level. In the Zymosan-induced edema and hyperalgesia, LONI 11 reduced the % paw volume increase and % paw latency after s.c. administration, also suggesting a potential anti-inflammatory activity at the periphery. Keywords. Cannabinoid receptor, Rimonabant, food intake, anorexant agent, edema

Novel 1,3-thiazolidin-4-one derivatives as promising anti-Candida agents endowed with anti-oxidant and chelating properties

Pursuing our recent outcomes regarding the antifungal activity of N-substituted 1,3-thiazolidin-4-ones, we synthesized thirty-six new derivatives introducing aliphatic, cycloaliphatic and heteroaromatic moieties at N1-hydrazine connected with C2 position of the thiazolidinone nucleus and functionalizing the lactam nitrogen with differently substituted (NO2, NH2, Cl and F) benzyl groups. These compounds were tested to evaluate their minimum inhibitory concentration (MIC) against several clinical Candida spp. with respect to topical and systemic reference drugs (clotrimazole, fluconazole, ketoconazole, mi- conazole, tioconazole, amphotericin B). Moreover, anti-oxidant properties were also evaluated by using different protocols including free radical scavenging (DPPH and ABTS), reducing power (CUPRAC and FRAP), metal chelating and phosphomolybdenum assays. Moreover, for the most active derivatives we assessed the toxicity (CC50) against Hep2 human cells in order to characterize them as multi-target agents for fungal infections

Open saccharin-based secondary sulfonamides as potent and selective inhibitors of cancer-related carbonic anhydrase IX and XII isoforms

A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis &gt; 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.</p

Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates

Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation. © 2016 Informa UK Limited, trading as Taylor &amp; Francis Group

Recent Advances in the Treatment of Neurodegenerative Diseases Based on GSH Delivery Systems

Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease(AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. Unfortunately, GSH delivery to the central nervous system (CNS) is limited due to a poor stability and low bioavailability. Medicinal-chemistry- and technology-based approaches are commonly used to improve physicochemical, biopharmaceutical, and drug delivery properties of therapeutic agents. This paper will focus primarily on these approaches used in order to replenish intracellular GSH levels, which are reduced in neurodegenerative diseases. Here, we discuss the beneficial properties of these approaches and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically from PD and AD

An overview on plants cannabinoids endorsed with cardiovascular effects.

Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life. The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis. Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics. One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs. The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system

Chemical composition and biological activity of Capparis spinosa L. from Lipari Island

Several plants belonging to the genus Capparis are the focus of growing interest due to their singular nutritional and medicinal properties. In the present study, flower bud samples from C. spinosa L. (Lipari Island, Italy) were subjected to decoction, Soxhlet, and microwave extraction techniques and the individual extracts investigated to better characterize the phytochemical and antioxidant profiles of the plant. Total phenolic and flavonoid amounts, phenolic composition, radical scavenging as well as reductive and metal chelating properties were determinated by well-established chemical and analytical procedures. Furthermore, cholinesterase inhibitory effects were evaluated by Ellman's method. Fatty acid percentage and essential oil composition were also detected by GC and GC-MS techniques respectively. Rutin was found to be the major component in the studied extracts. The Soxhlet extract exhibited the strongest radical scavenging and reductive activities as compared to the other extracts, most probably due to the highest concentration of phenolics, especially rutin. The best cholinesterase inhibitory effect was observed in the microwave extract. Palmitic acid was the most abundant fatty acid in the studied oil, whereas docosane was the major volatile compound in the essential oil. Present data corroborate the multipurpose potential of C. spinosa for designing bio-based drug formulations or functional applications. (c) 2018 SAAB. Published by Elsevier B.V. All rights reserved

Discovery of Novel mu-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

Morphine, oxycodone, fentanyl, and other mu-opioid receptors (MOR) agonists have been used for decades in antinociceptive therapies. However, these drugs are associated with numerous side effects, such as euphoria, addiction, respiratory depression, and adverse gastrointestinal reactions, thus, circumventing these drawbacks is of extensive importance. With the aim of identifying novel peptide ligands endowed with MOR inhibitory activity, we developed a virtual screening protocol, including receptor-based pharmacophore screening, docking studies, and molecular dynamics simulations, which was used to filter an in-house built virtual library of tetrapeptide ligands. The three top-scored compounds were synthesized and subjected to biological evaluation, revealing the identity of a hit compound (peptide 1) endowed with appreciable MOR inverse agonist effect and selectivity over delta-opioid receptors. These results confirmed the reliability of our computational approach and provided a promising starting point for the development of new potent MOR modulators