The pseudo-symmetric n-benzyl hydroxyethylamine core in a new series of heteroarylcarboxyamide hiv-1 pr inhibitors: Synthesis, molecular modeling and biological evaluation

Here, we report the synthesis, enzyme inhibition and structure–activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P’ and P” and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/mL BSA. Compounds 9a–c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compare

Biginelli Reaction and \u3b2-Secretase Inhibition: A Multicomponent Reaction as a Friendly Educational Approach to Bioactive Compounds

Multicomponent reactions (MCRs) represent very interesting tools to reach eco-friendly and sustainable transformations in organic chemistry. In particular, the Biginelli reaction furnishes a very easy approach to the synthesis of a library of biological active compounds in an academic course. Here we describe the realization of several experiments involving the synthesis of potential inhibitors of \u3b2-secretase by the Biginelli reaction. All of the obtained compounds were tested with a FRET fluorimetric assay. The experiments were proposed to students either at entry level or during advanced laboratory courses of organic and bioorganic chemistry. The learning objectives at the advanced level were to introduce the students to the practice of combinatorial synthesis and to the evaluation of biological activity of combinatorial libraries by enzyme inhibition assays. The meeting of the learning objectives was probed first by analyzing their daily performance in the laboratory and their increasing proactive attitude, and the contents of their final presentations. The resulting marks obtained by the students were compared with the average evaluation of their career. Second, the students were asked to evaluate the course and their own experience, and the outcome of their evaluation was compared with that of the teachers

[7,0]-metacyclophanes from biaryl coupling/macrocyclisation

The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century organic chemists have sought to develop new and more efficient aryl-aryl bond-forming methods (1). Cyclophanic natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophanic molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions (2). Among cyclophanic natural products, the diarylheptanoids are a structurally sub-class with their scaffold consisting of two benzene rings tethered by an oxygenated aliphatic heptyl chain. In this work we reported different metal catalysed approaches to obtain the biaryl motif of myricanol, a natural [7,0]-metacyclophane with very important and recently discovered biological activities (3),(4),(5),(6). (Figure 1) Figure 1 The desired product 1could be obtained from the functionalized linear diarylheptanoid 2 by Suzuki domino process (macrocyclisation by linkage of aryl moieties) or could be synthesized from ring closing metathesis of product 3 which derived from a biaryl coupling of fragments 4 and 5. (1) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107 (1), 174–238. (2) Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29 (8), 899-934. (3) Jones, J. R.; Lebar, M. D.; Jinwal, U. K.; Abisambra, J. F.; Koren, J.; Blair, L.; O’Leary, J. C.; Davey, Z.; Trotter, J.; Johnson, A. G.; Weeber, E.; Eckman, C. B.; Baker, B. J.; Dickey, C. A. J. Nat. Prod. 2011, 74 (1), 38–44. (4) Martin, M. D.; Calcul, L.; Smith, C.; Jinwal, U. K.; Fontaine, S. N.; Darling, A.; Seeley, K.; Wojtas, L.; Narayan, M.; Gestwicki, J. E.; Smith, G. R.; Reitz, A. B.; Baker, B. J.; Dickey, C. A. ACS Chem. Biol. 2015, 10 (4), 1099–1109. (5) Dai, G. H.; Meng, G. M.; Tong, Y. L.; Chen, X.; Ren, Z. M.; Wang, K.; Yang, F. Phytomedicine 2014, 21 (11), 1490–1496. (6) Dai, G.; Tong, Y.; Chen, X.; Ren, Z.; Ying, X.; Yang, F.; Chai, K. Int. J. Mol. Sci. 2015, 16 (2), 2717–2731

Antioxidant, Antidiabetic, and Anticholinesterase Activities and Phytochemical Profile of Azorella glabra Wedd

peer-reviewedSupplementary material available Table S1: LC-Q-Tof chromatograms showing the retention times of standard compounds mix used for the identification and quantification of various polyphenols and a terpene in the ethyl acetate fraction of Azorella glabra Wedd.Oxidative stress is involved in different diseases, such as diabetes and neurodegenerative diseases. The genus Azorella includes about 70 species of flowering plant species; most of them are commonly used as food and in particular as a tea infusion in the Andean region of South America in folk medicine to treat various chronic diseases. Azorella glabra Wedd. aerial parts were firstly analyzed for their in vitro antioxidant activity using different complementary assays. In particular, radical scavenging activity was tested against biological neutral radical DPPH; ferric reducing power and lipid peroxidation inhibitory capacity (FRAP and Beta-Carotene Bleaching tests) were also determined. The Relative Antioxidant Capacity Index (RACI) was used to compare data obtained by different assays. Then, the inhibitory ability of samples was investigated against α-amylase and α-glucosidase enzymes involved in diabetes and against acetylcholinesterase and butyrylcholinesterase enzymes considered as strategy for the treatment of Parkinson’s or Alzheimer’s diseases. Moreover, the phytochemical profile of the sample showing the highest RACI (1.35) and interesting enzymatic activities (IC50 of 163.54 ± 9.72 and 215.29 ± 17.10 μg/mL in α-glucosidase and acetylcholinesterase inhibition, respectively) was subjected to characterization and quantification of its phenolic composition using LC-MS/MS analysis. In fact, the ethyl acetate fraction derived from ethanol extract by liquid/liquid extraction showed 29 compounds, most of them are cinnamic acid derivatives, flavonoid derivatives, and a terpene. To the best of our knowledge, this is the first report about the evaluation of significant biological activities and phytochemical profile of A. glabra, an important source of health-promoting phytochemicals.This work was supported by the Regione Basilicata; the Fondazione Enrico Mattei DGR n. 1490 del 4/12/2014, vs. rep. n. 163 n8; and the Regional Project ALIMINTEGRA, GO NUTRIBAS financed on 16.1 PSR Basilicata founding ex D.G.R. No. 312/17 CUP: C31G18000210002

Antioxidant Activity and Phytochemical Characterization of Senecio clivicolus Wedd.

peer-reviewedAntioxidant phytochemicals play a key role in oxidative stress control and in the prevention of related disorders, such as premature aging, degenerative diseases, diabetes, and cancer. The aim of this study was to investigate the potential antioxidant activity and the phytochemical profile of Senecio clivicolus Wedd., a perennial shrub, belonging to the Asteraceae family. Despite the wide interest of this family, this specie has not been investigated yet. S. clivicolus aerial parts were extracted with 96% ethanol. Then, the ethanol extract was fractionated by liquid/liquid extraction using an increasing solvents polarity. Total polyphenol and terpenoid contents were measured. Moreover, the antioxidant activity was evaluated by six different complementary in vitro assays. The Relative Antioxidant Capacity Index (RACI) was used to compare data obtained by different tests. The sample showing the highest RACI was subjected to characterization and quantitation of its phenolic composition using LC-MS/MS analysis. The ethyl acetate fraction, investigated by LC-MS/MS analysis, showed 30 compounds, most of them are chlorogenic acid and flavonoid derivatives. To the best of our knowledge, this is the first report about the evaluation of antioxidant activity and phytochemical profile of S. clivicolus, underlying the importance of this species as a source of health-promoting phytochemicals.This research was supported by the University of Basilicata, Project “Monitoraggio delle acque marine costiere e profonde in Basilicata” D.G.R. 1490 of 4/12/2014

New heteroaryl carbamates: synthesis and biological screening in vitro and in mammalian cells of wild-type and mutant HIV-protease inhibitors

New heteroaryl HIV-protease inhibitors bearing a carbamoyl spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different substitution patterns were introduced onto a given isopropanoyl-sulfonamide core that can have either H or benzyl group. The in vitro inhibition activity against recombinant protease showed a general beneficial effect of both carbamoyl moiety and the benzyl group, ranging the IC50 values between 11 and 0.6 nM. In particular, benzofuryl and indolyl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such derivatives in terms of number of interactions in the active site, supporting the experimental results. The inhibition activity was also confirmed in HEK293 mammalian cells and was maintained against protease mutants. Furthermore, the metabolic stability was comparable with that of the commercially available inhibitors

PEGylated Liposomes Loaded with Carbamate Inhibitor ANP0903 Trigger Apoptosis by Enhancing ER Stress in HepG2 Cancer Cells

Liver cancer is one of the most common causes of cancer death worldwide. In recent years, substantial progress has been made in the development of systemic therapies, but there is still the need for new drugs and technologies that can increase the survival and quality of life of patients. The present investigation reports the development of a liposomal formulation of a carbamate molecule, reported as ANP0903, previously tested as an inhibitor of HIV-1 protease and now evaluated for its ability to induce cytotoxicity in hepatocellular carcinoma cell lines. PEGylated liposomes were prepared and characterized. Small, oligolamellar vesicles were produced, as demonstrated by light scattering results and TEM images. The physical stability of the vesicles in biological fluids was demonstrated in vitro, alongside the stability during storage. An enhanced cellular uptake was verified in HepG2 cells treated with liposomal ANP0903, resulting in a greater cytotoxicity. Several biological assays were performed to elucidate the molecular mechanisms explaining the proapoptotic effect of ANP0903. Our results allow us to hypothesize that the cytotoxic action in tumor cells is probably due to the inhibition of the proteasome, resulting in an increase in the amount of ubiquitinated proteins within the cells, which in turn triggers activation of autophagy and apoptosis processes, resulting in cell death. The proposed liposomal formulation represents a promising approach to deliver a novel antitumor agent to cancer cells and enhance its activity

Stereoselective Intramolecular Cyclization to 4-(Hydroxymethyl)-3-(1H-indolyl)oxazolidin-2-ones

A simple high-yield three-steps route to optically active 4-hydroxymethyl-3-(1Hindolyl) oxazolidin-2-ones from (S)-glycidol is described. The key intermediates (R)-oxiran-2- ylmethyl 1H-indol-4/-5-ylcarbamates are obtained in high yields from (S)-glycidol. These are readily transformed to oxazolidin-2-ones, very interesting building blocks in drug synthesis