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A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

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With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2' ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.

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A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4-3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.

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The leaves of Vitis vinifera L. have been used for a long time in traditional medicine for the treatment of many ailments. Grape polyphenols, indeed, have been demonstrated to be able to defend against oxidative stress, responsible for various disorders such as cancer, diabetes and neurodegenerative diseases. The effects of different extraction techniques, Soxhlet (SOX), Accelerated Solvent (ASE 40, ASE 50) and Ultrasound Assisted Extraction (UAE) were studied in this work to evaluate their impact on the chemical profile and bioactive potential of Vitis vinifera L. (cv. Aglianico) leaf extracts. The phytochemical profile was investigated by HPLC-DAD and 9 phenolic compounds were identified and quantified in the extract. Moreover, the antioxidant, anticholinesterase and antityrosinase activities were evaluated. In detail, the total polyphenol content and antioxidant activity (2,2-diphenyl-1-picrylhydrazyl, Oxygen Radical Absorbance Capacities and ß-Carotene Bleaching assays) were evaluated and compared to assess the Relative Antioxidant Capacity Index (RACI). To test the inhibitory activity of extracts towards cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assays were performed. SOX and ASE 50 have shown the highest value of RACI, 0.76 and 0.65, respectively. Regarding enzymatic inhibitory activity, ASE 50 (IC50 = 107.16 ± 8.12 µg/mL) and SOX (IC50 = 171.34 ± 12.12 µg/mL) extracts exhibited the highest AChE and BChE inhibitory activity, respectively, while UAE (IC50 = 293.2 ± 25.6 µg/mL, followed by SOX (IC50 = 302.5 ± 38.3 µg/mL) showed the highest tyrosinase inhibition value. Our results demonstrated for the first time that Aglianico leaves are important sources of phenols that could be used to prevent oxidative stress and be potentially helpful in diseases treatable with tyrosinase and cholinesterase inhibitors, like myasthenia gravis or Alzheimer's.

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BACKGROUND: Neurodegenerative disorders have achieved epidemic levels in the last decades; not only the elderly but also adult individuals have been increasingly affected. Among them, Alzheimer's disease is one of the most prevalent and crippling diseases, associated with high rates of multi-morbidities and dependency. Despite the existence of a wide variety of drugs used as the symptomatic treatment, they have some side effects and toxicity, apart from their limited effectiveness. Botanical preparations have a secular use, being widely recommended for a multitude of purposes, such as for the improvement of brain health. OBJECTIVE: The aim of the present report is to systematize the knowledge on plant-food derived bioactive molecules with promising in vitro enzymatic inhibitory activities. RESULTS: Alkaloids, phenolic compounds and terpenes are the most studied phytochemicals, both derived from natural and commercial sources. In spite of their efficient activity as enzymatic inhibitors, the number of in vivo studies and even clinical trials have confirmed that their real bioactive potential remains scarce. CONCLUSION: Thus, it is of the utmost importance to deepen knowledge in this area, once those relevant and informative tools can significantly contribute to the promising advances in the field of Alzheimer's disease treatment.

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Five new polyketides, namely, 5R-hydroxyrecifeiolide (1), 5S-hydroxyrecifeiolide (2), ent-cladospolide F (3), cladospolide G (4), and cladospolide H (5), along with two known compounds (6 and 7), were isolated from the endophytic fungal strain Cladosporium cladosporioides MA-299 that was obtained from the leaves of the mangrove plant Bruguiera gymnorrhiza. The structures of these compounds were established by extensive analysis of 1D/2D NMR data, mass spectrometric data, ECDs and optical rotations, and modified Mosher's method. The structures of 3 and 6 were confirmed by single-crystal X-ray diffraction analysis and this is the first time for reporting the crystal structures of these two compounds. All of the isolated compounds were examined for antimicrobial activities against human and aquatic bacteria and plant pathogenic fungi as well as enzymatic inhibitory activities against acetylcholinesterase. Compounds 1-4, 6, and 7 exhibited antimicrobial activity against some of the tested strains with MIC values ranging from 1.0 to 64 µg/mL, while 3 exhibited enzymatic inhibitory activity against acetylcholinesterase with the IC50 value of 40.26 µM.

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BACKGROUND: Steroids play an important role in life because they can regulate a variety of biological processes and have been widely used in medicine namely as antiinflammatory, anabolic, contraceptives and anticancer drugs. In recent years, there has been an increasing interest in the introduction of the oxime group in a large variety of molecules in order to increase their biological effects. This review highlights steroidal oximes with anticancer properties and their potential mechanisms of action, as well as data on their relative potencies reported in literature in the last few years. METHODS: To prepare this review, an extensive literature search was performed on three databases, PubMed, ISI Web of Knowledge and Science Direct, to generate a critical but comprehensive overview of the potential antitumor activities of steroidal oximes. The main keywords used for the search consisted of combinations of the following terms or their synonyms: steroidal oximes, anticancer activity and enzymatic inhibitory activity. The abstracts and full texts were evaluated for their clarity and scientific merit and to further help on the selection of other articles. RESULTS: Over the last decades the introduction of oxime groups in the steroid scaffold is originating molecules with relevant antitumor activities, as well as steroid sulfatase, aromatase, 17α-hydroxylase-17,20-lyase, 5α-reductase and 17ß-hydroxysteroid dehydrogenase type 1 inhibitory activities. As relevant examples, pregnenolone 20-oximes showed high activity as 17α-hydroxylase-17,20-lyase and 5α-reductase inhibitors and the introduction of an oxime group at C-6 in androstane series also led to relevant results as aromatase inhibitors. Interestingly, the introduction of this functional group frequently improves the bioactivity when compared with non-oxime analogous compounds, which can be due to extra interactions with biological targets. In addition, it has been observed that varying the position of the hydroximino group on the parent skeleton leads to remarkable changes in the antitumor activity. CONCLUSION: The recent advances in synthesis and in vitro bioactivity studies of steroidal oximes contributed to understand the potential interest of the introduction of this functional group in the steroidal nucleus in the development of anticancer molecules. Moreover, the cytotoxic/enzyme inhibitory activity usually depends on the position of the oxime group in different steroid scaffolds. However, despite the promising results, it is necessary to perform more in vitro and in vivo assays not only to better explore the mechanisms of action but also to confirm the potential effectiveness and safety of this interesting family of compounds in clinical practice.

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Our study of drug-drug interaction (DDI) started with the clarification of unusually large DDI observed between ramelteon (RAM) and fluvoxamine (FLV). The main cause of this DDI was shown to be the extremely small hepatic availability of RAM (vFh). Traditional DDI prediction assuming the well-stirred hepatic extraction kinetic ignores the relative increase of vFh by DDI, while we could solve this problem by use of the tube model. Ultimately, we completed a simple and useful method for prediction of DDI. Currently, DDI prediction becomes more complex and difficult when examining issues such as dynamic changes in perpetrator level, inhibitory metabolites, etc. The regulatory agents recommend DDI prediction by use of some sophisticated methods. However, they seem problematic in requiring plural in vitro data that reduce the flexibility and accuracy of the simulation. In contrast, our method is based on the static and two-compartment models. The two-compartment model has advantages in that it uses common pharmacokinetics (PK) parameters determined from the actual clinical data, guaranteeing the simulation of the reference standard in DDI. Our studies confirmed that dynamic changes in perpetrator level do not make a difference between static and dynamic methods. DDIs perpetrated by FLV and itraconazole were successfully predicted by use of the present method where two DDI predictors [perpetrator-specific inhibitory activities toward CYP isoforms (pAi, CYPs) and victim-specific fractional CYP-isoform contributions to the clearance (vfm, CYPs)] are determined successively as shown in the graphical abstract. Accordingly, this approach will accelerate DDI prediction over the traditional methods.

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