A new series of 6-substituted 2-aminobenzothiazole derivatives were synthesized and screened in vitro as potential antimicrobials. Almost all the compounds showed antifungal activity. In particular, compounds 1n,o, designed on the basis of molecular modeling studies, were the best of the series, showing MIC values of 4e8 mg/mL against Candida albicans, Candida parapsilosis and Candida tropicalis. None of the two compounds did show any cytotoxicity effect on human THP-1 cells.

llypcrtbrin ir a natural phloroglucinol tlraî hao baen knswn for îhe trc6lm{:!î of dsprer'niop. llyperforin clisplay* alro antibacr€rial. antiprolifcranr and ontiangiogenic activity. Synrhetie dsrivatives ofhypcrlnrin have also recsfltly been reportsd lo porisc$j incrcared bioactivity. The clinicnl applicttiols arE lirnitcd by tlre hydrophobie characteristics and the irstability nfthc molecule, In this rcview wc diserss abqut somc of thc dcrivrtive$ of hyperforin (nrirtoforin, tetrohydrohyperfbrin onil octalrydrohperlbrin) that dcmonsrratcd promising antitunror uetivity. Anrong the${], octahyrJrohyper{orin alsn pa$set$cf antibsdîsrial aqtivity 4Baif|rit both the planktonic and biofilm saatc$ ofbact$ria.

Thromboembolic events, principally stroke, represent among the leading causes of morbidity and mortality of subjects with atrial fibrillation, with an incidence about 5 times higher compared to healthy subjects. Chronic kidney disease, frequently associated with atrial fibrillation, determines itself a further increase of thromboembolic events, bleeding and mortality. In addition, the presence of renal failure complicates the pharmacological management of these patients, mainly due to the side effects of antiarrhythmic and anticoagulant drugs with renal excretion, due to their accumulation. Apixaban is a new oral anticoagulant characterized by good bioavailability and renal elimination accounting for only 25%, showing a safety profile and effectiveness in patients with renal impairment, who very often are under-treated or inadequately treated during atrial fibrillation. In this manuscript, we reviewed the data available in the literature regarding the use of apixaban in the management of non-valvular atrial fibrillation in patients with renal failure, in order to clarify an often-debated topic in clinical practice. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Bemiparin is a low molecular weight heparin (LMWH) indicated for the acute treatment of deep vein thrombosis with or without pulmonary embolism, for the prophylaxis of venous thromboembolism in surgical and non-surgical patients and for the prevention of clotting in the extracorporeal circuit during hemodialysis. Due to its excellent pharmacological profile—the second-generation LMWH with the lowest molecular weight, the longest half-life and the highest anti-Factor Xa/anti-Factor IIa activity ratio—it can be safely used in special categories of patients (children, elderly, patients with renal impairment and congestive heart failure). Several studies demonstrated its safety and efficacy, while cost analyses show the economic benefits of bemiparin treatment as compared to other heparins. Recent evidences suggested the application of bemiparin even in the management of diabetic foot ulcers. The aim of this narrative review was to evaluate literature according to results coming from studies involving bemiparin administration in various clinical conditions.

Bacterial biofilms are organized communities of microorganisms, embedded in a self-produced matrix, growing on a biotic surface and resistant to many antimicrobial agents when associated with a medical device. These biofilms require the development of new strategies for the prevention and treatment of infectious disease, including the potential use of natural products. One interesting natural product example is Hypericum, a plant genus that contains species known to have antimicrobial properties. The major constituent of Hypericum perforatum is an unstable compound named hyperforin (1); for this reason it was not believed to play a significant role in the pharmacological effects. In this investigation a hydrogenated hyperforin analogue (2) was tested on several ATCC and clinical isolate strains, in their planktonic and biofilm form (Staphylococcus aureus, MRSA, and Enterococcus faecalis). Compound 2 was effective against planktonic and biofilm cultures, probably due to higher stability, showing the percentage of cells killed in the range from 45% to 52%. These results are noteworthy from the point of view of future development of these polyprenylated phloroglucinols as potential antibiotics.

A series of chiral 2,3-dichlorophenoxy and 1-naphthyloxy alkylamines were synthesized, and their binding affinities towards 5-HT1D and h5-HT1B receptors were evaluated. In the naphthyloxy series, the (R)-prolinol derivative was the most selective 5-HT1D ligand, while (S)-N-methyl-2-(1-naphthyloxy)propan-1-amine showed the highest selectivity for h5-HT1B. Both compounds performed as 5-HT1D agonists in the isolated guinea pig assay and showed higher analgesic activity than both sumatriptan and the achiral analogue 20b in the mouse hotplate test. Neither ligand displayed any affinity for nicotinic ACh receptors present in mouse brain membranes, thus indicating that their analgesic activity does not arise through interaction with these receptors.

This paper deals with an extensive analytical approach, which uses two complementary tandem mass spectrometry techniques, to characterize the chlorogenic acids (CGAs) present in a typical Italian sweet cherry variety (cv Ferrovia). Sixteen monoacyl-quinic acids and esters, five diacyl-quinic acids, three caffeoyl-quinic acids glycosides, and two caffeic acid hexoses were detected by HPLC-MSn analyses (MSn up to MS4), among which four methyl coumaroyl quinate and three methyl caffeoyl quinate isomers were tentatively identified in sweet cherries for the first time. HPLC-MS/MS analyses through multiple reaction monitoring (MRM) experiments showed that trans-3-O-caffeoylquinic acid, cis-3-O-coumaroylquinic acid, trans-3-O-coumaroylquinic acid, trans-5-O-caffeoylquinic acid, and methyl-3-O-caffeoyl quinate were the main CGAs in the mature berries of cv Ferrovia. Considering that CGAs can have several health benefits depending on their amount but also on their structural features, the results of this study provide new insight into the knowledge of the quali-quantitative profile of these phytochemicals in a widespread fruit such as sweet cherry. © 2018 Elsevier Inc.

This paper describes an efficient route leading to new thienylpyridyl garlands as non-peptidic alpha helix mimetics and potential proteineprotein interactions disruptors. Firstly, we have studied the reactivity of boronic acids and halogenated pyridines and/or thiophenes towards the SuzukieMiyaura cross-coupling reaction in order to obtain bis-thienylpyridines. Secondly, we have functionalized these compounds by a reaction of bromination and the resultant bis-bromothienylpyridines have been found to undergo it- erative Pd-catalyzed coupling based on a pseudo-Garlanding approach with a range of pyridyl boronic acids to produce a new library of thienylpyridyl oligomers.

The role of voltage-gated sodium channels in the transmission of neuropathic pain is well recognized. For instance, genetic evidence recently indicate that the human Nav1.7 sodium channel subtype plays a crucial role in the ability to perceive pain sensation and may represent an important target for analgesic/anti-hyperalgesic drugs. In this study a newly synthesized tocainide congener, named NeP1, was tested in vitro on recombinant hNav1.4 and hNav1.7 channels using patch-clamp technique and, in vivo, in two rat models of persistent neuropathic pain obtained either by chronic constriction injury of the sciatic nerve or by oxaliplatin treatment. NeP1 efficiently blocked hNav1.4 and hNav1.7 channels in a dose- and use-dependent manner, being by far more potent than tocainide. Importantly, the new compound displayed a remarkable use-dependent effect, which likely resulted from a very high affinity for inactivated compared to closed channels. In both models of neuropathic pain, NeP1 was greatly more potent than tocainide in reverting the reduction of pain threshold in vivo. In oxaliplatin-treated rats, NeP1 even produced greater and more durable anti-hyperalgesia than the reference drug tramadol. In addition, in vivo and in vitro studies suggest a better toxicological and pharmacokinetic profile for NeP1 compared to tocainide. Overall, these results indicate NeP1 as a new promising lead compound for further development in the treatment of chronic pain of neuropathic origin.

The aim of this study was to verify the existence of synergistic antibacterial effect between four essential oils (Aniba rosaeodora, Melaleuca alternifolia, Origanum vulgare, and Pelargonium graveolens) individually combined with the antibacterial drug Gentamicin. We investigated the effectiveness in vitro of the association of essential oil/Gentamicin, against fifteen different strains of Gram positive and Gram negative bacteria. The antibacterial effects of these oils in combination with Gentamicin were evaluated by using the MHB microdilution method, while gas chromatography (GC) and GC/Mass spectrometry were used to analyze the chemical composition of the oils. A synergistic interaction was ob- served against all tested strains with the associations between the essential oils Aniba rosaeodora/Gentamicin and Pelar- gonium graveolens/Gentamicin. In particular a very strong synergistic interaction was observed against Acinetobacter baumannii ATCC 19606 (FIC index = 0.11). In contrast, the essential oils Origanum vulgare and Melaleuca alternifolia in association with Gentamicin were less effective on bacterial species growth. In vitro interaction can improve the antimi- crobial effectiveness of the Gentamicin and may contribute to reduce its dose correlated to side effects.

In this paper the authors investigated a synergistic antimycotic effect between four antifungal drugs Ampho- tericin B, Fluconazole, Tioconazole, and Flucytosine individually combined with Anidulafungin compound. This latter is considered a drug of choice in the treatment of fungal infections; it has good activity both in vitro and in vivo against yeasts and moulds, as Candida and Aspergillus. The goal of this study was to evaluate the in vitro interaction of Anidula- fungin in the synergic combinations with previous reported drugs against 12 Candida strains according to CLSI M27-A3 protocol. A synergistic interaction was observed against the most antifungal strains; in particular an increasing of the an- timycotic efficacy was obtained from the association between Anidulafungin and Amphotericin B or Fluconazole (Mix- ture 4:6). In contrast the association Tioconazole/Anidulafungin was less effective on fungal species growth. The antimy- cotics MIC reduction values were more evident against some strains as C. glabrata, C. krusei, C. tropicalis and C. parap- silosis.

Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.

A series of novel tocainide analogues were characterized for their HSA and RSA binding, by using high- performance liquid affinity chromatography (HPLAC) and circular dichroism (CD). In this HPLAC study, HSA and RSA were covalently immobilized to the silica matrix of HPLC columns, with a procedure that maintained unaltered the binding properties of the proteins. The tocainide analogues were ranked for their affinity to HSA and RSA on the basis of their bound fractions measured by the two albumin-based columns. This technique was also applied to characterize the high affinity binding sites of these tocainide analogues to the protein. For this purpose displacement experiments were carried out by means of increasing concentrations in the mobile phase of competitors known to bind selectively to the main bind- ing sites of HSA. The results obtained with the immobilized proteins were confirmed by investigating the same drug-protein systems in solution by circular dichroism. The comparison of the data collected with both methodologies highlighted the dramatic effect of small differences in the amino acidic sequences of the two proteins. In fact, despite their similar primary and secondary structures, a small difference in the amino acidic sequence leads to significant differences in their three-dimensional structure reflecting their different binding capacity and their stereoselectivity. Therefore, this study confirms how it is cru- cial to consider the significant differences among the animal models when performing pharmacokinetic studies. It is also clear that the knowledge of serum carrier binding parameters at an early stage of drug discovery represents a great advantage that may help to save time and efforts.

Enterococcus faecalis is a Gram-positive commensal inhabitant of the intestinal tract of humans, animals, and insects. However, it is also an opportunistic pathogen and has emerged as a leading cause of hospital-acquired extraintestinal infections. Fluoroquinolones have been frequently used to treat E. faecalis infections, and the emergence of fluoroquinolone-resistant E. faecalis strains has recently been reported in several countries. Thus, the identifications of new antibiotics specifically directed to E. faecalis may be envisaged. In this paper, a new series of N-1,3-benzothiazol-2-ylbenzamides have been designed, synthesized, and evaluated for their in vitro antimicrobial activities. Among the tested compounds, 3i was active against E. faecalis. © 2013 Domenico Armenise et al.

By using the Suzuki-Miyaura protocol, a simple straightforward synthesis of functionalized 2-arylaziridines has been developed. By means of this synthetic strategy from readily available ortho-, meta- and para-bromophenylaziridines and aryl-or heteroarylboronic acids, new aziridines could be obtained. The cross-coupling reactions occurred without ring opening of the three membered ring. Preliminary results on the antimicrobial activity of the heterosubstituted biaryl compounds have been also included.