Search

The widespread emergence of antimicrobial resistance (AMR) is a serious threat to global public health and among Gram-positive cocci, Streptococcus pneumoniae constitutes a priority in the list of AMR-threatening pathogens. To counteract this fundamental problem, the bacterial cell division cycle and the crucial proteins involved in this process emerged as novel attractive targets. FtsZ is an essential cell division protein, and FtsZ inhibitors, especially the benzamide derivatives, have been exploited in the last decade. In this work, we identified, for the first time, some benzodioxane-benzamide inhibitors capable of targeting FtsZ in Streptococcus pneumoniae , in addition to their previously demonstrated activity against other bacteria. These promising benzamides, with minimal inhibitory concentrations (MICs) ranging from 25 to 80 µg/mL, demonstrated bactericidal activity against S. pneumoniae . This was evidenced by their ability to dramatically affect growth and viability, further supported by the morphological changes observed through microscopy. Moreover, the compounds were characterized in vitro, combining turbidity measurements and confocal imaging, and significant alteration of a GTP-induced FtsZ assembly was found, in line with our previous data from other microorganisms.

The conserved process of cell division in bacteria has been a long-standing target for antimicrobials, although there are few examples of potent broad-spectrum compounds that inhibit this process. Most currently available compounds acting on division are directed towards the FtsZ protein, a self-assembling GTPase that is a central element of the division machinery in most bacteria. Benzodioxane-benzamides are promising candidates, but poorly explored in Gram-negatives. We have tested a number of these compounds on E. coli FtsZ and found that many of them significantly stabilized the polymers against disassembly and reduced the GTPase activity. Reconstitution in crowded cell-like conditions showed that FtsZ bundles were also susceptible to these compounds, including some compounds that were inactive on protofilaments in dilute conditions. They efficiently killed E. coli cells defective in the AcrAB efflux pump. The activity of the compounds on cell growth and division generally showed a good correlation with their effect in vitro, and our experiments are consistent with FtsZ being the target in vivo. Our results uncover the detrimental effects of benzodioxane-benzamides on permeable E. coli cells via its central division protein, implying that lead compounds may be found within this class for the development of antibiotics against Gram-negative bacteria., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Silvia Zorrilla reports financial support was provided by Spanish Ministerio de Ciencia e Innovación. Marta Sobrinos-Sanguino reports financial support was provided by Agencia Estatal de Investigación and the European Social Fund. William Margolin reports financial support was provided by National Institutes of Health., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

FtsZ is an essential bacterial protein abundantly studied as a novel and promising target for antimicrobials. FtsZ is highly conserved among bacteria and mycobacteria, and it is crucial for the correct outcome of the cell division process, as it is responsible for the division of the parent bacterial cell into two daughter cells. In recent years, the benzodioxane-benzamide class has emerged as very promising and capable of targeting both Gram-positive and Gram-negative FtsZs. In this study, we explored the effect of including a substituent on the ethylenic linker between the two main moieties on the antimicrobial activity and pharmacokinetic properties. This substitution, in turn, led to the generation of a second stereogenic center, with both erythro and threo isomers isolated, characterized, and evaluated. With this work, we discovered how the hydroxy group slightly affects the antimicrobial activity, while being an important anchor for the exploitation and development of prodrugs, probes, and further derivatives.

Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11 C-MGX-10S and 11 C-MGX-11S via carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro . In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11 C-MGX-10S compared to 11 C-MGX-11S . Subsequent use of 11 C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11 C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11 C-DPA-713-an existing radiotracer used to image innate immune activation in clinical research studies- 11 C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11 C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11 C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

1,4-Benzoxathiane, 2- or 3-substituted, is an important scaffold, and despite its presence in several therapeutic agents, it is chemically unexploited. Furthermore, only a few examples in literature report this moiety in its enantiopure form. Here, taking advantage to the formation of diastereomeric amides by using (S)-phenylethylamine, which show significant differences in terms of 1 H-nuclear magnetic resonance (NMR) spectra and other physical chemical properties, we defined for the first time the absolute configuration of each amide, both 2- or 3-substituted. Moreover, the diastereomeric amides were further hydrolyzed in acid conditions, letting to the achievement of the corresponding 1,4-benzoxathian carboxylic acids., (© 2022 The Authors. Chirality published by Wiley Periodicals LLC.)

The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe 6 demonstrated high binding affinity ( K i = 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT; K i = 1540 nM) and serotonin (SERT; K i = 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound 6 was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

Multidrug resistant Staphylococcus aureus is a severe threat, responsible for most of the nosocomial infections globally. This resistant strain is associated with a 64% increase in death compared to the antibiotic-susceptible strain. The prokaryotic protein FtsZ and the cell division cycle have been validated as potential targets to exploit in the general battle against antibiotic resistance. Despite the discovery and development of several anti-FtsZ compounds, no FtsZ inhibitors are currently used in therapy. This work further develops benzodioxane-benzamide FtsZ inhibitors. We seek to find more potent compounds using computational studies, with encouraging predicted drug-like profiles. We report the synthesis and the characterization of novel promising derivatives that exhibit very low MICs towards both methicillin-susceptible and -resistant S. aureus , as well as another Gram positive species, Bacillus subtilis, while possessing good predicted physical-chemical properties in terms of solubility, permeability, and chemical and physical stability. In addition, we demonstrate by fluorescence microscopy that Z ring formation and FtsZ localization are strongly perturbed by our derivatives, thus validating the target.

Antibiotic resistance is spreading worldwide and it has become one of the most important issues in modern medicine. In this context, the bacterial RNA degradation and processing machinery are essential processes for bacterial viability that may be exploited for antimicrobial therapy. In Staphylococcus aureus , RnpA has been hypothesized to be one of the main players in these mechanisms. S. aureus RnpA is able to modulate mRNA degradation and complex with a ribozyme ( rnpB ), facilitating ptRNA maturation. Corresponding small molecule screening campaigns have recently identified a few classes of RnpA inhibitors, and their structure activity relationship (SAR) has only been partially explored. Accordingly, in the present work, using computational modeling of S. aureus RnpA we identified putative crucial interactions of known RnpA inhibitors, and we used this information to design, synthesize, and biologically assess new potential RnpA inhibitors. The present results may be beneficial for the overall knowledge about RnpA inhibitors belonging to both RNPA2000-like thiosemicarbazides and JC-like piperidine carboxamides molecular classes. We evaluated the importance of the different key moieties, such as the dichlorophenyl and the piperidine of JC2, and the semithiocarbazide, the furan, and the i -propylphenyl ring of RNPA2000. Our efforts could provide a foundation for further computational-guided investigations.

We previously described synapsin III (Syn III) as a synaptic phosphoprotein that controls dopamine release in cooperation with α-synuclein (aSyn). Moreover, we found that in Parkinson's disease (PD), Syn III also participates in aSyn aggregation and toxicity. Our recent observations point to threo-methylphenidate (MPH), a monoamine re-uptake inhibitor that efficiently counteracts the freezing-gait characteristic of advanced PD, as a ligand for Syn III. We have designed and synthesised two different fluorescently labelled MPH derivatives, one with Rhodamine Red (RHOD) and one with 5-carboxytetramethylrhodamine (TAMRA), to be used for assessing MPH binding to Syn III by FRET. TAMRA-MPH exhibited the ideal characteristics to be used as a FRET acceptor, as it was able to enter into the SK-N-SH cells and could interact specifically with human green fluorescent protein (GFP)-tagged Syn III but not with GFP alone. Moreover, the uptake of TAMRA-MPH and co-localization with Syn III was also observed in primary mesencephalic neurons. These findings support that MPH is a Syn III ligand and that TAMRA-conjugated drug molecules might be valuable tools to study drug-ligand interactions by FRET or to detect Syn III in cytological and histological samples., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Loss of dopaminergic nigrostriatal neurons and fibrillary α-synuclein (α-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with α-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of α-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind α-syn and controls α-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and α-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of α-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate α-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the α-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing α-syn/Syn III co-aggregates. MPH enhanced full length (fl) α-syn/Syn III and even more (1-120) α-syn/Syn III interaction in cells exhibiting α-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce α-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Filamentous temperature-sensitive Z (FtsZ) is a prokaryotic protein with an essential role in the bacterial cell division process. It is widely conserved and expressed in both Gram-positive and Gram-negative strains. In the last decade, several research groups have pointed out molecules able to target FtsZ in Staphylococcus aureus , Bacillus subtilis and other Gram-positive strains, with sub-micromolar Minimum Inhibitory Concentrations (MICs). Conversely, no promising derivatives active on Gram-negatives have been found up to now. Here, we report our results on a class of benzamide compounds, which showed comparable inhibitory activities on both S. aureus and Escherichia coli FtsZ, even though they proved to be substrates of E. coli efflux pump AcrAB, thus affecting the antimicrobial activity. These surprising results confirmed how a single molecule can target both species while maintaining potent antimicrobial activity. A further computational study helped us decipher the structural features necessary for broad spectrum activity and assess the drug-like profile and the on-target activity of this family of compounds.

Binary fission is the most common mode of bacterial cell division and is mediated by a multiprotein complex denominated the divisome. The constriction of the Z-ring splits the mother bacterial cell into two daughter cells of the same size . The Z-ring is formed by the polymerization of FtsZ, a bacterial protein homologue of eukaryotic tubulin, and it represents the first step of bacterial cytokinesis. The high grade of conservation of FtsZ in most prokaryotic organisms and its relevance in orchestrating the whole division system make this protein a fascinating target in antibiotic research. Indeed, FtsZ inhibition results in the complete blockage of the division system and, consequently, in a bacteriostatic or a bactericidal effect. Since many papers and reviews already discussed the physiology of FtsZ and its auxiliary proteins, as well as the molecular mechanisms in which they are involved, here, we focus on the discussion of the most compelling FtsZ inhibitors, classified by their main protein binding sites and following a medicinal chemistry approach., Competing Interests: The authors declare no conflict of interest

FtsZ is a crucial prokaryotic protein involved in bacterial cell replication. It recently arose as a promising target in the search for antimicrobial agents able to fight antimicrobial resistance. In this work, going on with our structure-activity relationship (SAR) study, we developed variously 7-substituted 1,4-benzodioxane compounds, linked to the 2,6-difluorobenzamide by a methylenoxy bridge. Compounds exhibit promising antibacterial activities not only against multidrug-resistant Staphylococcus aureus, but also on mutated Escherichia coli strains, thus enlarging their spectrum of action toward Gram-negative bacteria as well. Computational studies elucidated, through a validated FtsZ binding protocol, the structural features of new promising derivatives as FtsZ inhibitors., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The pharmacokinetic profile of a new 800-mg tablet of nonanimal chondroitin sulfate (CS) (Mythocondro®, 800-mg tablets, Gnosis S.p.A., Italy) was investigated vs an animal CS in healthy volunteers for a total period of 48 hours. After a single 2400-mg dose of the test and the reference formulation, total CS, the compositional disaccharides (ΔDi6S, ΔDi4S and ΔDi0S), and the overall charge density were quantified in plasma. The safety and tolerability profile after a single dose of this new nonanimal CS tablets was excellent. After baseline-corrected concentrations, an overall greater plasma concentration was observed after 24 hours of ∼44% and after 48 hours of ∼45% from administration of nonanimal when compared to animal-derived CS. Moreover, nonanimal CS increases the specific sulfation in the 6-position of N-acetyl-galactosamine in human plasma CS and, as a consequence, the overall charge density, reaching double values (0.91), after 48 hours compared to bovine CS and to endogenous CS. In conclusion, nonanimal CS, possessing a lower molecular weight than an animal-derived sample, produces a greater CS concentration for a more prolonged period of time in plasma and an increase in charge density and specific 6-sulfation of endogenous plasma CS., (© 2018, The American College of Clinical Pharmacology.)

The exploration of different reaction conditions aiming to obtain both 2,3-dihydro-1,4-benzoxathiine-2-yl derivatives and 2,3-dihydro-1,4-benzoxathiine-3-yl ones is reported. The treatment of 1,2-mercaptophenol with an organic base and a specific 2-bromo acrylate results in a solvent- and substrate-dependent exclusive solvation of O- and S-anions, thus managing the regioselectivity.

Nowadays, parabens have been replaced by domiphen bromide, which is widely used in pharmaceutical and cosmetic products. The main aim of this study was to investigate stressed degradation products of domiphen bromide by mean of a rapid, specific and reliable LC-ESI MS/MS since phenyl bromination may occur due to the oxidation of bromide counter ion under oxidative conditions. LC-ESI-MS/MS have characterized a new compound, p-bromodomiphen, as the only degradation product and structure elucidation was also confirmed by the synthesis of the standard. Notably, the resulting p-bromodomiphen bromide is more stable then domiphen bromide in oxidizing conditions since no di-bromoderivatives were detected by MS studies; both domiphen and its p-bromo derivative were tested for antibacterial activity and were more effective on Gram positive (Staphylococcus aureus ATCC25923 and Bacillus cereus DSM31) compared to Gram negative bacteria (Escherichia coli ATCC25922 and Pseudomonas aeruginosa DSM22644). In conclusion, stressed degradation studies by LC-ESI-MS/MS have characterized a new compound that comprises an alternative to domiphen bromide since its antimicrobial activity is comparable to, if not better than, the parental compound., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several biologically active compounds structurally include the enantiopure 2-substituted-1,4-benzodioxane scaffold. The straightforward racemization that affects reactions involving most of the common chemical reactives is thus a crucial issue. The developing of a completely stereo-controlled synthetic route that does not affect the enantiomeric excess is consequently mandatory. It is also important to set up a reliable chiral HPLC method, able to follow the reaction, and to improve the synthetic performances. Here, we report the chiral investigation of two different synthons, we specifically evaluated the synthetic pathways that could be run in order to afford them, avoiding the racemization processes, which could normally occur in basic conditions. In addition, we developed peculiar chiral HPLC methods in order to resolve the enantiomers, define the enantiomeric excess, and fully characterize these compounds., (© 2018 Wiley Periodicals, Inc.)

A wide variety of drug-resistant microorganisms are continuously emerging, restricting the therapeutic options for common bacterial infections. Antimicrobial agents that were originally potent are now no longer helpful, due to their weak or null activity toward these antibiotic-resistant bacteria. In addition, none of the recently approved antibiotics affect innovative targets, resulting in a need for novel drugs with innovative antibacterial mechanisms of action. The essential cell division protein filamentous temperature-sensitive Z (FtsZ) has emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic β-tubulin. In the latest years, several compounds were shown to interact with this prokaryotic protein and selectively inhibit bacterial cell division. Recently, our research group developed interesting derivatives displaying good antibacterial activities against methicillin-resistant Staphylococcus aureus, as well as vancomycin-resistant Enterococcus faecalis and Mycobacterium tuberculosis. The aim of the present study was to summarize the structure-activity relationships of differently substituted heterocycles, linked by a methylenoxy bridge to the 2,6-difluorobenzamide, and to validate FtsZ as the real target of this class of antimicrobials., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lipophilic substituents at benzodioxane C (7) of 3-(benzodioxan-2-ylmethoxy)-2,6-difluorobenzamide improve the antibacterial activity against methicillin-resistant Staphylococcus aureus strains to MIC values in the range of 0.2-2.5 μg/mL, whereas hydrophilic substituents at the same position and modifications at the benzodioxane substructure, excepting for replacement with 2-cromanyl, are deleterious. Some of the lead compounds also exhibit good activity against Mtb. Parallel SARs to those of 3-(2-benzothiazol-2-ylmethoxy)-2,6-difluorobenzamide, well known FtsZ inhibitor, and cells alterations typical of FtsZ inhibition indicate such a protein as the target of these potent antibacterial benzodioxane-benzamides., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A SAR study was performed on 3-substituted 2,6-difluorobenzamides, known inhibitors of the essential bacterial cell division protein FtsZ, through a series of modifications first of 2,6-difluoro-3-nonyloxybenzamide and then of its 3-pyridothiazolylmethoxy analogue PC190723. The study led to the identification of chiral 2,6-difluorobenzamides bearing 1,4-benzodioxane-2-methyl residue at the 3-position as potent antistaphylococcal compounds., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

2-Substituted 1,4-benzodioxanes, such as 2-cyano-, 2-methoxycarbonyl-, 2-aminocarbonyl-, and 2-formyl-1,4-benzodioxane, are key synthons that for the most part are never described as enantiomers or are inadequately characterized for enantiomeric purity. They were prepared by quantitative N,N-dichlorination of (R)- and (S)-2-aminomethyl-1,4-benzodioxane and successive functional group conversions in high yields without any racemization of the stereogenic benzodioxane C(2).

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed as farnesyltransferase (FTase) inhibitors (FTIs) by replacing AA with o-aryl or o-heteroaryl substituted p-hydroxy- or p-aminobenzoic acid, while maintaining the replacement of C with 1,4-benzodioxan-2-ylmethyl or 2-amino-4-thiazolylacetyl residue as in previous CAAX mimetics. Both FTase inhibition and antiproliferative effect were showed by two thiazole derivatives, namely those with 1-naphthyl (10 and 10a) or 3-furanyl (15 and 15a) in the central spacer, and by the benzodioxane derivative with 2-thienyl (6 and 6a) in the same position. Accumulation of unprenylated RAS was demonstrated in cells incubated with 15a. Consistently with FTIs literature, such results delineate the biaryl scaffold not only as a spacer but also as a sensible area of these mimetic molecules, where modifications at the branching aromatic ring are not indifferent and should be matter of further investigation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Previous results have shown that replacement of one of the two o-methoxy groups at the phenoxy residue of the potent, but not subtype-selective, α1-AR antagonist (S)-WB4101 [(S)-1] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits α1D-AR antagonist affinity. Such observations inspired the design of four new analogues of 1 bearing, in lieu of the 2,6-dimethoxyphenoxy residue, a 6-methoxy-substituted 7-benzofuranoxy or 7-indolyloxy group or, alternatively, their corresponding 2,3-dihydro form. Of these new compounds, which maintain, rigidified, the characteristic ortho heterodisubstituted phenoxy substructure of 1, the S enantiomer of the dihydrobenzofuranoxy derivative exhibited the highest α1D-AR antagonist affinity (pA2 9.58) with significant α1D/α1A and α1D/α1B selectivity. In addition, compared both to α1D-AR antagonists structurally related to 1 and to the well-known α1D-AR antagonist BMY7378, this derivative had modest 5-HT1A affinity and neutral α1-AR antagonist behavior.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (βAla + His) thus emphasizing the unfavorable effect of the shortening of the βAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Unichiral 8-substituted analogues of 2-[(2-(2,6-dimethoxyphenoxy)ethyl)aminomethyl]-1,4-benzodioxane (WB4101) were synthesized and tested for binding affinity at cloned human α(1a)-, α(1b)-and α(1d)-adrenoreceptor (α(1a)-, α(1b)-and α(1d)-AR) and at native rat 5-HT(1A) receptor and for antagonist affinity at α(1A)-, α(1B)-and α(1D)-AR and at α(2A/D)-AR. Among the selected 8-substituents, namely fluorine, chlorine, methoxyl and hydroxyl, only the last caused significant decrease of α(1) binding affinity in comparison with the lead compound. Functional tests on the S isomers confirmed the detrimental effect of OH positioned in proximity to benzodioxane O(1). For the other three substituents (F, Cl, OMe), the α(1A) and the α(1D) antagonist affinities were generally lower than the α(1a) and α(1d) binding affinities, but not the α(1B) antagonist affinity, which was similar and sensibly higher compared to α(1b) binding affinity in the case of F and OMe respectively. This trend confers significant α(1B)-AR selectivity, in particular, to the 8-methoxy analogue of (S)-WB4101, a new potent (pA(2) 9.58) α(1B)-AR antagonist. The S enantiomers of all the tested compounds were proved to act as α(1)-AR inverse agonists in a vascular model., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The results of the analysis of some herbal products and powders adulterated with alkylindoles recovered on the Italian market between 2010 and 2011 are reported. Besides the well-known alkyindoles JWH-018 and JWH-073, other derivatives such as JWH-250 and AM-694 have been detected and for the first time in Italy 1-butyl-3-(1-(4-methyl)naphthoyl)indole (compound 1), the 4-methylnaphthoyl analogue of JWH-073. This compound as well as the other alkylindoles has been synthesized and characterized by (1)H NMR, (13)C NMR, DSC, GC/MS, and elemental analysis. The quantitative analyses of the samples have been carried out by means of the GC/FID method developed in our laboratory for the analysis of herbal high products containing naphthoylindoles; the quantity of the cannabimimetic substances ranged from 6 mg/g to 47 mg/g., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study aimed at measuring the lipophilicity and ionization constants of diastereoisomeric dipeptides, interpreting them in terms of conformational behavior, and developing statistical models to predict them., Methods: A series of 20 dipeptides of general structure NH(2)-L-X-(L or D)-His-OMe was designed and synthetized. Their experimental ionization constants (pK(1), pK(2) and pK(3)) and lipophilicity parameters (log P(N) and log D(7.4)) were measured by potentiometry. Molecular modeling in three media (vacuum, water, and chloroform) was used to explore and sample their conformational space, and for each stored conformer to calculate their radius of gyration, virtual log P (preferably written as log P(MLP), meaning obtained by the molecular lipophilicity potential (MLP) method) and polar surface area (PSA). Means and ranges were calculated for these properties, as was their sensitivity (i.e., the ratio between property range and number of rotatable bonds)., Results: Marked differences between diastereoisomers were seen in their experimental ionization constants and lipophilicity parameters. These differences are explained by molecular flexibility, configuration-dependent differences in intramolecular interactions, and accessibility of functional groups. Multiple linear equations correlated experimental lipophilicity parameters and ionization constants with PSA range and other calculated parameters., Conclusion: This study documents the differences in lipophilicity and ionization constants between diastereoisomeric dipeptides. Such configuration-dependent differences are shown to depend markedly on differences in conformational behavior and to be amenable to multiple linear regression., (© 2012 Wiley Periodicals, Inc.)

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing internal dipeptide AA with 4-amino-2-phenylbenzoic acid and cysteine (C) with 2-amino-4-thiazolyl-, 2-mercapto-4-thiazolyl-, 2-mercapto-4-imidazolyl- and 2-methylmercapto-4-thiazolyl-acetic or propionic acid. The compound in which C is replaced by 2-amino-4-thiazolylacetic acid inhibited FTase activity in the low nanomolar range and showed antiproliferative effect on rat aortic smooth muscle cells interfering with Ras farnesylation. On the basis of these results, 2-aminothiazole can be considered as an alternative to heterocycles, such as pyridine and imidazole, normally used in FTase inhibitors designed as non-thiol CAAX mimetics., (Copyright © 2011 Elsevier Ltd. All rights reserved.)