Repositioning of Endonuclear Receptors Binders as Potential Antibacterial and Antifungal Agents. Eptyloxìm: A Potential and Novel Gyrase B and Cytochrome Cyp51 Inhibitor.

A novel class of antibacterial and antifungal agents is here identified by means of dockings and virtual screening techniques. Biological data proved the initial effort, formulated on the structure similarity of nuclear receptors binders with known quinolones or thiazole derivatives, to reposition PPARs agonists as likely bacterial type II topoisomerases inhibitors.

Kidney CLC-K chloride channels inhibitors: structure-based studies and efficacy in hypertension and associated CLC-K polymorphisms.

Objective: Alterations in the handling of renal salt reabsorption may contribute to interindividual differences in blood pressure regulation and susceptibility to hypertension. CLC-K chloride channels and their accessory subunit barttin play a pivotal role in kidney by controlling chloride and water absorption. Compounds selective for CLC-Ks, such as the benzofuran derivative MT-189, may have a significant therapeutic potential.

Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis.

Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor α/γ ligand LT175.

The effects resulting from the introduction of an oxime group in place of the distal aromatic ring of the diphenyl moiety of LT175, previously reported as a PPARα/γ dual agonist, have been investigated. This modification allowed the identification of new bioisosteric ligands with fairly good activity on PPARα and fine-tuned moderate activity on PPARγ. For the most interesting compound (S)-3, docking studies in PPARα and PPARγ provided a molecular explanation for its different behavior as full and partial agonist of the two receptor isotypes, respectively.

Growth hormone secretagogues exert differential effects on skeletal muscle calcium homeostasis in male rats depending on the peptidyl/nonpeptidyl structure.

The orexigenic and anabolic effects induced by ghrelin and the synthetic GH secretagogues (GHSs) are thought to positively contribute to therapeutic approaches and the adjunct treatment of a number of diseases associated with muscle wasting such as cachexia and sarcopenia. However, many questions about the potential utility and safety of GHSs in both therapy and skeletal muscle function remain unanswered. By using fura-2 cytofluorimetric technique, we determined the acute effects of ghrelin, as well as of peptidyl and nonpeptidyl synthetic GHSs on calcium homeostasis, a critical biomarker of muscle function, in isolated tendon-to-tendon male rat skeletal muscle fibers.

Molecular determinants for nuclear receptors selectivity: chemometric analysis, dockings and site-directed mutagenesis of dual peroxisome proliferator-activated receptors α/γ agonists.

A series of previously synthesized chiral derivatives of clofibric and phenylacetic acids, acting as dual agonists towards the peroxisome proliferator-activated receptors (PPARs) α and γ, was taken into account, and the efficacy of these compounds was analyzed by means of 2D-, 3D-QSAR and docking studies with the goal to gain deeper insights into the three-dimensional determinants governing ligands selectivity for PPARs. By multiregressional analysis a correlation between the lipophilicity and PPARα activity was found, whereas for PPARγ the correlation was achieved once efficacy was related to the presence of polar groups on agonists scaffold. Docking of these compounds further corroborated this hypothesis, and then provided a valid support for subsequent chemometric analysis and pharmacophore models development for both receptors subtypes.

Regular CPAP utilization reduces nasal inflammation assessed by nasal cytology in obstructive sleep apnea syndrome.

Objectives: To analyze nasal inflammation in a group of patients with obstructive sleep apnea syndrome (OSAS) by means of nasal cytology and to describe the changes induced by continuous positive air pressure (CPAP) treatment.

Subjects And Methods: Thirty-two consecutive patients affected by OSAS (mean age 46.9 years) and 13 control subjects (mean age 49.

Synthesis, biological evaluation and molecular investigation of fluorinated peroxisome proliferator-activated receptors α/γ dual agonists.

PPARs are transcription factors that govern lipid and glucose homeostasis and play a central role in cardiovascular disease, obesity, and diabetes. Thus, there is significant interest in developing new agonists for these receptors. Given that the introduction of fluorine generally has a profound effect on the physical and/or biological properties of the target molecule, we synthesized a series of fluorinated analogs of the previously reported compound 2, some of which turned out to be remarkable PPARα and PPARγ dual agonists.

Might the observed α(2A)-adrenoreceptor agonism or antagonism of allyphenyline analogues be ascribed to different molecular conformations?

We recently reported that the α(2)-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its α(2C)-AR agonism), was devoid of sedative side effects (due to its α(2A)-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (π) and electronic (σ) contributions in all the possible combinations. Effective novel α(2C)-agonists/α(2A)-antagonists (2, 3, 10, 12, and 17) were obtained.

Structural nucleotide analogs are potent activators/inhibitors of pancreatic β cell KATP channels: an emerging mechanism supporting their use as antidiabetic drugs.

The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic β cell ATP-sensitive K+ (KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic β cell KATP channel and the Kir6.2ΔC36 subunit were investigated using a patch-clamp technique.

Novel imidazoline compounds as partial or full agonists of D2-like dopamine receptors inspired by I2-imidazoline binding sites ligand 2-BFI.

Based on the well known biological versatility of the imidazoline nucleus, we prepared the novel derivatives 3a-k inspired by 2-BFI scaffold to assess imidazoline molecules as D(2)-like dopamine receptor ligands. Conservative chemical modifications of the lead structure, such as the introduction of an hydroxy group in the aromatic ring alone or associated with N-benzyl substitution, provided partial (3f) or nearly full (3e and 3h) agonists, all endowed with D(2)-like potency comparable to that of dopamine.

Synthesis, biological evaluation, and molecular modeling investigation of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives with PPARalpha and PPARgamma agonist activity.

PPARs are ligand-activated transcription factors that govern lipid and glucose homeostasis and play a central role in cardiovascular disease, obesity, and diabetes. Herein, we present screening results for a series of chiral 2-(4-chloro-phenoxy)-3-phenyl-propanoic acid derivatives, some of which are potent PPARgamma agonists as well as PPARalpha agonists. To investigate the binding modes of the most interesting derivatives into the PPARalpha and PPARgamma binding clefts and evaluate their agonist activity, docking experiments, molecular dynamics simulations, and MM-PBSA analysis were performed.

Molecular determinants for the activating/blocking actions of the 2H-1,4-benzoxazine derivatives, a class of potassium channel modulators targeting the skeletal muscle KATP channels.

The 2H-1,4-benzoxazine derivatives are modulators of the skeletal muscle ATP-sensitive-K(+) channels (K(ATP)), activating it in the presence of ATP but inhibiting it in the absence of nucleotide. To investigate the molecular determinants for the activating/blocking actions of these compounds, novel molecules with different alkyl or aryl-alkyl substitutes at position 2 of the 1,4-benzoxazine ring were prepared. The effects of the lengthening of the alkyl chain and of branched substitutes, as well as of the introduction of aliphatic/aromatic rings on the activity of the molecules, were investigated on the skeletal muscle K(ATP) channels of the rat, in excised-patch experiments, in the presence or absence of internal ATP (10(-4) M).

Molecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.

ClC-Ka and ClC-Kb Cl(-) channels are pivotal for renal salt reabsorption and water balance. There is growing interest in identifying ligands that allow pharmacological interventions aimed to modulate their activity. Starting from available ligands, we followed a rational chemical strategy, accompanied by computational modeling and electrophysiological techniques, to identify the molecular requisites for binding to a blocking or to an activating binding site on ClC-Ka.

Enantiomeric separation of 2-aryloxyalkyl- and 2-arylalkyl-2-aryloxyacetic acids on a Penicillin G Acylase-based chiral stationary phase: influence of the chemical structure on retention and enantioselectivity.

The chiral recognition mechanism of Penicillin G Acylase (PGA) was investigated with a set of 18 new chiral acidic compounds. A series of 2-aryloxyalkyl- and 2-arylalkyl-2-aryloxyacetic acids in which the absolute configuration has been reported to exert a strong influence on pharmacological activity, were synthesized and analysed on PGA-based chiral stationary phase (CSP) and 11 racemates were completely resolved with a mobile phase composed of 50 mM phosphate buffer (pH 7.0).

Synthesis, biological evaluation, and molecular modeling investigation of chiral phenoxyacetic acid analogues with PPARalpha and PPARgamma agonist activity.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis, and play a central role in cardiovascular disease, obesity, and diabetes. Thus, there is significant interest in developing new and specific agonists for these receptors. Herein we present screening results for a series of chiral phenoxyacetic acid analogues, some of which are potent PPARalpha agonists as well as PPARgamma agonists.

[The ultrasound microbubble contrast in the diagnosis and the decisional iter of the treatment of the traumatic spleen lesions].

Aim Of The Study: To estimate our 3-year experience on the diagnosis and monitoring of the spleen traumatic lesions with the employment of ultrasound microbubbles contrast.

Method: From the 174 patients who were joints to our department in regimen of urgency for abdominal traumatic lesions, we have estimated 24 patiens including our criteria. The selected patients have been subordinate to the echographic examination with microbubbles contrast and to TC multi-detector (MDCT) with contrast with multiphasic technique.

Exploring the molecular basis of the enantioselective binding of penicillin G acylase towards a series of 2-aryloxyalkanoic acids: a docking and molecular dynamics study.

In the present paper, molecular modeling studies were undertaken in order to shed light on the molecular basis of the observed enantioselectivity of penicillin G acylase (PGA), a well known enzyme for its industrial applications, towards 16 racemic 2-aryloxyalkanoic acids, which have been reported to affect several biological systems. With this intention docking calculations and MD simulations were performed. Docking results indicated that the (S)-enantiomers establish several electrostatic interactions with SerB1, SerB386 and ArgB263 of PGA.

Elucidation of the enantioselective recognition mechanism of a penicillin G acylase-based chiral stationary phase towards a series of 2-aryloxy-2-arylacetic acids.

A series of structurally related 2-aryloxy-2-arylacetic acids (1-3, 5-16) together with a thioisostere derivative (4) have been synthesized and characterized by GC-MS and 1H NMR. The designed compounds were analyzed on a Penicillin G Acylase chiral stationary phase (PGA-CSP) and the influence of the structure variations on retention and enantioselectivity was investigated. The chromatographic study includes the direct separation of the enantiomers of the synthesized compounds and the determination of the elution order of selected racemic mixtures.

Activation and inhibition of kidney CLC-K chloride channels by fenamates.

CLC-K Cl(-) channels are selectively expressed in kidney and ear, where they are pivotal for salt homeostasis, and loss-of-function mutations of CLC-Kb produce Bartter's syndrome type III. The only ligand known for CLC-K channels is a derivative of the 2-p-chlorophenoxypropionic acid (CPP), 3-phenyl-CPP, which blocks CLC-Ka, but not CLC-Kb. Here we show that in addition to this blocking site, CLC-K channels bear an activating binding site that controls channel opening.

Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats.

Carbonic-anhydrase (CA) inhibitors are used in the treatment of hypokalaemic periodic paralysis (hypoPP) and related channelopathies but their mechanism of action is unknown. Patch-clamp experiments and molecular modeling investigations were performed to evaluate the mechanism of actions of CA inhibitors on skeletal muscle Ca2+-activated-K+ (BK) channel of K+-deficient rats used as animal model of hypoPP. CA inhibitors showing different degree of CA inhibition such as acetazolamide (ACTZ), dichlorphenamide (DCP), hydrochlorthiazide (HCT), etoxzolamide (ETX), methazolamide (MTZ), and bendroflumethiazide (BFT), which lacks inhibitory effects on CA enzymes, were tested in vitro on BK channels.

Molecular requisites for drug binding to muscle CLC-1 and renal CLC-K channel revealed by the use of phenoxy-alkyl derivatives of 2-(p-chlorophenoxy)propionic acid.

CLC channels are a gene family of Cl(-) channels that serve a variety of functions, several of which are involved in genetic diseases. Few specific ligands of CLC channels are known that could be useful as pharmacological tools or potential drugs. We synthesized various derivatives of 2-(p-chlorophenoxy)propionic acid, the S(-)-enantiomer of which is a specific blocker of the muscle channel CLC-1.