Ligand Binding and Functional Effect of Novel Bicyclic α5 GABA Receptor Negative Allosteric Modulators.

The significant importance of GABA receptors in the treatment of central nervous system (CNS) disorders has been known for a long time. However, only in recent years have experimental protein structures been published that can open the door to understanding protein-ligand interactions and may effectively help the rational drug design for the future. In our previous work (Szabó, G.

Discovery of Novel Steroid-Based Histamine H Receptor Antagonists/Inverse Agonists.

Steroid-based histamine H receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent HR activity together with significant in vivo H antagonism.

Using Kern model to design, implement, and evaluate an infection control program for improving knowledge and performance among undergraduate nursing students: a mixed methods study.

Background: Nurses and Nursing students are the front line of care in managing the care of infectious patients then they have more contact with patients than other students. Therefore, the aim of this study was designing, implementing and evaluating the infection control program among undergraduate nursing students using a mixed study.

Method: The mixed method approach with sequential exploratory (qualitative-quantitative) method was used.

HILIC-UV determination of lysine and chloride counterions in active pharmaceutical ingredients.

A rapid, robust, and routinely applicable HILIC based HPLC-UV assay was developed for the quantitative determination of the L-Lysine content of Atorvastatin lysine active substance. During the method validation it turned out that with UV detection at 200 nm, the method is also capable for the direct determination of chloride ions. To the best of our knowledge, the phenomenon of chloride determination by short wavelength UV detection had only been once highlighted earlier in the literature.

Triterpenes from as Cytotoxic Agents and Chemosensitizers to Overcome Multidrug Resistance of Cancer Cells.

The detailed mycochemical analysis of the -hexane extract of led to the isolation of four new lanostane diesters, named pholiols A-D (-), together with an acyclic triterpene, (3,6,10,14,18,22)-2,3,22,23-tetrahydroxy-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene (), ergosterol (), and 3β-hydroxyergosta-7,22-diene (). The isolation was carried out by multistep flash chromatography, and the structures were elucidated using extensive spectroscopic analyses, including 1D and 2D NMR and MS measurements. The isolated metabolites (-) were investigated for cytotoxic activity against Colo205 and Colo320 colon adenocarcinoma and nontumoral MRC-5 cell lines.

Multivariable analysis of clinical and laboratory data manifestations predicting severity and mortality risk in patients with Coronavirus disease 2019 in the mountainous west of Iran: a retrospective single-center study.

Background: Few reports have addressed the clinical and laboratory features of patients with coronavirus disease-2019 (COVID-19) in mountainous areas, especially in Iran.

Objectives: To report the clinical and laboratory data and manifestations predicting mortality of patients with COVID-19 in the west of Iran.

Methods: We conducted a retrospective cohort study of 286 patients hospitalized with COVID-19 between 25 February 2020 and 12 May 2020 to describe their clinical symptoms and laboratory test findings when they were admitted at the Hajar Hospital affiliated with the Shahrekord University of Medical Sciences, and a multivariable analysis of factors that predict their disease severity and mortality.

Synthesis and Characterization of New V Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers.

A new class of selective vasopressin receptor 1A (V) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized.

Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine.

Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions.

Diversity-oriented synthesis through gamma radiolysis: Preparation of unusual ecdysteroid derivatives activating Akt and AMPK in skeletal muscle cells.

Gamma-ray radiation is a unique way to induce chemical transformations of bioactive compounds. In the present study, we pursued this approach to the diversity-oriented synthesis of analogs of 20-hydroxyecdysone (20E), an abundant ecdysteroid with a range of beneficial, non-hormonal bioactivities in mammals including humans. Gamma irradiations of aqueous solutions of 20E were conducted either in N- or NO-saturated solutions.

Triterpenes and Phenolic Compounds from the Fungus : Isolation, Structure Determination and Biological Activity.

Investigation of the methanol extract of the poroid fungus resulted in the isolation of a novel triterpene, fuscoporic acid (), together with inoscavin A and its previously undescribed isomer ( and ), 3,4-dihydroxy-benzaldehide (), osmundacetone (), senexdiolic acid (), natalic acid (), and ergosta-7,22-diene-3-one (). The structures of fungal compounds were determined on the basis of NMR and MS spectroscopic analyses, as well as molecular modeling studies. Compounds , - were examined for their antibacterial properties on resistant clinical isolates, and cytotoxic activity on human colon adenocarcinoma cell lines.

Discovery of novel positive allosteric modulators of the α7 nicotinic acetylcholine receptor: Scaffold hopping approach.

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized.

AAPH or Peroxynitrite-Induced Biorelevant Oxidation of Methyl Caffeate Yields a Potent Antitumor Metabolite.

Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl--coumarate () and methyl caffeate () was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of and oxidized with peroxynitrite (ONOO¯), a biologically relevant reactive nitrogen species (RNS), or with α,α'-azodiisobutyramidine dihydrochloride (AAPH) as a chemical model for reactive oxygen species (ROS).

Discovery of New Heterocyclic Ring Systems as Novel and Potent V Receptor Antagonists.

Autism spectrum disorder is a neurodevelopmental disease with increasing occurrence. Recent studies focus on the development of novel V receptor antagonists which can influence the core symptoms of autism through the AVP pathway. In this study, we describe the synthesis of new heterocyclic ring systems.

Cerebrosides and Steroids from the Edible Mushroom with Antioxidant Potential.

The detailed chemical analysis of the methanol extract of (Pers.) P. Karst.

Discovery of dihydropyrazino-benzimidazole derivatives as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs).

A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure-activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies.

Triterpenes from the Mushroom : Isolation, Structure Determination and Investigation in Bdelloid Rotifer Assays.

Twelve compounds (⁻) were isolated from the methanol extract of brick cap mushroom ( (Schaeff.) P. Kumm.

Antioxidant-Inspired Drug Discovery: Antitumor Metabolite Is Formed in Situ from a Hydroxycinnamic Acid Derivative upon Free-Radical Scavenging.

Cancer cells generally possess higher levels of reactive oxygen species than normal cells, and this can serve as a possible therapeutic target. In this proof-of-concept study, an antioxidant-inspired drug discovery strategy was evaluated using a hydroxycinnamic acid derivative. The processing of oxidized mixtures of p-coumaric acid methyl ester (pcm) revealed a new antitumor lead, graviquinone.

Isolation and Structure Determination of Antiproliferative Secondary Metabolites from the Potato Earthball Mushroom, Scleroderma bovista (Agaricomycetes).

Mycochemical examination of a methanol extract of Scleroderma bovista Fr. (Agaricomycetes) led to the isolation of 7 compounds, which were, to our knowledge, identified for the first time in this species. The chemical structures of these compounds were determined through extensive spectroscopic methods (nuclear magnetic resonance and mass spectrometry).

Biomimetic Synthesis of Drug Metabolites in Batch and Continuous-Flow Reactors.

A medium-throughput screening (MTS) of biomimetic drug metabolite synthesis is developed by using an iron porphyrin catalyst. The microplate method, in combination with HPLC-MS analysis, was shown to be a useful tool for process development and parameter optimization in the production of targeted metabolites and/or oxidation products of forty-three different drug substances. In the case of the biomimetic oxidation of amiodarone, the high quantity and purity of the isolated products enabled detailed HRMS and NMR spectroscopic studies.

Bioactivity-Guided Isolation of Antimicrobial and Antioxidant Metabolites from the Mushroom .

Bioassay-guided fractionation of the chloroform extract of led to the isolation of four secondary metabolites ⁻. Two of the compounds are lactones—osmundalactone () and 5-hydroxy-hex-2-en-4-olide ()—while and were identified as terphenyl quinones, spiromentins C and B, respectively. The structures of the compounds were established on the basis of NMR and MS spectroscopic analysis.

Effect of iris registration on outcomes of FEMTOLASIK for myopia and myopic astigmatism.

Purpose: To compare the visual and refractive outcomes after FEMTOLASIK with and without iris registration.

Methods: In this randomized, prospective, comparative, contralateral eye study, 118 eyes of 59 patients with myopia and myopic astigmatism underwent LASIK using the Femto LDV femtosecond laser (160 µm) and the MEL80 with or without iris registration. For each patient, iris registration FEMTOLASIK was performed on one eye and non-iris registration FEMTOLASIK was performed on the other eye, assigned at random.

Synthesis and pK determination of new enantiopure dimethyl-substituted acridino-crown ethers containing a carboxyl group: Useful candidates for enantiomeric recognition studies.

New enantiopure dimethyl-substituted acridino-18-crown-6 and acridino-21-crown-7 ethers containing a carboxyl group at position 9 of the acridine ring [(S,S)-8, (S,S)-9, (R,R)-10] were synthesized. The pK values of the new crown ethers [(S,S)-8, (S,S)-9, (R,R)-10] and of an earlier reported macrocycle [(R,R)-2] were determined by UV-pH titrations. Crown ether (S,S)-8 was attached to silica gel by covalent bonds and the enantiomeric separation ability of the newly prepared chiral stationary phase [(S,S)-CSP-12] was studied by high-performance liquid chromatography (HPLC).

Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu) receptor negative allosteric modulators.

Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck.

Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications.

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore.