Detailed Studies on the Methoxylation and Subsequent Dealkylation of -Diethylbenzenesulfonamide Using a Tailor-Made Electrosynthetic Reactor.

Benzenesulfonamides are an outstandingly important family of compounds in organic and medicinal chemistry. Herein, we report detailed studies on the electrochemical mono- and dideethylation of model compound -diethylbenzenesulfonamide. In this context, all parameters of the electrosynthesis were systematically investigated, with a special emphasis on solvent screening and the effect of water on the outcome of the reaction.

Computational Studies on the Diastereospecific Lithium Variant of Oppenauer Oxidation of a Tofisopam Intermediate.

During the synthesis of tofisopam drug substance, an interesting diastereospecific lithium variant of Oppenauer oxidation was observed and investigated by density functional theory (DFT) calculations. The computations revealed energetic differences caused by steric differences between the diastereomers that might provide an explanation for the experimentally formed products. In addition, the trend in the measured NMR shifts was also in line with the computed values, which allowed the assignment of the absolute configuration of the diastereomers.

Studies on the total syntheses of ‑carboline alkaloids orthoscuticellines A and B.

Orthoscuticellines A and B are newly isolated natural -carboline alkaloids from the moss animal . Herein, we report the first targeted total synthesis of orthoscuticelline B and an analogous synthetic method for the preparation of dihydro derivate of orthoscuticelline A. The new synthetic approach is based on commercially available and inexpensive reagents leading to a practical synthesis of the target molecules.

Extending the limitations in the prediction of PAMPA permeability with machine learning algorithms.

Gastrointestinal absorption is a key factor amongst the ADME-related (absorption, distribution, metabolism and excretion) pharmacokinetic properties; therefore, it has a major role in drug discovery and drug safety determinations. The Parallel Artificial Membrane Permeability Assay (PAMPA) can be considered as the most popular and well-known screening assay for the measurement of gastrointestinal absorption. Our study provides quantitative structure-property relationship (QSPR) models based on experimental PAMPA permeability data for almost four hundred diverse molecules, which is a great extension of the applicability of the models in the chemical space.

Soluplus® promotes efficient transport of meloxicam to the central nervous system via nasal administration.

In our present series of experiments, we investigated the nasal applicability of the previously developed Soluplus® - meloxicam polymeric micelle formulation. Utilizing the nasal drug investigations, moderately high mucoadhesion was experienced in nasal conditions which alongside the appropriate physicochemical properties in liquid state, contributed to rapid drug absorption through human RPMI 2650 cell line. Ex vivo studies also confirmed that higher nasal mucosal permeation could be expected with the polymeric micelle nanoformulation compared to a regular MEL suspension.

New synthesis of a late-stage tetracyclic key intermediate of lumateperone.

New approaches have been tested for the synthesis of lumateperone intermediates. As a result of these efforts, a novel synthesis of the late-stage tetracyclic key intermediate of lumateperone starting from the commercially available quinoxaline is described. The tetracyclic skeleton was constructed by the reaction of 1-trifluoroacetyl-4-aminoquinoxaline with ethyl 4-oxopiperidine-1-carboxylate in a Fischer indole synthesis.

Mucoadhesive meloxicam-loaded nanoemulsions: Development, characterization and nasal applicability studies.

Intranasally administered non-steroidal anti-inflammatory drugs (NSAIDs) offer an innovative opportunity in the field of pain management. Combination of the nasal physiological advantages such as the rich vascularization and large absorption area along with novel nanomedical formulations can fulfill all the necessary criteria of an advanced drug delivery system. Nanoemulsions represent a versatile formulation approach suitable for nasal drug delivery by increasing the absorption and the bioavailability of many drugs for systemic and nose-to-brain delivery due to their stability, small droplet size and optimal solubilization properties.

Experimental and computational study of BF-catalyzed transformations of -(pivaloylaminomethyl)benzaldehydes: an unexpected difference from TFA catalysis.

Previously, we have studied the trifluoroacetic acid (TFA)-catalyzed rearrangements of unsubstituted and alkoxy-substituted -(pivaloylaminomethyl)benzaldehydes and revealed the formation of rearranged, regioisomeric aldehydes along with dimer-like products ("TFA dimers"). In the present study, related reactions of -(pivaloylaminomethyl)benzaldehydes are described with the difference that boron trifluoride diethyl etherate (BF·OEt) is used as the catalyst. Although in these reactions the formation of the same "TFA dimers" can be observed after a couple of hours reaction time, during further stirring these are transformed into a new dimer-like keto compound ("BF dimer") that gradually becomes the main product.

Development of In Situ Gelling Meloxicam-Human Serum Albumin Nanoparticle Formulation for Nose-to-Brain Application.

The aim of this study was to develop an intranasal in situ thermo-gelling meloxicam-human serum albumin (MEL-HSA) nanoparticulate formulation applying poloxamer 407 (P407), which can be administered in liquid state into the nostril, and to increase the resistance of the formulation against mucociliary clearance by sol-gel transition on the nasal mucosa, as well as to improve drug absorption. Nanoparticle characterization showed that formulations containing 12-15% / P407 met the requirements of intranasal administration. The Z-average (in the range of 180-304 nm), the narrow polydispersity index (PdI, from 0.

Recent Advances in the Synthesis of β-Carboline Alkaloids.

β-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates.

Basicity-Tuned Reactivity: -[1,2]-Wittig versus -[1,3]-Wittig Rearrangements of 3,4-Dihydro-2-1,2,3-benzothiadiazine 1,1-Dioxides.

The base-induced (-BuOK) rearrangement reactions of 3,4-dihydro-2-1,2,3-benzothiadiazine 1,1-dioxides result in a ring opening along the N-N bond, followed by ring closure with the formation of new C-N bonds. The position of the newly formed C-N bond can selectively be tuned by the amount of the base, providing access to new, pharmacologically interesting ring systems with high yield. While with 2 equiv of -BuOK 1,2-benzisothiazoles can be obtained in a -[1,2]-Wittig reaction, with 6 equiv of the base 1,2-benzothiazine 1,1-dioxides can be prepared in most cases as the main product, in a -[1,3]-Wittig reaction.

Synthesis of Indolo[2,3-]quinolin-6(7)-ones and Antimalarial Isoneocryptolepine. Computational Study on the Pd-Catalyzed Intramolecular C-H Arylation.

The synthesis of variously substituted indolo[2,3-]quinolin-6(7)-ones was developed Pd-catalyzed intramolecular C-H arylation. This method highlights a strategy for preparing indoloquinoline precursors bearing versatile functional groups and provides a new approach for the synthesis of antimalarial isoneocryptolepine analogues. The plausible ring closure mechanism was examined with quantum chemical calculations, where a trigonal bipyramidal concerted metalation-deprotonation transition state is presumable.

Rearrangement of -(pivaloylaminomethyl)benzaldehydes: an experimental and computational study.

Treatment of alkoxy-substituted -(pivaloylaminomethyl)benzaldehydes under acidic conditions resulted in the formation of the regioisomeric aldehydes and/or dimer-like products. Detailed NMR studies and single-crystal X-ray measurements supported the structure elucidation of the compounds. DFT calculations were also carried out to clarify the reaction mechanism, and to explain the observed product distributions and structural variances in the dimer-like products.

First total synthesis of β-carboline alkaloid trigonostemine G and its derivatives.

The β-carboline core is the base structure of several biologically active natural and unnatural compounds. Herein, we report the first total synthesis of trigonostemine G, which is a newly isolated natural β-carboline alkaloid from the twigs of . Synthesis of two structurally close derivatives of trigonostemine G is also reported.

Development and Evaluation of Two Potential 5-HT Receptor PET Tracers: [F]ENL09 and [F]ENL10.

The latest addition to the serotonin (5-HT) receptor family is the 5-HT receptor (5-HTR). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HTR available.

A novel tool for structure assignment of hydroxylated metabolites of (arylpiperazinylbutyl)oxindole derivatives based on relative HPLC retention times.

Incubation of oxindole derivatives containing an arylpiperazine pharmacophore in rat liver microsomes in vitro formed several metabolites hydroxylated at various positions of the aromatic rings of the oxindole carbocycle or the arylpiperazine moiety. In order to substitute the sites of metabolic attack on these positional isomers, the exact structure of the molecules had to be identified. As polarities of the compounds depend on the site of hydroxylation, we measured retention times of the metabolites using reversed-phase HPLC.

Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors.

Most of the known inhibitors of D-amino acid oxidase (DAAO) are small polar molecules recognized by the active site of the enzyme. More recently a new class of DAAO inhibitors has been disclosed that interacts with loop 218-224 at the top of the binding pocket. These compounds have a significantly larger size and more beneficial physicochemical properties than most reported DAAO inhibitors, however, their structure-activity relationship is poorly explored.

Synthesis of 8-Fluoro-3,4-dihydroisoquinoline and Its Transformation to 1,8-Disubstituted Tetrahydroisoquinolines.

A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed -lithiation reaction. This key intermediate was then applied in various transformations. Fluorine⁻amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines.

Synthesis of new tricyclic imidazotriazepine derivatives condensed with various heterocycles.

Previously synthesized 9-aryl-5H-imidazo[2,1-d][1,2,5]triazepin-6(7H)-ones have been used as starting materials for the synthesis of three new tricyclic ring systems, where an imidazotriazepine is condensed with an imidazole, triazole or tetrazole ring. These novel compounds could be potential drug candidates for central nervous system diseases because of their closely related structure to known tricyclic derivatives with anticonvulsant activity.

Study on the Alkylation Reactions of N(7)-Unsubstituted 1,3-Diazaoxindoles.

The chemistry of the 5,7-dihydro-6-pyrrolo[2,3-]pyrimidin-6-one (1,3-diazaoxindole) compound family, possessing a drug-like scaffold, is unexplored. In this study, the alkylation reactions of (7)-unsubstituted 5-isopropyl-1,3-diazaoxindoles bearing various substituents at the (2) position have been investigated. The starting compounds were synthesized from the (5)-unsubstituted parent compounds by condensation with acetone and subsequent catalytic reduction of the 5-isopropylidene moiety.

Thermal Ring Contraction Reactions of 9-Aryl-5H,7H-[1,2,5]thiadiazolo[3,4-h][2,3,4]benzothiadiazepine 6,6-Dioxides. Experimental and Computational Studies for Understanding the Course of the Transformations.

When refluxing with sodium hydrogen carbonate in acetonitrile, 7-chloro-5-(4-fluorophenyl)-1,3-dihydro-2,3,4-benzothiadiazepine 2,2-dioxide afforded, after loss of dinitrogen and subsequent ring contraction, the corresponding sulfone in 83% yield. Similar treatment of the related thiadiazolo-fused tricycles, i.e.

Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles. Practical Synthesis of N-Unprotected 3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring.

The paper provides a comprehensive review of the base-catalysed C3-alkylation of N-unprotected-3-monosubstituted oxindoles. Based on a few, non-systematic studies described in the literature using butyllithium as the deprotonating agent, an optimized method has now been elaborated, via the corresponding lithium salt, for the selective C3-alkylation of this family of compounds. The optimal excess of butyllithium and alkylating agent, and the role of the halogen atom in the latter (alkyl bromides vs.

A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential.

Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test.

Evaluation of 3-Ethyl-3-(phenylpiperazinylbutyl)oxindoles as PET Ligands for the Serotonin 5-HT₇ Receptor: Synthesis, Pharmacology, Radiolabeling, and in Vivo Brain Imaging in Pigs.

We have investigated several oxindole derivatives in the pursuit of a 5-HT7 receptor PET ligand. Herein the synthesis, chiral separation, and pharmacological profiling of two possible PET candidates toward a wide selection of CNS-targets are detailed. Subsequent (11)C-labeling and in vivo evaluation in Danish landrace pigs showed that both ligands displayed high brain uptake.

Interactions of non-charged tadalafil stereoisomers with cyclodextrins: capillary electrophoresis and nuclear magnetic resonance studies.

The single isomer drug R,R-tadalafil (Cialis) contains two chiral centers thus four stereoisomers (R,R-, S,S-, S,R- and R,S-tadalafil) exist, however, only the most potent inhibitor, the R,R-tadalafil is in clinical use. In our study, over 20 charged cyclodextrin (CD) derivatives were studied for enantiospecific host-guest type interactions in CD-modified capillary electrophoresis. Tadalafil stereoisomers are non-charged; therefore, their electrophoretic separation poses a challenge.