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A new total synthesis of the β-carboline alkaloid brevicarine is disclosed. The synthesis was carried out starting from an aromatic triflate key intermediate, allowing the introduction of various substituents into position 4 of β-carboline by cross-coupling reactions. Thanks to its scalability, this novel approach ensures a broad accessibility to the target compound for potential pharmacological measurements. Using detailed NMR studies, the NMR signals have been assigned for both the base and its dihydrochloride salt for further confirming their structures. A new synthesis of the related alkaloid brevicolline was also attempted from the same intermediate. However, after successful coupling of β-carboline with N -methylpyrrole, the trials to saturate the pyrrole ring under various conditions led to unexpected reactions: reduction of ring A of the β-carboline skeleton or trifluoroethylation of the pyrrole moiety occurred, leading to interesting and potentially useful derivatives.

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. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex β-carboline frameworks. In this review, we describe the recent developments in the synthesis of β-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted.

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 N,N-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. Beside a commercially available electrochemical reactor, a custom-made device has also successfully been designed and used in these transformations. Optimization of the reaction led to a green, scaled-up synthesis of the dealkylated products. Our experiments also render the synthesis and potential in situ use of the corresponding N-methoxyalkyl intermediate, a precursor of the reactive and versatile N-sulfonyliminium cation, possible.

New tetra- and pentacyclic derivatives of the dibenzo[ , ][1,2]thiazepine ring system have been synthesized. The target compounds contain methylenedioxy or ethylenedioxy substituents linked to the benzene ring. The key step for the construction of the ring systems has been implemented by an intramolecular Friedel-Crafts cyclization. Altogether eight new ring systems are described here, five of them are also characterized by single-crystal X-ray diffraction.

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. The inexpensive starting material , the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability.

Copper-containing minerals are among the most abundant minerals on Earth. They play a fundamental role in our economy and, as presented in prebiotic studies, in the origin of life. Over 700 copper-containing minerals are present in nature with well-defined structure and formula. By utilizing the catalytic effect of such minerals, highly economical and green methods can be developed. One of such methods is presented in this study in copper mineral-catalyzed Goldberg arylation reactions of amides. A total of seven readily available minerals were tested in the reaction of iodobenzene with pyrrolidin-2-one with chrysocolla [(Cu,Al)2H2Si2O5(OH)4·n H2O] and malachite [Cu2(CO3)(OH)2] being the best applicable ones. After optimization, a wide variety of arylated amide derivatives were synthesized utilizing the catalytical effect of the above-mentioned minerals. The procedure proved to be feasible regardless of the origin of the catalyst making this method even more attractive.

Motivated by the in vivo anxiolytic activity of previously described 1,2,3-benzothiadiazine 1,1-dioxides, we aimed at elaborating a synthetic procedure for the preparation of their pyrrole-fused counterparts, 2,9-dihydro[1,2,3]thiadiazino[5,6- g ]indole 1,1-dioxide derivatives. The simple and versatile process led, via Fischer indole cyclization of the corresponding hydrazones, to a wide structural variety of new tri-, tetra- and pentacyclic ring systems. The structural characterization of ( E )- and ( Z )-hydrazones was supported by 2D NMR techniques, while that of the target compounds by single-crystal X-ray measurements. The hydrazone intermediates and the new title compounds were subjected to a physicochemical and early ADME characterization study, in the framework of which log P , p K a and log k values were calculated. Following that, kinetic solubility and in vitro gastrointestinal membrane-specific permeability measurements were carried out to assess the lead-likeness of the compounds. Subsequently, the metabolic stability of the most promising derivatives was also determined using human liver microsomes.

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. iodides) were also studied. The alkylation protocol has also been extended to some derivatives substituted at the aromatic ring. Finally, various substituents were introduced into the aromatic ring of the N-unprotected 3,3-dialkyloxindoles obtained by this optimized method.

Cilostazol (CIL), a BCS class II antiplatelet aggregation and vasodilator agent, is used for cerebrovascular diseases to minimize blood–brain barrier dysfunction, white matter-lesion formation, and motor deficits. The current work aimed to develop and optimize cilostazol-loaded spanlastics (CIL-SPA) for nose-to-brain delivery to overcome the low solubility and absorption, the first pass-metabolism, and the adverse effects. The optimal CIL-SPA formulation was loaded into Phytagel® (SPA-PG), Poloxamer-407 (SPA-P407), and chitosan (SPA-CS) gel bases and characterized in terms of colloidal properties, encapsulation efficiency (EE%), mucoadhesive properties, and biopharmaceutical aspects. The developed in situ gelling formulations showed a <300 nm average hydrodynamic diameter, <0.5 polydispersity index, and >|±30| mV zeta potential with a high EE% (>99%). All formulations met the droplet size-distribution criteria of nasal requirements (<200 µm), and all formulations showed adequate mucoadhesion properties. Both the BBB-PAMPA and horizontal permeability study through an artificial membrane revealed that all formulations had higher CIL flux and cumulative permeability at in vitro nose-to-brain conditions compared to the initial CIL. The in vitro drug-release study showed that all formulations released ca. 100% of CIL after 2 h. Therefore, the developed formulations could be promising for improving the low bioavailability of CIL through nose-to-brain delivery.

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% w/w P407 met the requirements of intranasal administration. The Z-average (in the range of 180–304 nm), the narrow polydispersity index (PdI, from 0.193 to 0.328), the zeta potential (between −9.4 and −7.0 mV) and the hypotonic osmolality (200–278 mOsmol/L) of MEL-HSA nanoparticles predict enhanced drug absorption through the nasal mucosa. Based on the rheological, muco-adhesion, drug release and permeability studies, the 14% w/w P407 containing formulation (MEL-HSA-P14%) was considered as the optimized formulation, which allows enhanced permeability of MEL through blood–brain barrier-specific lipid fraction. Cell line studies showed no cell damage after 1-h treatment with MEL-HSA-P14% on RPMI 2650 human endothelial cells’ moreover, enhanced permeation (four-fold) of MEL from MEL-HSA-P14% was observed in comparison to pure MEL. Overall, MEL-HSA-P14% can be promising for overcoming the challenges of nasal drug delivery.