No abstract

A facile one-pot approach based on a thermally induced metal- and solvent-free 5-endo-dig cyclization reaction of the amino propargylic alcohols in combination with Dess-Martin periodinane-promoted oxidative dearomatization of 4,5,6,7-tetrahydroindole intermediates provides an efficient and robust access to 5,6-dihydro-1H-indol-2(4H)ones. Green, relatively mild and operationally simple characteristics of the synthetic sequence are the major advantages, which greatly amplify the developed methodology. The utility of obtained indolones as unified key precursors is demonstrated by the application of these products to the formal total syntheses of a whole pleiad of Erythrina- and Lycorine-type alkaloids, namely (±)-erysotramidine, (±)-erysotrine, (±)-erythravine, (±)-γ-lycorane, and abnormal erythrinanes (±)-coccoline and (±)-coccuvinine.

Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top-ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin-based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.

Excitotoxicity in the brain is a causal factor in several neurological and neurodegenerative disorders. Excitatory amino acid transporter 2 (EAAT2), an astrocytic glutamate transporter involved in the clearance of >80% of synaptic glutamate, is considered a therapeutically relevant target for excitotoxicity. We have previously designed GT951, an activator of EAAT2 with nanomolar efficacy but limited in vivo bioavailability. In this study, a pharmacophore-based screening and optimization resulted in the design of GTS467 and GTS511. GTS467 and GTS511 have low nanomolar efficacy in the glutamate uptake assay. Pharmacokinetic profiles (PK) of GTS511 show a >6 h half-life and higher bioavailability in plasma and the brain under all three routes of administration in rats. Similarly, GTS467 has high oral bioavailability (80−85%) in the brain and plasma with a >1 h halflife under all three dosing routes. These encouraging efficacy and PK profiles suggest that GTS511 and GTS467 can be further developed to treat neurological disorders caused by excitotoxicity.

— The study has been devoted to the complexation of hydroxypropyl-β-cyclodextrin (HPCD) with antibacterial drugs, namely, ceftriaxone (CT) and levofloxacin (LV), which are used to treat respiratory diseases, including bacterial infections of the respiratory tract. FTIR and NMR spectroscopic investigations have shown that the LV–HPCD complex is formed mainly due to the inclusion of the aromatic fragment of LV into the HPCD cavity; while the CT–HPCD complex is realized on the HPCD surface. Being a more hydrophobic molecule, LV forms ten times stronger complexes with HPCD than does CT: K disLV-HPCD ~ 10 –3 M, while K disCT-HPCD ~10 –2 M at pH 7.4. It has been shown that, for singly charged forms of the drugs, the complexes are two times more stable. Fluorescence spectroscopy has been employed to study the thermodynamic parameters for the interaction of dosage forms with human serum albumin. Negative values of Δ H and Δ S of the reaction have indicated both hydrogen bonding and van der Waals interactions during the complexation of both drugs with human serum albumin. It has been found that the protein is ~4 times more strongly bound to LV at 37°C as compared with CT. The data obtained will make it possible to improve the characteristics of the studied drugs and bring the methods of treating severe forms of respiratory diseases to a new level.