- In silico/in vitro screening and hit evaluation identified new phenothiazine anti-prion derivatives
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Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare neurodegenerative disorders. TSEs are characterized by the accumulation of prions (PrPSc) that represent pathological isoforms of the physiological cellular prion protein PrPC. Although the conversion of PrPC to PrPSc is still not completely understood, blocking this process may lead to develop new therapies. Here, we have generated a pharmacophore model, based on anti-prion molecules reported in literature to be effective in phenotypic assay. The model was used to conduct a virtual screen of commercial compound databases that selected a small library of ten compounds. These molecules were then screened in mouse neuroblastoma cell line chronically infected with prions (ScN2a) after excluding neurotoxicity. 1 has been identified as the therapeutic hit on the basis of the following evidence: chronic treatments of ScN2a cells using 1 eliminate PrPSc loaded in both Western blotting analysis and Real-Time Quaking-Induced Conversion (RT-QuIC) assay. We also proposed the mechanism of action of 1 by which it has the ability to bind PrPC and consequentially blocks prion conversion. Herein we describe the results of these efforts.
- Bolognesi, Maria Laura,Carloni, Paolo,Colini Baldeschi, Arianna,Gandini, Annachiara,Legname, Giuseppe,Rossetti, Giulia,Salzano, Giulia,Tran, Thanh Hoa,Zaccagnini, Ludovica
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supporting information
(2020/04/21)
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- Assembly of substituted phenothiazines by a sequentially controlled CuI/L-proline-catalyzed cascade C-S and C-N bond formation
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(Chemical equation presented) In the pro-line of fire: A general and efficient cascade reaction approach to substituted phenothiazines, which relies on controlled sequential Cul/L-prolinecatalyzed C-S and C-N bond formations, is described. DMSO = dimethylsulfoxide.
- Dawei, Ma.,Geng, Qian,Zhang, Hui,Jiang, Yongwen
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supporting information; experimental part
p. 1291 - 1294
(2010/05/17)
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- Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs
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Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of K(i) and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. K(i) data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them.
- Chan, Cecil,Yin, Hong,Garforth, Jacqui,McKie, James H.,Jaouhari, Rabih,Speers, Peter,Douglas, Kenneth T.,Rock, Peter J.,Yardley, Vanessa,Croft, Simon L.,Fairlamb, Alan H.
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p. 148 - 156
(2007/10/03)
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- Decane-1,10-diisocyanates and methods of making the same
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Decane-1,10-diisocyanates corresponding to the formula STR1 wherein R1 is an alkyl or cycloalkyl radical, and R2 is a hydrogen atom or an alkyl or cycloalkyl radical and the method of making these diisocyanates by the phosgenation of 1,10-diaminodecanes of the formula STR2
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