Search results for "IPR"

Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.

2020

Starting from the reversible rhodesain inhibitors 1 a-c, which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversibl…

In vitro and in vivo antileishmanial and trypanocidal studies of new N-benzene- and N-naphthalenesulfonamide derivatives.

2013

We report in vivo and in vitro antileishmanial and trypanocidal activities of a new series of N-substituted benzene and naphthalenesulfonamides 1-15. Compounds 1-15 were screened in vitro against Leishmania infantum , Leishmania braziliensis , Leishmania guyanensis , Leishmania amazonensis , and Trypanosoma cruzi . Sulfonamides 6e, 10b, and 10d displayed remarkable activity and selectivity toward T. cruzi epimastigotes and amastigotes. 6e showed significant trypanocidal activity on parasitemia in a murine model of acute Chagas disease. Moreover, 6e, 8c, 9c, 12c, and 14d displayed interesting IC50 values against Leishmania spp promastigotes as well as L. amazonensis and L. infantum amastigot…

New ligand-based approach for the discovery of antitrypanosomal compounds.

2005

The antitrypanosomal activity of 10 already synthesized compounds was in silico predicted as well as in vitro and in vivo explored against Trypanosoma cruzi. For the computational study, an approach based on non-stochastic linear fingerprints to the identification of potential antichagasic compounds is introduced. Molecular structures of 66 organic compounds, 28 with antitrypanosomal activity and 38 having other clinical uses, were parameterized by means of the TOMOCOMD-CARDD software. A linear classification function was derived allowing the discrimination between active and inactive compounds with a confidence of 95%. As predicted, seven compounds showed antitrypanosomal activity (%AE > 7…

Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes

2018

Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, pro…

Synthesis and biological evaluation of papain-family cathepsin L-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antipr…

2014

Novel papain-family cathepsin L-like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure-activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzod…

Synthesis and biological evaluation of 2-(3 ',4 ',5 '-trimethoxybenzoyl)-3-amino 5-aryl thiophenes as a new class of tubulin inhibitors

2006

2-(3',4',5'-Trimethoxybenzoyl)-3-amino-5-aryl/heteroaryl thiophene derivatives were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. SARs were elucidated with various substitutions on the aryl moiety 5-position of the thienyl ring. Substituents at the para-position of the 5-phenyl group showed antiproliferative activity in the order of F=CH(3) > OCH(3)=Br=NO(2) > CF(3)=I > OEt. Several of these compounds led to arrest of HL-60 cells in the G2/M phase of the cell cycle and induction of apoptosis.

Kultura i więzi społeczne. Przypadek Tunezji

2020

Artykuł ukazuje przemiany więzi społecznej wtrzech wymiarach: pokrewieństwa, więzi wynikającej zwyboru uczestnictwa iwięzi uczestnictwa organicznego. Te trzy wyróżnienia więzi zostały przedstawione wkontekście solidarności idaru oraz dokonujących się transformacji. Więzi pokrewieństwa akcentują pochodzenie, więzi wynikające zwyboru uczestnictwa oznaczają kontakty jednostek zinnymi osobami, również grupami iinstytucjami od których nabywa wiedzę, awięź uczestnictwa organicznego charak-teryzuje się uczeniem iwykonywaniem określonej funkcji worganizacji pracy. Dokonujące się przemiany nie wyrugowały zasady wzajemnej pomocy rodzinnej isolidarności między generacjami, przybierając różne formy wza…

Direct Numerical Simulation of Pulsatile Turbulent Channel Flow

2008

Religió i religiositat en el Tirant lo Blanc

2019

Resum: El treball posa en relleu dues maneres de desenvolupar els aspectes religiosos en el Tirant lo Blanc. Una manera que encaixa amb dificultat amb la doctrina de l’Església, però que sembla ajustar-s’hi quan la pràctica de la cavalleria pren forma de croada, mentre s’exposa una vivència formal, externa i rutinària del cristianisme, malgrat la seva omnipresència; i una altra en què hom procura respectar els articles de la fe i reconduir les conductes dels personatges a una experiència de la fe menys acomodatícia, i més preocupada per les exigències doctrinals.Paraules clau: Religió, Martorell, Tirant, croada, cavalleria, erotisme, humor, psalms, litúrgia.Abstract: This paper highlights t…

Evaluación de la liberación de antibióticos incorporados en cementos utilizados en artroplastia

2017

Una de las complicaciones más serias de la artroplastia se encuentra asociada con el desarrollo de una infección, que, aunque la prevalencia de sitúa entre un 0,5 y un 3%, en algunos casos tiene consecuencias devastadoras. Por ello, uno de los mayores retos en la actualidad es la prevención de infecciones cuando un paciente es sometido a una artroplastia. El uso de antibióticos cargados en cementos óseos destinados a la artroplastia podría ser una herramienta eficaz debida a sus numerosas ventajas, la mayor ventaja de este sistema de liberación deriva de que la liberación del antibiótico se realiza en biofase y por ello permite alcanzar altas concentraciones con una baja o nula toxicidad si…