Synthesis of New Substituted 4,5-Dihydro-3H-spiro[1,5]-benzoxazepine-2,4′-piperidine and Biological Properties

2006 ◽  
Vol 59 (11) ◽  
pp. 812 ◽  
Author(s):  
Younes Laras ◽  
Nicolas Pietrancosta ◽  
Vincent Moret ◽  
Sylvain Marc ◽  
Cédrik Garino ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Functional Groups ◽  
Biological Properties ◽  
Hiv Protease ◽  
Aspartyl Protease ◽  
Electronic Effects ◽  
The Creation ◽  
Hiv 1 ◽  
Bace 1 ◽  
Aspartyl Protease Inhibitors

The reduction of substituted spiro-piperidinyl chromanone oximes with DIBAH reagents has been known to afford the corresponding substituted 4,5-dihydro-3H-spiro[1,5]-benzoxazepine-2,4′-piperidine. The position and electronic effects of the substituents on the aryl moiety control the observed rearrangement. Spiro-benzoxazepine analogue 5j represents a key intermediate for the creation of a library of diverse potential bioactive drugs. With three functional groups that could be selectively and orthogonally protected, many different substituents can be introduced. The obtained analogues were assayed as the possible aspartyl protease inhibitors HIV protease (HIV-1), and β-secretase (BACE-1).

scholarly journals Inhibitory Activity of Human Immunodeficiency Virus Aspartyl Protease Inhibitors against Encephalitozoon intestinalis Evaluated by Cell Culture-Quantitative PCR Assay

2005 ◽  
Vol 49 (6) ◽  
pp. 2362-2366 ◽  
Author(s):  
Jean Menotti ◽  
Maud Santillana-Hayat ◽  
Bruno Cassinat ◽  
Claudine Sarfati ◽  
Francis Derouin ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Quantitative Pcr ◽  
Inhibitory Effect ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Aspartyl Protease ◽  
Pcr Assay ◽  
Real Time Quantitative Pcr ◽  
Quantitative Pcr Assay ◽  
Aspartyl Protease Inhibitors

ABSTRACT Immune reconstitution might not be the only factor contributing to the low prevalence of microsporidiosis in human immunodeficiency virus (HIV)-infected patients treated with protease inhibitors, as these drugs may exert a direct inhibitory effect against fungi and protozoa. In this study, we developed a cell culture-quantitative PCR assay to quantify Encephalitozoon intestinalis growth in U-373-MG human glioblastoma cells and used this assay to evaluate the activities of six HIV aspartyl protease inhibitors against E. intestinalis. A real-time quantitative PCR assay targeted the E. intestinalis small-subunit rRNA gene. HIV aspartyl protease inhibitors were tested over serial concentrations ranging from 0.2 to 10 mg/liter, with albendazole used as a control. Ritonavir, lopinavir, and saquinavir were able to inhibit E. intestinalis growth, with 50% inhibitory concentrations of 1.5, 2.2, and 4.6 mg/liter, respectively, whereas amprenavir, indinavir, and nelfinavir had no inhibitory effect. Pepstatin A, a reference aspartyl protease inhibitor, could also inhibit E. intestinalis growth, suggesting that HIV protease inhibitors may act through the inhibition of an E. intestinalis-encoded aspartyl protease. These results showed that some HIV protease inhibitors can inhibit E. intestinalis growth at concentrations that are achievable in vivo and that the real-time quantitative PCR assay that we used is a valuable tool for the in vitro assessment of the activities of drugs against E. intestinalis.

Analogues of Key Precursors of Aspartyl Protease Inhibitors:  Synthesis of Trifluoromethyl Amino Epoxides

2005 ◽  
Vol 70 (2) ◽  
pp. 699-702 ◽  
Author(s):  
Nguyen Thi Ngoc Tam ◽  
Guillaume Magueur ◽  
Michèle Ourévitch ◽  
Benoit Crousse ◽  
Jean-Pierre Bégué ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Aspartyl Protease ◽  
Aspartyl Protease Inhibitors

scholarly journals Human immunodeficiency virus type 1 (HIV-1) protease inhibitors block cell-to-cell HIV-1 endocytosis in dendritic cells

2009 ◽  
Vol 90 (11) ◽  
pp. 2777-2787 ◽  
Author(s):  
Claudia Muratori ◽  
Eliana Ruggiero ◽  
Antonella Sistigu ◽  
Roberta Bona ◽  
Maurizio Federico
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hiv Protease ◽  
Donor Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

Sexual transmission is now the most frequent means of diffusion of human immunodeficiency virus type 1 (HIV-1). Even if the underlying mechanism is still largely unknown, there is a consensus regarding the key role played by mucosal dendritic cells (DCs) in capturing HIV through contact with infected subepithelial lymphocytes, and their capacity to spread HIV by trans-infection. We found that HIV protease inhibitors (PIs) reduced virion endocytosis strongly in monocyte-derived immature (i) DCs contacting HIV-1-infected cells, and that this phenomenon led to dramatically impaired trans-infection activity. This inhibitory effect was not mediated by the block of viral protease activity, as it was also operative when donor cells were infected with a PI-resistant HIV-1 strain. The block of virus maturation imposed by PIs did not correlate with significant variations in the levels of virus expression in donor cells or of Gag/Env virion incorporation. Also, PIs did not affect the endocytosis activity of DCs. In contrast, we noticed that PI treatment inhibited the formation of cell–cell conjugates whilst reducing the expression of ICAM-1 in target iDCs. Our results contribute to a better delineation of the mechanisms underlying HIV-1 trans-infection activity in DCs, whilst having implications for the development of new anti-HIV microbicide strategies.

HIV aspartyl protease inhibitors modify the percentage of activated leukocytes, as well as serum levels of IL-17A and NO during experimental leishmaniasis

2018 ◽  
Vol 60 ◽  
pp. 179-188 ◽  
Author(s):  
Daniele Luísa Ribeiro Alvarenga ◽  
Amanda Helen dos Santos Silva ◽  
Jacqueline Araújo Fiuza ◽  
Soraya Torres Gaze ◽  
Jaquelline Germano de Oliveira ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Serum Levels ◽  
Aspartyl Protease ◽  
Aspartyl Protease Inhibitors

scholarly journals Novel aspartyl protease inhibitors, YF-0200R-A and B.

1994 ◽  
Vol 47 (5) ◽  
pp. 566-570 ◽  
Author(s):  
TSUTOMU SATO ◽  
KOJI NAGAI ◽  
MITSUYOSHI SHIBAZAKI ◽  
KENJI ABE ◽  
YUKIHIRO TAKEBAYASHI ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Aspartyl Protease ◽  
Aspartyl Protease Inhibitors

scholarly journals Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors

2005 ◽  
Vol 49 (9) ◽  
pp. 3825-3832 ◽  
Author(s):  
Joseph Yanchunas ◽  
David R. Langley ◽  
Li Tao ◽  
Ronald E. Rose ◽  
Jacques Friborg ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Cross Resistance ◽  
Titration Calorimetry ◽  
Binding Affinities ◽  
The Novel ◽  
Immunodeficiency Virus ◽  
Effective Drugs ◽  
Hiv 1

ABSTRACT Protease inhibitors (PIs) are highly effective drugs against the human immunodeficiency virus (HIV), yet long-term therapeutic use is limited by emergence of HIV type 1 (HIV-1) protease substitutions that confer cross-resistance to multiple protease inhibitor drugs. Atazanavir is a highly potent HIV protease inhibitor with a distinct resistance profile that includes effectiveness against most HIV-1 isolates resistant to one or two PIs. The signature resistance substitution for atazanavir is I50L, and it is frequently (53%) accompanied by a compensatory A71V substitution that helps restore viability and increases atazanavir resistance levels. We measured the binding affinities of wild-type (WT) and I50L/A71V HIV-1 proteases to atazanavir and other currently approved PIs (ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, and amprenavir) by isothermal titration calorimetry. Remarkably, we find that all of the PIs have 2- to 10-fold increased affinities for I50L/A71V protease, except for atazanavir. The results are also manifested by thermal stability measures of affinity for WT and I50L/A71V proteases. Additional biophysical and enzyme kinetics experiments show I50L/A71V protease is a stable enzyme with catalytic activity that is slightly reduced (34%) relative to the WT. Computational modeling reveals that the unique resistance phenotype of I50L/A71V protease likely originates from bulky tert-butyl groups at P2 and P2′ (specific to atazanavir) that sterically clash with methyl groups on residue L50. The results of this study provide a molecular understanding of the novel hypersusceptibility of atazanavir-resistant I50L/A71V-containing clinical isolates to other currently approved PIs.

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