- Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands
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It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex combination of more than one drug. In this paper, we have designed three hybrid molecules combining WM5, a quinolone derivative we previously identified as HIV Tat-mediated transcription (TMT) inhibitor, with the tricyclic core of nevirapine and BILR 355BS (BILR) non-nucleoside reverse transcriptase inhibitors (NNRTIs) to investigate whether it could be possible to obtain molecules acting on both transcription steps of the HIV replicative cycle. One among the three designed multiple ligands, reached this goal. Indeed, compound 1 inhibited both TMT and reverse transcriptase (RT) activity. Unexpectedly, while the anti-TMT activity exerted by compound 1 resulted into a selective inhibition of HIV-1 reactivation from latently infected OM10.1 cells, the anti-RT properties shown by all of the synthesized compounds did not translate into an anti-HIV activity in acutely infected cells. Thus, we have herein produced the proof of concept that the design of dual TMT-RT inhibitors is indeed possible, but optimization efforts are needed to obtain more potent derivatives.
- Sancineto, Luca,Iraci, Nunzio,Barreca, Maria Letizia,Massari, Serena,Manfroni, Giuseppe,Corazza, Gianmarco,Cecchetti, Violetta,Marcello, Alessandro,Daelemans, Dirk,Pannecouque, Christophe,Tabarrini, Oriana
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- PYRIDYL CARBENE PHOSPHORESCENT EMITTERS
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Organometallic compounds comprising an imidazole carbene ligand having a N-containing ring fused to the imidazole ring are provided. In particular, the N-containing ring fused to the imidazole ring may contain one nitrogen atom or more than one nitrogen a
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- PYRIDYL CARBENE PHOSPHORESCENT EMITTERS
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Organometallic compounds comprising an imidazole carbene ligand having a N- containing ring fused to the imidazole ring are provided. In particular, the N-containing ring fused to the imidazole ring may contain one nitrogen atom or more than one nitrogen
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Page/Page column 83
(2012/09/22)
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- NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Compounds represented by formula (1), wherein R1 is H, halogen, (C1-4)alkyl, O(C1-4)alkyl, and haloalkyl; R2 is H or methyl; R3 is H or (C1-4)alkyl; R4 is H or (C1-4)a
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- Non-nucleoside reverse transcriptase inhibitors
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Compounds represented by formula I: wherein R1 is H, halogen, (C1-4)alkyl, O(C1-4)alkyl, and haloalkyl; R2 is H or (C1-4)alkyl; R3 is H or (C1-4)alkyl; R4 is (C1-4)alkyl, (C1-4)alkyl(C3-7)cycloalkyl, or (C3-7)cycloalkyl; and Q is a fused phenyl-5 or 6-membered saturated heterocycle having one to two heteroatoms selected from O and N, said Q being optionally substituted with hydroxy, or (C1-4)alkyl which in turn maybe optionally substituted with pyridinyl-N-oxide or C(O)OR wherein R is H or (C1-4)alkyl; or a salt thereof. The compounds have inhibitory activity against Wild Type, and single and double mutants strains, of HIV.
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- Non-nucleoside reverse transcriptase inhibitors
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Provided are compounds of the general formula I: wherein R2 is selected from the group consisting of H, F, Cl, (C1-4) alkyl, (C3-4) cycloalkyl and CF3; R4 is H or Me; R5 is H, Me or Et, wit
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- Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8- Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild- type and mutant enzymes
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Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.
- Klunder, Janice M.,Hoermann, MaryAnn,Cywin, Charles L.,David, Eva,Brickwood, Janice R.,Schwartz, Racheline,Barringer, Kevin J.,Pauletti, Daniel,Shih, Cheng-Kon,Erickson, David A.,Sorge, Christopher L.,Joseph, David P.,Hattox, Susan E.,Adams, Julian,Grob, Peter M.
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p. 2960 - 2971
(2007/10/03)
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- 8-arylalkyl- and 8-arylheteroalkyl-5,11-dihydro-6H-dipyrido?3,2-B:2',3'-e!?1!diazepines and their use in the treatment of HIV-1 infection
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Disclosed are novel 8-arylalkyl-5,11-dihydro-6H-dipyrido?3,2-b:2',3'-e!?1,4!diazepines. These are useful in the treatment of HIV-1 infection.
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- 8-Arylalkyl- and 8-arylheteroalkyl-5, 11-dihydro-6H-dipyrido-[3,2-b:2', 3'-e][1,4]diazepines and their use in the prevention or treatment of HIV infection
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The invention relates to novel 8-arylalkyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepines of general formula 1 which are useful in the prevention or treatment of HIV infection.
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- 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection
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Disclosed are novel 5,11-dihydro-6H-dipyrido[3,2-b; 2',3'-e][1,4]diazepines. These are useful in the prevention or treatment of HIV infection.
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