HIV-1 integrase inhibition by dimeric bisbenzimidazoles with different spacer structures

Korolev, S. P.; Tashlitsky, Vadim N.; Smolov, M. A.; Gromyko, A. V.; Жузе, А. Л.; Agapkina, Yu. Yu.; Gottikh, Marina

doi:10.1134/s0026893310040199

Cited by 9 publications

(2 citation statements)

References 16 publications

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“…The aldehyde group was introduced into the structure of the modified thymidine analogue (T m ), which occupied position 3 counting from the 5’-end of oligonucleotide U5A ( Figure, A ), since it was located close to the amino acid residues of the IN catalytic domain [ 33 ]. The feasibility of this approach was described in [ 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

et al. 2013

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Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

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Section: Resultsmentioning

confidence: 99%

Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

et al. 2013

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“…This suggests that it might be possible for a single tethered inhibitor to bind both of the catalytically relevant IN active sites in the intasome. There have been reports of linker-dependency in symmetrically-joined dimeric IN inhibitors, although the basis for the dependency has not been clearly explained [29, 30]. The PFV co-crystal structure that contains 4b shows that the sulfonamide group projects outward from the catalytic site [26].…”

Section: Synthesismentioning

confidence: 99%

6,7-Dihydroxyisoindolin-1-one and 7,8-Dihydroxy-3,4-Dihydroisoquinolin- 1(2H)-one Based HIV-1 Integrase Inhibitors

Zhao

Métifiot²,

Smith³

et al. 2015

CTMC

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Integrase (IN) is an essential viral enzyme required for HIV-1 replication, which has been targeted by anti-AIDS therapeutics. Integrase strand transfer inhibitors (INSTIs) represent a new class of antiretroviral agents developed for the treatment of HIV-1 infections. Important structural features that are shared by many INSTIs include a coplanar arrangement of three heteroatoms that chelate two catalytic Mg(2+) ions in the IN active site and a linked halophenyl ring that binds in the hydrophobic pocket formed by the complex of IN with viral DNA. We recently reported bicyclic 6,7-dihydroxyoxoisoindolin-1-one-based IN inhibitors. In the current study, we modified these inhibitors in three ways. First, we increased the spacer length between the metalchelating triad and the halophenyl group. Second, we replaced the indoline [5,6] bicycle with a fused dihydroxyisoquinolinones [6,6] ring system. Finally, we prepared bis-6,7-dihydroxyisoindolin-1-one-4-sulfonamides as dimeric HIV-1 IN inhibitors. These new analogues showed low micromolar inhibitory potency in in vitro HIV-1 integrase assays.

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Bisbenzimidazole derivatives as potent inhibitors of the trypsin-like sites of the immunoproteasome core particle

et al. 2015

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HIV-1 integrase inhibition by dimeric bisbenzimidazoles with different spacer structures

Cited by 9 publications

References 16 publications

Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

6,7-Dihydroxyisoindolin-1-one and 7,8-Dihydroxy-3,4-Dihydroisoquinolin- 1(2H)-one Based HIV-1 Integrase Inhibitors

Bisbenzimidazole derivatives as potent inhibitors of the trypsin-like sites of the immunoproteasome core particle

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