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Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2014 Sep 01; Vol. 22 (17), pp. 4658-66. Date of Electronic Publication: 2014 Jul 22. - Publication Year :
- 2014
-
Abstract
- 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.<br /> (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Subjects :
- Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Cell Line
Dose-Response Relationship, Drug
HIV genetics
Humans
Ligands
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Quinolones chemical synthesis
Quinolones chemistry
Structure-Activity Relationship
Virus Replication drug effects
Virus Replication genetics
Anti-HIV Agents pharmacology
HIV drug effects
Quinolones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 22
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25127466
- Full Text :
- https://doi.org/10.1016/j.bmc.2014.07.018