Title: Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands
Authors: Sancineto, Luca ×
Iraci, Nunzio
Barreca, Maria Letizia
Massari, Serena
Manfroni, Giuseppe
Corazza, Gianmarco
Cecchetti, Violetta
Marcello, Alessandro
Daelemans, Dirk
Pannecouque, Christophe
Tabarrini, Oriana #
Issue Date: Sep-2014
Publisher: Pergamon
Series Title: Bioorganic & Medicinal Chemistry vol:22 issue:17 pages:4658-4666
Article number: 10.1016/j.bmc.2014.07.018
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.
ISSN: 0968-0896
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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