Design and Synthesis of WM5 Analogues as HIV-1 TAR RNA Binders

Jenny Desantis1, 2, Serena Massari1, *, Alice Sosic3, Giuseppe Manfroni1, Rolando Cannalire1, Tommaso Felicetti1, Christophe Pannecouque4, Barbara Gatto3, Oriana Tabarrini1
1 Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
2 Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy
3 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy
4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, K.U. Leuven, B-3000 Leuven, Belgium

© 2019 Desantis et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: ( This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy; Tel: +390755855134; E-mail:



The 6-aminoquinolone WM5, previously identified by us, is among the most selective small molecules known as TAR RNA binders to show anti-HIV activity.


Starting from WM5, a series of analogues modified at N-1, C-6 or C-7 position was prepared by inserting guanidine or amidine groups as well as other protonable moieties intended to electrostatically bind the phosphate backbone of TAR. All the compounds were tested for their ability to inhibit HIV-1 replication in MT-4 cells and in parallel for their cytotoxicity. The active compounds were also evaluated for their ability to interfere with the formation of the Tat-TAR complex using a Fluorescence Quenching Assay (FQA).


Some of the synthesized compounds showed an anti-HIV-1 activity in the sub-micromolar range with the naphthyridone derivatives being the most potent. Three of the synthesized derivatives were able to interact with the Tat-TAR complex formation presenting Ki values improved as compared to the values obtained with WM5.


The addition of a pyridine-based protonable side chain at the N-1 position of the quinolone/naphthyridone core imparted to the compounds the ability to interfere with Tat-TAR complex formation and HIV-1 replication.

Keywords: Anti-HIV quinolones, Tat-mediated transcription inhibitors, Antiviral agents, Medicinal chemistry, WM5, Fluorescence quenching assay.