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
Identifiers and Pagination:Year: 2019
First Page: 16
Last Page: 28
Publisher Id: TOMCJ-13-16
Article History:Received Date: 05/11/2018
Revision Received Date: 26/01/2019
Acceptance Date: 05/02/2019
Electronic publication date: 28/02/2019
Collection year: 2019
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: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.