Abstract
Background: 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. Methods: 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). Results: 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. Conclusion: 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.
Highlights
In the past decades, considerable work has been done in exploiting small non-coding hairpin RNA fragments as drug targets
Among the small molecules known as Transactivation response element (TAR) RNA binder, the 6-aminoquinolone WM5 Fig. (1), which was developed in our lab, inhibits the Tat-mediated transactivation by interfering selectively with the bulge region of TAR RNA [20]
The synthesis of the C-7 4-carbamimidoylpiperazine derivative 2 started by reacting derivative 14 [28] with methyl imidothiocarbamate sulfate to give intermediate 15, which, after reduction of the nitro group accomplished with FeSO4 and NH4OH followed by acid hydrolysis of the ethyl ester intermediate, led to the target compound 2 Scheme (2)
Summary
Considerable work has been done in exploiting small non-coding hairpin RNA fragments as drug targets. One of the most studied RNA structures is the Transactivation response element (TAR) of HIV-1 genome [4 - 9], a short stem-bulge-loop structure located in the long terminal repeat. TAR RNA is extremely conserved among viral isolates making it a very attractive target. During the last two decades, many small molecules, aminoglycosides-conjugates, Tat-based peptidomimetics, and peptides have been reported as TAR binders [12 - 19]. Among the small molecules known as TAR RNA binder, the 6-aminoquinolone WM5 Fig. (1), which was developed in our lab, inhibits the Tat-mediated transactivation by interfering selectively with the bulge region of TAR RNA [20]. The 6-aminoquinolone WM5, previously identified by us, is among the most selective small molecules known as TAR RNA binders to show antiHIV activity
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