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. 2019 Aug 20;9(45):26014-26023.
doi: 10.1039/c9ra06313g. eCollection 2019 Aug 19.

Ramified derivatives of 5-(perylen-3-ylethynyl)uracil-1-acetic acid and their antiviral properties

Ksenia A Sapozhnikova  1 , Nikita A Slesarchuk  1   2 , Alexey A Orlov  2   3   4 , Evgeny V Khvatov  1   3 , Eugene V Radchenko  2 , Alexey A Chistov  1 , Alexey V Ustinov  1   5   6 , Vladimir A Palyulin  2 , Liubov I Kozlovskaya  3   4 , Dmitry I Osolodkin  2   3   4 , Vladimir A Korshun  1   6 , Vladimir A Brylev  1   5
Affiliations

Ramified derivatives of 5-(perylen-3-ylethynyl)uracil-1-acetic acid and their antiviral properties

Ksenia A Sapozhnikova et al. RSC Adv. .

Abstract

The propargylamide of N3-Pom-protected 5-(perylen-3-ylethynyl)uracil acetic acid, a universal precursor, was used in a CuAAC click reaction for the synthesis of several derivatives, including three ramified molecules with high activities against tick-borne encephalitis virus (TBEV). Pentaerythritol-based polyazides were used for the assembly of molecules containing 2⋯4 antiviral 5-(perylen-3-ylethynyl)uracil scaffolds, the first examples of polyvalent perylene antivirals. Cluster compounds showed enhanced absorbance, however, their fluorescence was reduced due to self-quenching. Due to the solubility issues, Pom group removal succeeded only for compounds with one peryleneethynyluracil unit. Four compounds, including one ramified cluster 9f, showed remarkable 1⋯3 nM EC50 values against TBEV in cell culture.

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Conflict of interest statement

There are no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1. Structures of broad spectrum antiviral peryleneethynyluracil compounds.
Scheme 1
Scheme 1. Synthesis of azides. Conditions: (a) methanesulfonyl chloride, NEt3, DCM; (b) NaN3, DMSO, rt, 12 h, 32% (2), 27% (3), 8% (4).
Scheme 2
Scheme 2. Synthesis of the model and target compounds. Conditions: (a) propargylamine, PyBOP, DIPEA, DMF, 0 °C, 55%; (b) CuSO4·5H2O, TBTA, aq. ascorbic acid, DMSO, rt, 12 h, azide (benzylazide, azidoethanol, or 2–5), 75% (9a); 67% (9b); 81% (9c), 70% (9d), 54% (9e), 38% (9f); (c) NaOH, DMSO, MeOH, rt, 30 min, 35% (10a), 40% (10b), 30% (10c).
Fig. 2
Fig. 2. Absorbance spectra of compounds 9c–f, 10c at 5 μM concentrations: (A) 0.2% DMSO in 96% EtOH, (B) 2% DMSO in 96% EtOH, (C) 20% DMSO in 96% EtOH.
Fig. 3
Fig. 3. Fluorescence spectra of 9c–f, 10c (0.1 μM, 96% EtOH, λex 420 nm).
Fig. 4
Fig. 4. Structures of compounds optimized using SYBYL-X 2.1 software; molecular surfaces are colored by the hydrophobic potential (left scale).
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