Insights into targeting SARS-CoV-2: design, synthesis, studies and antiviral evaluation of new dimethylxanthine derivatives
Aiming to achieve efficient activity against severe acute respiratory syndrome coronavirus (SARS-CoV-2), the expansion of the structure- and ligand-based drug design approaches was adopted, which has been recently reported by our research group. Purine ring is a corner stone in the development of SA...
Gespeichert in:
Veröffentlicht in: | RSC medicinal chemistry 2023-05, Vol.14 (5), p.899-92 |
---|---|
Hauptverfasser: | , , , , , , , , |
Format: | Artikel |
Sprache: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Aiming to achieve efficient activity against severe acute respiratory syndrome coronavirus (SARS-CoV-2), the expansion of the structure- and ligand-based drug design approaches was adopted, which has been recently reported by our research group. Purine ring is a corner stone in the development of SARS-CoV-2 main protease (M
pro
) inhibitors. The privileged purine scaffold was elaborated to achieve additional affinity based on hybridization and fragment-based approaches. Thus, the characteristic pharmacophoric features that are required for the inhibition of M
pro
and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 were utilized along with the crystal structure information of both targets. The designed pathways involved rationalized hybridization with large sulfonamide moieties and a carboxamide fragment for the synthesis of ten new dimethylxanthine derivatives. The synthesis was performed under diverse conditions to afford
N
-alkylated xanthine derivatives, and cyclization afforded tricyclic compounds. Molecular modeling simulations were used to confirm and gain insights into the binding interactions at both targets' active sites. The merit of designed compounds and the
in silico
studies resulted in the selection of three compounds that were evaluated
in vitro
to estimate their antiviral activity against SARS-CoV-2 (compounds
5
,
9a
and
19
with IC
50
values of 38.39, 8.86 and 16.01 μM, respectively). Furthermore, oral toxicity of the selected antiviral candidates was predicted, in addition to cytotoxicity investigations. Compound
9a
showed IC
50
values of 8.06 and 3.22 μM against M
pro
and RdRp of SARS-CoV-2, respectively, in addition to promising molecular dynamics stability in both target active sites. The current findings encourage further specificity evaluations of the promising compounds for confirming their specific protein targeting.
The expanded structure- and ligand-based drug design strategy was utilized to obtain a multitargeting SARS-CoV-2 inhibitor, compound
9a
, with an IC
50
value of 8.86 μM. |
---|---|
ISSN: | 2632-8682 |
DOI: | 10.1039/d3md00056g |