5-chloro-3-(2-(2,4-dinitrophenyl) hydrazono)indolin-2-one: synthesis, characterization, biochemical and computational...

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Developing broad-spectrum antiviral agents is crucial for combating existing and emerging viral infections.
• The SARS-CoV-2 spike protein's binding to the ACE2 receptor is essential for viral entry.
• Emerging SARS-CoV-2 variants possess mutations that can evade vaccine and antibody responses.

Purpose of the Study:

• To identify novel chemical entities capable of disrupting the SARS-CoV-2 spike protein-ACE2 interaction.
• To evaluate the efficacy of these compounds against SARS-CoV-2 variants, including Omicron.

Main Methods:

• Synthesis of 5-chloro-3-(2-(2,4-dinitrophenyl)hydrazono)indolin-2-one (H₂L) via condensation reaction.
• Characterization of H₂L using elemental analysis and spectral data (IR, electronic, Mass, NMR).
• In vitro assessment of H₂L's inhibitory activity against the SARS-CoV-2 spike RBD-ACE2 interaction.
• Molecular docking studies to predict binding modes and interactions within the ACE2 receptor.

Main Results:

• H₂L was synthesized in good yield and characterized, exhibiting keto-enol tautomerism.
• H₂L selectively inhibited the SARS-CoV-2 spike RBD-ACE2 binding with an IC₅₀ of 0.26 μM.
• Molecular docking indicated H₂L binds to a distinct region in the ACE2 receptor, unaffected by common spike mutations.
• H₂L demonstrated similar efficacy in disrupting ACE2 interactions with RBDs from Beta, Delta, Lambda, and Omicron variants.

Conclusions:

• H₂L is a potent inhibitor of SARS-CoV-2 entry by disrupting the spike protein-ACE2 interaction.
• The compound shows broad-spectrum activity against multiple SARS-CoV-2 variants, including immune-evasive ones.
• H₂L-derived compounds represent a promising therapeutic avenue for managing SARS-CoV-2 infections.