5-chloro-3-(2-(2,4-dinitrophenyl) hydrazono)indolin-2-one: synthesis, characterization, biochemical and computational screening against SARS-CoV-2
Felicite Majoumo‐Mbe, Neba Abongwa Sangbong, Alain Tadjong Tcho, Cyril T. Namba-Nzanguim, Conrad V. Simoben, Donatus Bekindaka Eni, Mustafa Alhaji Isa, Adi Narayana Reddy Poli, Joel Cassel, Joseph M. Salvino, Luis J. Montaner, Ian Tietjen, Fidele Ntie‐Kang
Abstract
Abstract Chemical prototypes with broad-spectrum antiviral activity are important toward developing new therapies that can act on both existing and emerging viruses. Binding of the SARS-CoV-2 spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor is required for cellular entry of SARS-CoV-2. Toward identifying new chemical leads that can disrupt this interaction, including in the presence of SARS-CoV-2 adaptive mutations found in variants like omicron that can circumvent vaccine, immune, and therapeutic antibody responses, we synthesized 5-chloro-3-(2-(2,4-dinitrophenyl)hydrazono)indolin-2-one (H 2 L) from the condensation reaction of 5-chloroisatin and 2,4-dinitrophenylhydrazine in good yield. H 2 L was characterised by elemental and spectral (IR, electronic, Mass) analyses. The NMR spectrum of H 2 L indicated a keto–enol tautomerism, with the keto form being more abundant in solution. H 2 L was found to selectively interfere with binding of the SARS-CoV-2 spike receptor-binding domain (RBD) to the host angiotensin-converting enzyme 2 receptor with a 50% inhibitory concentration (IC 50 ) of 0.26 μM, compared to an unrelated PD-1/PD-L1 ligand–receptor-binding pair with an IC 50 of 2.06 μM in vitro (Selectivity index = 7.9). Molecular docking studies revealed that the synthesized ligand preferentially binds within the ACE2 receptor-binding site in a region distinct from where spike mutations in SARS-CoV-2 variants occur. Consistent with these models, H 2 L was able to disrupt ACE2 interactions with the RBDs from beta, delta, lambda, and omicron variants with similar activities. These studies indicate that H 2 L-derived compounds are potential inhibitors of multiple SARS-CoV-2 variants, including those capable of circumventing vaccine and immune responses.