ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

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 B. Eni, Mustafa Alhaji Isa, Adi Narayana Reddy Poli, Joel Cassel, Joseph M. Salvino, Luis J. Montaner, Ian Tietjen, and Fidele Ntie-Kang

Department of Chemistry, Faculty of Science, University of Buea, Buea, Cameroon

E-mail: felicite.majoumo@ubuea.cm

Received: 29 July 2023  Accepted: 4 December 2023

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 (H₂L) from the condensation reaction of 5-chloroisatin and 2,4-dinitrophenylhydrazine in good yield. H₂L was characterised by elemental and spectral (IR, electronic, Mass) analyses. The NMR spectrum of H₂L indicated a keto–enol tautomerism, with the keto form being more abundant in solution. H₂L 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 (IC₅₀) of 0.26 μM, compared to an unrelated PD-1/PD-L1 ligand–receptor-binding pair with an IC₅₀ 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, H₂L was able to disrupt ACE2 interactions with the RBDs from beta, delta, lambda, and omicron variants with similar activities. These studies indicate that H₂L-derived compounds are potential inhibitors of multiple SARS-CoV-2 variants, including those capable of circumventing vaccine and immune responses.

Keywords: Angiotensin-converting enzyme 2 receptor; Antivirals; Coronavirus; Isatin hydrazine; Molecular docking; SARS-CoV-2 spike

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-03274-5

Chemical Papers 78 (6) 3431–3441 (2024)