One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

• Main Authors: Samar A. El-Kalyoubi (Author), Ahmed Ragab (Author), Ola A. Abu Ali (Author), Yousry A. Ammar (Author), Mohamed G. Seadawy (Author), Aya Ahmed (Author), Eman A. Fayed (Author)
• Format: Book
• Published: MDPI AG, 2022-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15030376; 1424-8247
• Keywords: spiro-oxindoles; isatin sulfonamide derivatives; SARS-CoV-2 inhibitory agents; RNA-polymerase (RdRp) and spike glycoprotein inhibition; computational studies; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 3, p 376 (2022)

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives <b>2a</b>-<b>e</b> and isatin derivatives <b>1a</b>-<b>c</b> to synthesize spiro-oxindoles <b>3a</b>-<b>d</b>, <b>4a</b>-<b>e</b>, and <b>5a</b>-<b>e</b>. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5'-pyrido[2,3-<i>d</i>:6,5-<i>d</i>']dipyrimidine derivatives <b>3a</b>, <b>4b</b>, <b>4d</b>, and <b>4e</b> showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids.