Synthesis of bis-furyl-pyrrolo[3,4-b]pyridin-5-ones via Ugi-Zhu reaction and in vitro activity assays against human SARS-CoV-2 and in silico studies on its main proteins.

Abstract

An Ugi-Zhu three-component reaction (UZ-3CR) coupled in one pot manner to a cascade process (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of bis-furyl-pyrrolo[3,4-b]pyridin-5-ones in 45 to 82% overall yields using ytterbium triflate as a catalyst, toluene as a solvent, and microwaves as a heat source. The synthesized molecules were evaluated in vitro against human SARS-CoV-2 through a time-of-addition approach, finding that compound 1e, at a concentration of 10.0 μM, exhibited a significant reduction at the initial infection stages, thus showing prophylactic potential. On the other hand, it was found that compound 1d, at the same concentration, was significantly active when applied post-infection, thus exhibiting a therapeutic profile. Moreover, compound 1f showed both, prophylactic and therapeutic activity. Then, to understand interactions between synthesized compounds and the main proteins related to the virus, docking studies were performed on spike-glycoprotein, main-protease, and Nsp3 protein, finding moderate to strong binding energies, matching accurately with the in vitro results. Additionally, a pharmacophore model was computed behind further rational drug design.

• Authors: Ivette Morales-Salazar, Flora P Montes-Enríquez, Carlos E Garduño-Albino, M A García-Sánchez, Ilich A Ibarra, Yareli Rojas-Aguirre, Montserrat Elemi García-Hernández, Rosa Elena Sarmiento-Silva, Sofía Lizeth Alcaraz-Estrada, Erik Díaz-Cervantes, Eduardo González-Zamora, Alejandro Islas-Jácome
• Journal: RSC medicinal chemistry (RSC Med Chem) Vol. 14 Issue 1 Pg. 154-165 (Jan 25 2023) ISSN: 2632-8682 [Electronic] England
• PMID: 36760742 (Publication Type: Journal Article)
• Copyright: This journal is © The Royal Society of Chemistry.