Synthesis of bis-furyl-pyrrolo[3,4-<i>b</i>]pyridin-5-ones <i>via</i> Ugi-Zhu reaction and <i>in vitro</i> activity assays against human SARS-CoV-2 and <i>in silico</i> studies on its main proteins.
Morales-Salazar I, Montes-Enríquez FP, Garduño-Albino CE, García-Sánchez MA, Ibarra IA, Rojas-Aguirre Y, García-Hernández ME, Sarmiento-Silva RE, Alcaraz-Estrada SL, Díaz-Cervantes E, González-Zamora E, Islas-Jácome A.
An Ugi-Zhu three-component reaction (UZ-3CR) coupled in one pot manner to a cascade process (<i>N</i>-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of bis-furyl-pyrrolo[3,4-<i>b</i>]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 <i>in vitro</i> 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 <i>in vitro</i> results. Additionally, a pharmacophore model was computed behind further rational drug design.