Multi-Component Synthesis of New Fluorinated-Pyrrolo[3,4-]pyridin-5-ones Containing the 4-Amino-7-chloroquinoline Moiety and In Vitro-In Silico Studies Against Human SARS-CoV-2.

A one-pot synthetic methodology that combines an Ugi-Zhu three-component reaction (UZ-3CR) with a cascade sequence (intermolecular Diels-Alder cycloaddition/intramolecular -acylation/decarboxylation/dehydration) using microwave-heating conditions, ytterbium (III) triflate (Yb(OTf)) as the catalyst, and chlorobenzene (for the first time in a multi-component reaction (MCR)) as the solvent, was developed to synthesize twelve new fluorinated-pyrrolo[3,4-]pyridin-5-ones containing a 4-amino-7-chloroquinoline moiety, yielding 50-77% in 95 min per product, with associated atom economies around 88%, also per product. Additionally, by in vitro tests, compounds and were found to effectively stop early SARS-CoV-2 replication, IC = 6.74 µM and 5.29 µM, at 0 h and 1 h respectively, while cell viability remained above 90% relative to the control vehicle at 10 µM. Additional computer-based studies revealed that the most active compounds formed strong favorable interactions with important viral proteins (M, NTDα and NTDo) of coronavirus, supporting a two-pronged approach that affects both how the virus infects the cells and how it replicates its genetic material. Finally, quantum chemistry analyses of non-covalent interactions were performed from Density-Functional Theory (DFT) to better understand how the active compounds hit the virus.