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Volume 26
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Article

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

by
Roberto E. Blanco-Carapia
1,
Ricardo Hernández-López
1,
Sofía L. Alcaraz-Estrada
2,
Rosa Elena Sarmiento-Silva
3,
Montserrat Elemi García-Hernández
3,
Nancy Viridiana Estrada-Toledo
4,
Gerardo Padilla-Bernal
1,
Leonardo D. Herrera-Zúñiga
1,5,
Jorge Garza
1,
Rubicelia Vargas
1,*,
Eduardo González-Zamora
1 and
Alejandro Islas-Jácome
1,*
1
Departamento de Química, Universidad Autónoma Metropolitana–Iztapalapa, Av. Ferrocarril San Rafael Atlixco 186, Col. Leyes de Reforma 1A Sección, Iztapalapa, Ciudad de México C.P. 09310, Mexico
2
División de Medicina Genómica, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Félix Cuevas 540, Col. Del Valle Sur, Benito Juárez, Ciudad de México C.P. 03100, Mexico
3
Departamento de Microbiología e Inmunología, Facultad de Medicina, Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Av. Universidad 3000, Ciudad Universitaria, Coyoacán, Ciudad de México C.P. 04510, Mexico
4
Health Pharma Professional Research S.A de C.V., Av. Insurgentes Sur 662-Piso 3, Col. Del Valle, Benito Juárez, Ciudad de México C.P. 03100, Mexico
5
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana–Cuajimalpa, Vasco de Quiroga 4871, Col. Contadero, Cuajimalpa, Ciudad de México C.P. 05348, Mexico
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(15), 7651; https://doi.org/10.3390/ijms26157651 (registering DOI)
Submission received: 13 June 2025 / Revised: 31 July 2025 / Accepted: 4 August 2025 / Published: 7 August 2025
(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)
Versions Notes

Abstract

A one-pot synthetic methodology that combines an Ugi-Zhu three-component reaction (UZ-3CR) with a cascade sequence (intermolecular aza Diels–Alder cycloaddition/intramolecular N-acylation/decarboxylation/dehydration) using microwave-heating conditions, ytterbium (III) triflate (Yb(OTf)3) 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-b]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 19d and 19i were found to effectively stop early SARS-CoV-2 replication, IC50 = 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 (Mpro, 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.
Keywords: multi-component reactions; polyheterocycles; fluorinated-compounds; pyrrolo[3,4-b]pyridin-5-ones; quinoline; SARS-CoV-2; antiviral activity; drug design multi-component reactions; polyheterocycles; fluorinated-compounds; pyrrolo[3,4-b]pyridin-5-ones; quinoline; SARS-CoV-2; antiviral activity; drug design

Share and Cite

MDPI and ACS Style

Blanco-Carapia, R.E.; Hernández-López, R.; Alcaraz-Estrada, S.L.; Sarmiento-Silva, R.E.; García-Hernández, M.E.; Estrada-Toledo, N.V.; Padilla-Bernal, G.; Herrera-Zúñiga, L.D.; Garza, J.; Vargas, R.; et al. Multi-Component Synthesis of New Fluorinated-Pyrrolo[3,4-b]pyridin-5-ones Containing the 4-Amino-7-chloroquinoline Moiety and In Vitro–In Silico Studies Against Human SARS-CoV-2. Int. J. Mol. Sci. 2025, 26, 7651. https://doi.org/10.3390/ijms26157651

AMA Style

Blanco-Carapia RE, Hernández-López R, Alcaraz-Estrada SL, Sarmiento-Silva RE, García-Hernández ME, Estrada-Toledo NV, Padilla-Bernal G, Herrera-Zúñiga LD, Garza J, Vargas R, et al. Multi-Component Synthesis of New Fluorinated-Pyrrolo[3,4-b]pyridin-5-ones Containing the 4-Amino-7-chloroquinoline Moiety and In Vitro–In Silico Studies Against Human SARS-CoV-2. International Journal of Molecular Sciences. 2025; 26(15):7651. https://doi.org/10.3390/ijms26157651

Chicago/Turabian Style

Blanco-Carapia, Roberto E., Ricardo Hernández-López, Sofía L. Alcaraz-Estrada, Rosa Elena Sarmiento-Silva, Montserrat Elemi García-Hernández, Nancy Viridiana Estrada-Toledo, Gerardo Padilla-Bernal, Leonardo D. Herrera-Zúñiga, Jorge Garza, Rubicelia Vargas, and et al. 2025. "Multi-Component Synthesis of New Fluorinated-Pyrrolo[3,4-b]pyridin-5-ones Containing the 4-Amino-7-chloroquinoline Moiety and In Vitro–In Silico Studies Against Human SARS-CoV-2" International Journal of Molecular Sciences 26, no. 15: 7651. https://doi.org/10.3390/ijms26157651

APA Style

Blanco-Carapia, R. E., Hernández-López, R., Alcaraz-Estrada, S. L., Sarmiento-Silva, R. E., García-Hernández, M. E., Estrada-Toledo, N. V., Padilla-Bernal, G., Herrera-Zúñiga, L. D., Garza, J., Vargas, R., González-Zamora, E., & Islas-Jácome, A. (2025). Multi-Component Synthesis of New Fluorinated-Pyrrolo[3,4-b]pyridin-5-ones Containing the 4-Amino-7-chloroquinoline Moiety and In Vitro–In Silico Studies Against Human SARS-CoV-2. International Journal of Molecular Sciences, 26(15), 7651. https://doi.org/10.3390/ijms26157651

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