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ORIGINAL RESEARCH ARTICLE

Potent and selective inhibitory effect of 4-aminoquinoline derivatives on SARS-CoV-2 replication

Nicolas Glanzmann1† ,  Thamara Kelcya F. Oliveira2,3† ,  Vinicius Carius de Souza4† ,  Amanda R. Tucci2,3 ,  Eduarda Alves Penna4 ,  Alice Santos Rosa2,3 ,  Maria Luiza Pereira Baltazar4 ,  Matheus José Novais Landim4 ,  Vivian Neuza S. Ferreira2 ,  Pamella Constantino-Teles2,3 ,  Daniel Dias Countinho Souza2,3 ,  Sylvia Roxo2 ,  Caroline Souza de Freitas5,6 ,  Aline de Paula Dias da Silva5,6 ,  Thiago Moreno Lopes Souza5,6 ,  Priscila Vanessa S. Zabala Capriles4†* ,  Milene Dias Miranda2,3†* ,  Adilson D. da Silva1†*
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1 Department of Chemistry, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
2 Viral Morphology and Morphogenesis Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
3 Postgraduate Program in Cellular and Molecular Biology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
4 Department of Computer Science, Institute of Exact Sciences, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
IMO 2024, 1(1), 88–106; https://doi.org/10.36922/imo.3442
Submitted: 17 April 2024 | Accepted: 23 May 2024 | Published: 21 June 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

The global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had resulted in significant mortality worldwide. In 2020, the World Health Organization started the solidarity clinical trial to assess the efficacy of four proposed therapeutic strategies, including chloroquine (CQ), a 4-aminoquinoline molecule. However, CQ lacks clinical benefit and, therefore, failed to show in vitro anti-SARS-CoV-2 activity in TMPRSS2-expressing cells, such as Calu-3 cell line, which recapitulate human type II pneumocytes. Nevertheless, other 4-aminoquinoline derivatives have shown high affinity toward the SARS-CoV-2 main protease (Mpro). This study aimed to evaluate, in vitro and in silico, the inhibitory potential of nine 4-aminoquinoline derivatives against SARS-CoV-2, building upon the observed antiviral activity of established antimalarial drugs. We assessed the ability of these derivatives to inhibit SARS-CoV-2 (wild type and Omicron variant) replication in Vero E6 and Calu-3 cell lines. In addition, we conducted docking studies to determine the binding affinity and protein-ligand interactions. Notably, these derivatives exhibited potent antiviral activity with low cytotoxicity in Vero E6 and Calu-3 cell models. In silico investigations targeting the Mpro enzyme supported the potential of the derivatives as promising agents in the fight against SARS-CoV-2. Our findings underscore the potential of these 4-aminoquinoline derivatives as robust inhibitors of SARS-CoV-2 and advocate for further research to explore their therapeutic applications, providing valuable insights for future drug development strategies.

Keywords
SARS-CoV-2
4-aminoquinolines
Vero E6
Calu-3
Molecular docking
Funding
This research was funded by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). T.K.F.O., A.R.T., A.S.R., V.N.S.F., P.C.T., D.D.C.S., J.N.H.L, S.R., and M.D.M. supported by Laboratório de Morfologia e Morfogênese Viral, Instituto Oswaldo Cruz (IOC), Fiocruz, FIOTEC (grant number IOC-023-FIO-18-2-58), Inova Fiocruz (grant number VPPIS-004-FIO-22-2-21), CNPq (Bolsista DT grant number: 312027/2022-2), CAPES (scholarships and grant numbers: 88881.506711/2020-01, 88887.648435/2021- 00, 88887.636136/2021-00, 88887.717861/2022-00, 88887.694990/2022-00, 88887.719751/2022-00), and FAPERJ (E-26/201.426/2022, E-26/203.183/2023). The authors would also like to thank CAPES (process 88887.506710/2020-00, 88887.647774/2021-00 and 88887.722759/2022-00) and CNPq (process 312295/2020-0).
Conflict of interest
The authors declare that they have no competing interests.
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