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Innovative Medicines & Omics SARS-CoV-2 inhibition by quinolines

5 Immunopharmacology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
6 National Institute for Science and Technology on Innovation in Diseases of Neglected Populations, Center for Technological Development
in Health Fiocruz, Rio de Janeiro, RJ, Brazil

1. Introduction With the ongoing emergence of new SARS-CoV-2
variants and the enduring challenge posed by other
The ongoing battle against the severe acute respiratory emerging and reemerging pathogens, the pursuit of
syndrome coronavirus 2 (SARS-CoV-2), the causative effective antivirals remains a critical global public health
agent of the coronavirus disease 2019 (COVID-19) priority. While significant strides have been made in
pandemic, underscores the urgent need for effective developing vaccines and therapies to combat COVID-19,
1-3
therapeutics. While vaccines have emerged as pivotal the unpredictable viral evolution underscores the urgent
tools in mitigating the spread of the virus, the development
of potent antiviral agents remains crucial, particularly need for a diverse and robust therapeutic arsenal. The
ability of viruses to rapidly mutate and develop resistance to
in combating emerging variants and addressing the existing treatments necessitates a proactive and continuous
challenges of global vaccine distribution. In this context, approach to antiviral research. Therefore, investigating
4,5
the exploration of small molecules with potential antiviral new antiviral compounds, as well as repurposing existing
activity has garnered significant attention in the scientific drugs, provides a vital strategy to enhance our response
community. 6-8
capacity to current and future outbreaks, ensuring global
Among these compounds, chloroquine and health and safety. Hence, this work aims to contribute to
hydroxychloroquine, both 4-aminoquinoline derivatives, the antiviral field, exploring novel therapeutic possibilities
gained considerable attention early in the pandemic due that may hold promise against SARS-CoV-2, reinforcing
to their known antiviral properties and safety profiles. 9-13 the importance of continuous innovation and scientific
However, subsequent in vitro and clinical trials revealed vigilance in the post-pandemic era.
mixed results regarding their efficacy against COVID-19,
prompting a reassessment of their therapeutic potential. 14-16 2. Materials and methods
Nonetheless, the early investigations underscored the 2.1. Materials
potential of 4-aminoquinoline derivatives as viable
candidates for antiviral drug development. 17-20 All chemicals in this study were used without purification
and acquired from Sigma-Aldrich (St. Louis, MO, USA). An
Despite chloroquine and hydroxychloroquine,
other 4-aminoquinoline derivatives have demonstrated MQAPF-301-Microchemical digital apparatus was used in
the measurement of melting points. A BRUKER AVANCE
promising antiviral activity against SARS-CoV-2. 21,22 These III 500 MHz spectrometer was used for the obtention of
compounds, characterized by their structural versatility nuclear magnetic resonance (NMR) spectra, in which the
and pharmacological properties, offer a diverse array of
targets and mechanisms for inhibiting viral replication and chemical shifts were expressed in ppm related to TMS.
infectivity. 20,23-26 2.2. Physicochemical properties analysis
The main protease (M ) of SARS-CoV-2 is a critical To examine important physicochemical characteristics
pro
target for therapeutic interventions to curb viral replication. of compounds, we evaluated the Lipinski and Veber
This protease plays an indispensable role in processing parameters for each substance. We used the Swiss-ADME
the polyproteins that are translated from the viral RNA, software, available at http://www.swissadme.ch/index.php,
making it a focal point for antiviral drug development. 27,28 and the molinspiration property engine (v2018.10) and
Studies have highlighted the potential of molecules derived molinspiration bioactivity score (v2018.03), both accessible
from or analogous to 4-aminoquinolines in inhibiting this at https://www.molinspiration.com/cgi-bin/properties.
vital viral protease. 22,29
2.3. Synthesis
Herein, we analyzed nine 4-aminoquinoline derivatives
against SARS-CoV-2 replication in Vero E6 and Calu-3 The compounds Q1a – Q4a and Q1b – Q4b were
cell models, and its affinity toward to the SARS-CoV-2 synthesized as described by Carmo et al. The compounds
30
M enzyme. The experimental findings suggest that the were obtained as beige solids with yields of 65 – 87% for
pro
4-aminoquinolinic derivatives represent a promising Q1a – Q4a and 47 – 62% for Q1b – Q4b. The products
avenue in the quest for effective antiviral agents against were confirmed by melting point values and H NMR
1
SARS-CoV-2, including the Omicron variant. spectra. The compound Q1bS was synthesized as described

Volume 1 Issue 1 (2024) 89 doi: 10.36922/imo.3442