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

in key tissues where coronavirus entry is critical. In From the results obtained using the Swiss-ADME
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contrast, ferroquine, a synthetic ferrocenic derivative of and Molinspiration softwares, none of the compounds
chloroquine, initially designed for antimalarial purposes, violated Lipinski’s rules. The molecules analyzed here as
has shown promising antiviral properties. Notably, it has controls, including mefloquine, atazanavir, daclatasvir,
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demonstrated effectiveness against SARS-CoV in renal molnupiravir, chloroquine, lopinavir, and ritonavir, also
cells from non-human primates, presenting favorable did not violate any of Lipinski’s parameters. Compound
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EC values and a selective index. In addition, ferroquine Q3a had 5 rotatable bonds, a TPSA of 50.94 Ų, and a
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exhibits dose-dependent antiviral effects against the LogPw/o of 2.68, indicating certain lipophilicity; it had two
hepatitis C virus (HCV) in Huh-7 cells, a cell line derived hydrogen donor groups and two hydrogen bond acceptor
from hepatocellular carcinoma. 55 groups.
Additional data reported that other quinoline Physicochemical parameters, including Lipinski’s rule,
derivatives, such as quinine and amodiaquine, were able are important for future in silico evaluation of molecules’
to inhibit the replication of influenza virus (H1N1) at non- absorption, distribution, metabolism, excretion, and
toxic concentrations in Calu-3 cells, considered a primary toxicity (ADMET). This assessment allows for better
target for respiratory viral infection, and Madin-Darby selection of candidates for in vitro testing. With favorable
canine kidney cells (MDCK). Quinines have also been in silico physicochemical results, these molecules are more
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described as inhibitors of the replicative capacity of DENV likely to exhibit optimal oral bioavailability and absorption.
virus (DENV-1 [strain Hawaii], DENV-2 [strain 16681], It should be noted that Lipinski’s rule is a simplified tool
DENV-3 [strain H87], and DENV-4 [strain H241]) in that only covers some of the complexities involved in a
human hepatocarcinoma cell line (HepG2), human lung molecule’s ADMET properties. It is intended as an initial
carcinoma cell line (A549), and human umbilical vein guide and cannot definitively predict the success of a
cell line (EA.hy926), while maintaining their cell viability molecule as a drug.
above 80%. 17 The expanding body of research into the antiviral
The molecules that are the subject of this work consist properties of quinolinic derivatives, particularly their
of quinolinic derivatives that have been previously assessed capacity to interfere with viral replication mechanisms,
has prompted an evaluation of their effectiveness as in vitro
against tuberculosis, leishmaniasis, and malaria.
inhibitors of SARS-CoV-2 replication. This investigation
Regarding the antileishmanial activity, Q1a – Q3a aligns with the global initiative to identify viable treatments
provided good EC values against promastigotes for COVID-19 by examining the effects of quinolinic
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of Leishmania amazonensis and Q1bS showed derivatives on inhibiting the novel coronavirus within
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good selectivity and promising results against both controlled laboratory environments. The study utilized
promastigotes and amastigotes of L. amazonensis and Vero E6 and Calu-3 cells, which are standard models in
Leishmania infantum, as well as against promastigotes of SARS-CoV-2 infection research, to assess the anti-SARS-
Leishmania braziliensis, leading to in vivo studies with L. CoV-2 activity of these compounds. 61-63
infantum-infected mice, which highlighted this compound Notably, Calu-3 cells, derived from human lung
as a therapeutic agent. 31,57 As for the antitubercular profile, cancer, express the TMPRSS2 receptor, which is integral
compounds Q1b – Q3b showed low minimum inhibitory to the cellular entry of SARS-CoV-2. This receptor is
concentration values for Mycobacterium tuberculosis. 30 crucial for the priming of the SARS-CoV-2 spike protein,

In respect to their antiplasmodial effect, it is facilitating viral attachment and subsequent entry into
interesting to note that the tested derivatives consist of host cells. Therefore, Calu-3 cells are an invaluable model
4-aminoquinolines with similar structures to mefloquine, for studying the interaction between potential anti-SARS-
amodiaquine, chloroquine, and hydroxychloroquine, all CoV-2 molecules and the virus. 62,64,65
of which have well-known antiplasmodial potency. Q1b Despite the lack of significant in vitro activity
– Q3b showed good inhibition of Plasmodium berghei observed with chloroquine and hydroxychloroquine
in infected mice at 25 mg/kg. Q1b showed outstanding in Calu-3 cells, there is emerging evidence that other
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in vitro EC values against Plasmodium falciparum with 4-aminoquinolines may display potent antiviral effects.
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good selectivity. This encouraged us to produce its Recent investigations have identified compounds like
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hydrochloride, Q1bS, which is a water-soluble molecule mefloquine, which effectively inhibits SARS-CoV-2
and that was tested in vitro against P. falciparum and in vivo infection in physiologically relevant cells, including Calu-
in a murine model of cerebral malaria, being able to inhibit 3, contrasting with the ineffectiveness of chloroquine
the development of the infection. 60 and hydroxychloroquine. 16,66 Further research into the

Volume 1 Issue 1 (2024) 97 doi: 10.36922/imo.3442