Bioorganic Chemistry
Synthesis, molecular docking, and in silico ADME/Tox profiling studies of
new 1-aryl-5-(3-azidopropyl)indol-4-ones: Potential inhibitors of SARS
CoV-2 main protease
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Francisco Xavier Domínguez-Villa , Noemi Angeles Duran-Iturbide ,
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Jose Gustavo Avila-Zarraga
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Facultad de Química, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, 04510 Coyoacan, DF, Mexico
A R T I C L E I N F O
A B S T R A C T
Keywords:
The virus SARS CoV-2, which causes the respiratory infection COVID-19, continues its spread across the world
and to date has caused more than a million deaths. Although COVID-19 vaccine development appears to be
progressing rapidly, scientists continue the search for different therapeutic options to treat this new illness. In
this work, we synthesized five new 1-aryl-5-(3-azidopropyl)indol-4-ones and showed them to be potential in-
hibitors of the SARS CoV-2 main protease (3CLpro). The compounds were obtained in good overall yields and
molecular docking indicated favorable binding with 3CLpro. In silico ADME/Tox profile of the new compounds
were calculated using the SwissADME and pkCSM-pharmacokinetics web tools, and indicated adequate values of
absorption, distribution and excretion, features related to bioavailability. Moreover, low values of toxicity were
indicated for these compounds. And drug-likeness levels of the compounds were also predicted according to the
Lipinski and Veber rules.
Indolones
Alkylazides
COVID-19
Molecular docking
ADME/Tox
1. Introduction
3CLpro, also known as main protease (Mpro) [8,9]. Mpro is interesting
because it is fundamental for the life cycle of SARS CoV-2 [2] and the
In December 2019, a contagion of atypical and severe pneumonia
was first reported in Wuhan, Hubei Province, China and has since widely
spread worldwide [1]. This new disease was subsequently attributed to a
new class of coronavirus, specifically severe acute respiratory syndrome
coronavirus 2 (SARS CoV-2), which probably emerged as a zoonotic
disease from bats or pangolins, and was named coronavirus disease 2019
(COVID-19) [2]. By the end of January 2020 the outbreak was declared a
Public Health Emergency of International Concern by the World Health
Organization [3].
absence of homologous proteins in humans make it an attractive target
for the development of new antiviral drugs.
The catalytic site of 3CLpro is a dimeric unit containing a Cys-Hys
dyad [10]. The thiol group in Cys acts as a nucleophile in the proteo-
lytic process. So the inhibition of 3CLpro can be achieved using peptidic
inhibitors containing electrophilic groups such as epoxides, ketones,
aldehydes and Michael acceptors [11].
In this context, organic azides (R-N3) are groups with an electrophilic
behavior. As illustrated in Scheme 1, the nitrogen directly attached to
the organic group (labeled a) can work as a nucleophile and the distal
nitrogen (c) shows electrophilic reactivity [12]. Zidovudine is an
example of an antiviral containing the azide group, and the presence of
the –N3 functional group (specifically the presence of nitrogen c) is
determinant for the interaction of the antiviral with its reverse tran-
scriptase pharmacological target [13,14].
COVID-19 causes symptoms such as dry cough, headache, fever,
difficult breathing (dyspnea), and pneumonia, which can trigger respi-
ratory failure and as a result death [4]. To date, no highly effective
therapy for treating coronavirus infections has been made available, so
many research groups worldwide are working to develop therapeutic
options to fight this pathogen. Some structural elements of SARS CoV-2
have been identified in silico as possible therapeutic targets [5–7]. The
most promising targets so far identified have been the spike protein,
RNA-dependent RNA polymerase (RdRp), and the papain-like protease
Also, indolones constitute an important family of fused heterocycles
with potential for use against SARS CoV-2. They are found in many
natural products [15] and drugs [16], and show diverse biological
* Corresponding author.
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Received 12 August 2020; Received in revised form 13 October 2020; Accepted 19 November 2020
Available online 24 November 2020
0045-2068/© 2020 Elsevier Inc. All rights reserved.
Domínguez-Villa, Francisco Xavier
