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Hydroxychloroquine for the Treatment of COVID-19: Evidence, Possible Mode of Action and Industrial Supply of the Drug


Abstract and Figures

Hydroxychloroquine, a known antiviral metabolite of chloroquine, is increasingly used along with antibiotic azithromycin for the treatment of COVID-19 infection. In about one month India, the world's largest manufacturer, delivered hydroxychloroquine for treating COVID-19 to over 50 countries. The therapy is being used across the world both for patients staying at home at the early phase of symptoms, as well as for patients hospitalized. We summarize achievements as of late April 2020, review possible modes of action and suggest avenues for the quick scale-up of production of hydroxychloroquine.
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Hydroxychloroquine for the treatment of COVID-19: Evidence,
possible mode of action and industrial supply of the drug
Mario Pagliaro,
Francesco Meneguzzo
Abstract: Hydroxychloroquine, a known antiviral metabolite of
chloroquine, is increasingly used along with antibiotic azithromycin
for the treatment of COVID-19 infection. In about one month India,
the world’s largest manufacturer, delivered hydroxychloroquine for
treating COVID-19 to over 50 countries. The therapy is being used
across the world both for patients staying at home at the early phase
of symptoms, as well as for patients hospitalized. We summarize
achievements as of late April 2020, review possible modes of action
and suggest avenues for the quick scale-up of production of
1. Introduction
On March 20, 2020, Raoult and co-workers reported the
outcomes of treating 26 patients (on average 51.2 years old)
affected by the coronavirus disease 2019 (COVID-19) syndrome
with the hydroxychloroquine sulfate alone and in combination
with azithromycin [1]. After 6 days, all patients treated with
hydroxychloroquine (HCQ) and azithromycin combination were
virologicaly cured. The team extended the new therapy to a
much larger cohort of patients and on April 10, 2020 published
online on the website of the Research Unit in Infectious and
Tropical Emergent Diseases in Marseille the outcomes of the
new protocol applied to 1,061 patients on average 43.6 years
old (46.4% male) [2]. The scholars observed no cardiac toxicity
and virological cure was obtained for 1,019 patients at day 15
(96%), with 973 (91.7%) cured within 10 days [2].
South Korean doctors were reported to recommend the use of
HCQ in combination with antivirals as early as of March 12,
2020 [3]. Even earlier, Bahrain was amid the firss countries in
the world to administer the drug on February 26, 2020 following
the registration of its first case on February 24
. One month later,
the country recorded 225 COVID-19 patients, 4 deaths, and had
already 190 patients cured and discharged from hospitals [4].
On March 23, 2020 a physician (Vladimir Zelenko) in Monroe,
New York state, published online similar excellent outcomes on
treating his patients with shortness of breath and any patient in
the high-risk category with HCQ, azithromycin and zinc sulfate
for five days in order to prevent hospitalization [5].
Doctors in several other countries readily started to treat COVID-
19 patients with this aminoquinoline used since decades across
the world for the treatment of rheumatoid arthritis, lupus
erythematosus and other autoimmune, inflammatory and
dermatologic conditions [6].
Italy, the country with the world’s highest mortality rate chiefly
due to deaths in one region (Lombardy), approved the use of
HCQ, chloroquine and several antivirals for the treatment of the
disease by mid-March 2020 [7]. Italy’s doctors started to
administer the drug to patients under home isolation and
hospitalized. News of success were reported shortly afterwards,
starting from Sicily where doctors in Catania were reported to
observe rapid improvements in both the clinical and virological
profiles of several patients as early as of March 27, 2020 [8].
The 1949 patent [9] disclosing the preparation of racemic
hydroxychloroquine, namely 2-[[4-[(7-chloro-4-
quinolinyl)amino]pentyl]ethylamino]ethanol, expired long ago.
Hence, likewise to what happens for several other “generics” (a
jargon term to indicate active pharmaceutical ingredients no
longer under exclusivity manufacturing rights after the expiry of
patent), its manufacturing chiefly occurs in India and in south
east Asia, with Taiwan hosting the world’s second largest plant.
Hence, when the COVID-19 infection became widespread in
many countries several governments asked India’s government
the urgent supply of the drug. India’s government first on March
25, 2020 issued a ban the export of the drug [10], and then lifted
the ban starting to supply by mid-April a first list of 13 countries
including the United States of America, Spain, Germany,
Bahrain, Brazil, Nepal, Bhutan, Sri Lanka, Afghanistan, Maldives,
Bangladesh, Seychelles, Dominican Republic [11].
On April 17, 2020 doctors from a health care provider focused
on mostly elderly and chronic patients in Brazil confirmed
Raoul’s and Zelenko’s findings reporting that out of 636
symptomatic outpatients of the 224 who refused treatment
(control group), 12 were hospitalized (5.4%), and of these 12
hospitalized, 5 patients died (41%) [12]. On the other hand, of
the 412 outpatients treated with HCQ and azithromycin, only 8
were hospitalized (1.94%), and no deaths were observed.
In case of early treatment (<7 days of symptoms) only 1.17% of
treated patients needed hospitalization, while the percentage
raised to 3.2% for late treatment (>7 days of symptoms). These
outcomes were even more remarkable considering that patients
in the treatment groups had higher prevalence of comorbidities
including diabetes, immunosuppression state and stroke [12].
The mechanism of action of HCQ against coronavirus is not yet
known, even though the antiviral activity of chloroquine against
flaviviruses, retroviruses, and the first SARS coronavirus (SARS-
CoV) was reported in the early 2000s [13].
Dr. M. Pagliaro
Istituto per lo Studio dei Materiali Nanostrutturati, CNR
via U. La Malfa 153
90146 Palermo (Italy)
Dr. F. Meneguzzo
Istituto per la Bioeconomia, CNR
via Madonna del Piano 10
50019 Sesto Fiorentino FI (Italy)
Preprints ( | NOT PEER-REVIEWED | Posted: 21 April 2020 doi:10.20944/preprints202004.0381.v1
© 2020 by the author(s). Distributed under a Creative Commons CC BY license.
In the following, we summarize achievements in the use of
hydroxychloroquine as an antiviral against COVID-19 as of late
April 2020. We review hypotheses concerning the possible
modes of action, and suggest avenues for the quick scale-up of
production of this valued pharmaceutical substance.
2. Achievements in the treatment of COVID-19
In a 2003 review on the use of chloroquine to treat viral
infections Italy’s scholars raised “the question of whether this old
drug may experience a revival in the clinical management of
viral diseases such as…severe acute respiratory syndrome” [13].
Indeed, the powerful in vitro inhibitory activity of chloroquine
against the first severe acute respiratory syndrome coronavirus
(SARS-CoV) infection and spread activity was reported in 2005
[14], namely less than three years after the outbreak of SARS in
China’s Guangdong province.
Similar evidence of in vitro action of chloroquine against the
second severe acute respiratory syndrome coronavirus (SARS-
CoV-2) was reported by Chinese scholars in early February
2020 [15]. Less than a month later, Raoult and co-workers
reported synergistic effect in vitro of hydroxychloroquine sulfate
(Figure 1) combined with azithromycin [16].
Figure 1. RNA viral quantification between 0 and 60 hours post infection for
azithromycin (A) and hydroxychloroquine sulfate (H) tested alone (A) or in
combination (B) at different micromolar concentration specified by numbers
(A10 = azithromycin 10 µM, and so on). [Reproduced from Ref.16, with kind
Remarkably, the synergy between azithromycin and
hydroxychloroquine wwas observed at concentrations achieved
in vivo and detected in pulmonary tissues. In closer detail, while
the team observed only a moderate effect on viral production for
HCQ at 5 µM (Figure 2A) compared to the positive control, for
the combination of azithromycin and HCQ, they observed
inhibition of viral replication for wells containing HCQ at 5 µM in
combination with azithromycin at 10 and 5 µM (Figure 1B).
Learning about the effective action of the combined therapy,
using blood analysis data obtained between March 13 and
March 23, 2020 from another set of 13 COVID-19 patients on
average 68 years old hospitalized in intensive care unit, scholars
in France recommended a dosage of 800 mg of HCQ once daily
on the first day so as to more rapidly reach therapeutic levels in
patients that otherwise, using the 200 mg three times daily
dosing regimen would fail to reach the therapeutic blood level
of 1-2 mg/L [17]. Simulations used in the same prospective
study to evaluate the pharmacokinetic properties of HCQ in the
aforementioned patients, led the team to suggest that the HCQ
dosing regimen should be optimized on the basis of
pharmacokinetic data available in special populations.
Interestingly, the latter regimen is similar to that used by
Brazilian doctors which led to the marked reduction in the need
for hospitalization when treating 412 symptomatic outpatients
with HCQ and azithromycin, namely HCQ 800 mg day 1,
followed by 400 mg/day for 6 days, plus azithromycin 500
mg/day for 5 days [12].
A first international survey of 6,227 physicians in 30 countries
launched on March 25, 2020 and fielded over three days (25-27
March) found that 37% of those treating COVID-19 patients
rated hydroxychloroquine as the “most effective therapy” from a
list of 15 options [18]. The third survey of 4016 COVID-19
treaters fielded over April 6-9, 2020 [19] found globally a 17%
increase in the share of physicians who have used HCQ (from
33% to 50%) and azithromycin (from 41% to 58%) with the top
three treatments prescribed being azithromycin (58%),
hydroxychloroquine (50%), and bronchodilators (48%) [19].
Overall, HCQ rated second most effective treatment after
plasma and doctors in France (59%), Italy (52%), Spain (50%)
and China (49%) had higher perception of hydroxychloroquine
efficacy [19].
3. Possible modes of action
On late March 2020 chemistry scholars in the USA published the
outcomes of molecular quantum mechanical modeling of the
interaction of hydroxychloroquine and azithromycin to the SARS-
CoV-2 Spike (S)protein - ACE2 complex [20].
Present in endothelial cells, arterial smooth muscle cells, and
most abundant in humans epithelia of the lung and small
intestine, human cell receptor angiotensin converting enzyme II
(ACE2) is the critical receptor for SARS-CoV [21] and also for
SARS-CoV-2 [22] viruses so that, in principle, inhibiting this
interaction with a suitable drug or cocktail of drugs will prevent
and cure the COVID-19 infection.
According to said modeling, HCQ does not bind to ACE2 but
increases its acidity in the interaction between the ACE2 and
SARS-CoV-2 spike thus inducing degradation of the spike and
lowering the virus ability to spread further, whereas azithromycin
directly targets the binding interaction site between the SARS-
CoV-2 spike and ACE2 thanks to high binding affinity [20].
Since the early 2000s several studies, recently summarized by
Chinese scholars [23], have been addressed to investigate the
origins of the antiviral action of chloroquine and HCQ.
Hydroxychloroquine is the first metabolite of chloroquine.
Besides the role of both aminoquinolines as bases raising the
pH within endosomes and lysosomes and interfering with viral
infection, a key role of HCQ is in the inhibition of the production
of three key proinflammatory cytokines (tumor necrosis factor
alpha, interleukin 1, and interleukin 6) produced by the immune
Preprints ( | NOT PEER-REVIEWED | Posted: 21 April 2020 doi:10.20944/preprints202004.0381.v1
system from mononuclear phagocytes in
response to the viral
infection [24, 23, 13].
The latter cytokines have a
primary role in the pathogenesis of
several inflammatory diseases including
rheumatoid arthritis
A vast number of highly oxidant fr
ee radicals are released by
immune cells in reaction to t
hese and other proinflammatory
cytokines causing
acute respiratory distress syndrome and
failure of multiple organs [25],
to prevent and attenuate
Preventing cytokine formation, HCQ
cytokine storm, which
have been implicated in
outcomes of both SARS and COVID-19
infectious disease
Remarkably, also an
other immunosupressant such as
monoclonal antibody tocilizumab has
been used
cytokine storm [27] and severe COVID-19
Industrial supply of hydroxycloroquine
Classified as an essential
medication for a basic healthcare
system, hydroxycloroquine (Figure 2)
is still syn
according to the same route developed in
Hammer [29].
Figure 2. Molecular structure of hydroxychloroquine.
The patent on the compound and the
method of preparation
HCQ as
hydroxychloroquine diphosphate
dichloroquinoline with N'-ethyl-
pentadiamine in the presence of potassium iodide and ph
a temperature of 125-130 °C for >18 h to
eventually obtain
hydroxychloroquine further isolated as
overall yield of 35% [9] has long expired.
a recent study on today’s manufacturing of
hydroxychloroquine sulfate,
aimed to identify needs in case of
urgent scale-
up of its current production levels due to CO
found that Surrey’s route “is sti
ll practiced by a majority of API
suppliers, variants of improvement notwithstanding
manufactured in India,
and to a lesser extent in
and Europe at about 300 tonnes
per year rate
million rheumatoid arthritis and lupus
patients across the world,
HCQ has been historically priced at less
Its multi-step
synthesis epitomizes manufacturing processes in
the fine chemical industry supplying APIs to the pharmaceutical
response to the viral
primary role in the pathogenesis of
rheumatoid arthritis
ee radicals are released by
hese and other proinflammatory
acute respiratory distress syndrome and
which requires the employment of
to prevent and attenuate
cytokine storms.
the possibility of a
have been implicated in
many fatal
infectious disease
s [26].
other immunosupressant such as
been used
both to treat
Industrial supply of hydroxycloroquine
medication for a basic healthcare
is still syn
by Surrey and
method of preparation
hydroxychloroquine diphosphate
by reacting 4,7-
pentadiamine in the presence of potassium iodide and ph
enol at
eventually obtain
salt with an
a recent study on today’s manufacturing of
aimed to identify needs in case of
up of its current production levels due to CO
ll practiced by a majority of API
suppliers, variants of improvement notwithstanding
” [30]. Chiefly
and to a lesser extent in
China, Taiwan
per year rate
to treat about 3
patients across the world,
$150/kg [30].
synthesis epitomizes manufacturing processes in
the fine chemical industry supplying APIs to the pharmaceutical
sector as it takes place in b
atch reactors starting
reactants including 5-
purchased by other fine chemical suppliers
general, the r
eactants used in HCQ synthesis
oil and include substances a
vailable in virtually unlimited
amounts such as
benzene, ethylene, propylene
chlorine and other commodit
y chemicals
Once synthesized and purified
pharmaceutical companies across the world which
commercialize their drugs
containing HCQ as active ingredient
under over one hundred
different brand names [
Figure 3. Semi-continuous
synthesis of
of the oxime obtained via a combination of packed bed
[Reproduced from Ref.32
, with kind permission]
An alternative and
more efficient route
conventional process) mostly
based on flow chemistry was
reported by Gupton and co-
workers in 201
Demonstrated by the team
at a multigram
continuous process
affords the key intermediate
aminopentane (
catalytic hydrogenation of the
oxime quickly obtained via a
combination of packed bed
then reacted in batch with 4,7-
with an isolated yield of 78%.
Outlook and Conclusions
Following the outbreak of COVID
hydroxychloroquine combined
(and zinc sulfate in another experimental therapeutic approach)
emerged in several countries as one of the most
effective treatments for patients.
Especially useful during the early phase of the syndrome
preventing symptomatic
scholars and physicians
including France [1], Brazil [12]
Bahrain [4] and Senegal [33
] reported that
several countries asked India’s
supply of the drug.
India’s government first issued a ban the
export of the drug [10
], and then
the pharmaceutical susbtance t
o over 50 countries
atch reactors starting
from multiple
pentan-2-one and 4,7-
purchased by other fine chemical suppliers
. In
eactants used in HCQ synthesis
are derived from
vailable in virtually unlimited
benzene, ethylene, propylene
, ammonia,
y chemicals
HCQ is supplied to tens of
pharmaceutical companies across the world which
containing HCQ as active ingredient
different brand names [
synthesis of
key intermediate HCQ precursor 5-
through catalytic hydrogenation
of the oxime obtained via a combination of packed bed
flow reactors.
, with kind permission]
more efficient route
(52% yield increase on
based on flow chemistry was
workers in 201
8 [32].
at a multigram
-scale, the new semi-
affords the key intermediate
aminopentane (
12 in Figure 3) through
oxime quickly obtained via a
reactors. The intermediate is
to afford HCQ
Outlook and Conclusions
19 infection due to Sars-CoV-2
hydroxychloroquine combined
with antibiotic azithromycin
(and zinc sulfate in another experimental therapeutic approach)
emerged in several countries as one of the most
Especially useful during the early phase of the syndrome
from being hospitalized,
scholars and physicians
in several countries
[5], Italy [3], South Korea,
] reported that
the treatment was
several countries asked India’s
government the urgent
India’s government first issued a ban the
], and then
lifted the ban starting to supply
o over 50 countries
Preprints ( | NOT PEER-REVIEWED | Posted: 21 April 2020 doi:10.20944/preprints202004.0381.v1
Reports of hydroxycloroquine shortages, with people depleting
stocks at pharmacies in several European, North and South
American and African countries shortly followed, causing
concern [35] for over 3 million patients of malaria, rheumatoid
arthritis, lupus erythematosus and other autoimmune,
inflammatory and dermatologic conditions regularly treated with
HCQ across the world [6].
Three main lessons emerge from findings summarized in this
study reviewing early achievements in the use of
hydroxychloroquine for COVID-19 treatment, its possible modes
of action and commercial supply.
First, quick action of pioneering medical teams from Bahrain to
France to South Korea inspired by reasons of urgency is an
exemplary case of situational leadership in clinical practice [36]
as well as in biomedical research quickly transferring the
outcomes of laboratory research [16] to experimental therapy [1].
In other words, physicians from across the world did not wait for
large randomized double blind placebo control studies, but
quickly acted using well-known and long approved drugs such
as hydroxychloroquine, azithromicyin and zinc sulfate in the
attempt to save lives, thereby honoring their Hyppochratic oath.
Second, policy makers should evaluate the opportunity to
establish Government-owned pharmaceutical production of
essential medicines, most of which today are free from patent
protection such as hydroxychloroquine and azithromicyin, based
on state of the art industrial flow chemistry techniques which
uniquely enable to scale-up production levels without the need
to scale-up production facilities [37].
Indeed, regardless of HCQ being listed amid the essential
medicines for the treatment of rheumatoid disorders in the WHO
Model List of Essential Medicines [38], several countries with no
domestic production of the drug asked India, the world’s leading
production country, to urgently supply the drug. This forced
India’s government first to ban the export of the drug [10], and
then to lift the ban to supply over 50 countries [34].
Third, scholars of all disciplines should embrace the posting of
preprints as a normal communication tool of their research
activity. Also during the ongoing COVID-19 crisis, indeed,
preprints largely emerged as a key resource to immediately
share progress [1,5,12,16,18] on experimental therapy as well
as for potentially therapeutic molecules such as hesperidin
[39,40]. Highly accessed immediately after online publication on
different servers such as research hospital websites and preprint
servers, these studies are already widely cited showing once
again to scholars of disciplines so far reluctant to embrace
preprints such as chemists [41], that the transition to open
science only provides benefits for all.
M.P. thanks Professor B. Frank Gupton, Virginia Commonwealth
University, for useful discussion concerning the semi-continuous
synthesis of hydroxychloroquine. The image of SARS-CoV-2
virus by National Institute of Allergy and Infectious Diseases
retrieved from for the graphics illustrating
this study is reproduced under CC BY license.
Keywords: hydroxychloroquine; COVID-19; immunomodulator;
cytokine storm; flow chemistry
[1] P. Gautret, J. C. Lagier, P. Parola, V. T. Hoang, L. Medded, M.
Mailhe, B. Doudier, J. Courjon, V. Giordanengo, V. Esteves Vieira ,
H. Tissot Dupont, S. Honore, P. Colson, E. Chabriere, B. La Scola,
J. M. Rolain, P. Brouqui, D. Raoult, Hydroxychloroquine and
Azithromycin as a treatment of COVID-19: preliminary results of an
open-label non-randomized clinical trial, medRxiv 2020, DOI:
[2] See at the URL:
[3] E. Shim, South Korea experts recommend anti-HIV, anti-malaria
drugs for COVID-19, UPI, 12 March 2020. See at the URL:
[4] T. Khalid, Bahrain among first countries to use Hydroxychloroquine
to treat coronavirus, Al Arabiya English, 26 March 2020. See at the
[5] V. Zelenko, A Report on Successful Treatment of Coronavirus,
March 23, 2020. See at the URL:
[6] E. Schrezenmeier, T. Dörner, Mechanisms of action of
hydroxychloroquine and chloroquine: implications for rheumatology,
Nat. Rev. Rheumatol. 2020, 16, 155.
[7] Agenzia italiana del farmaco, Determina 17 marzo 2020,
Rimborsabilita' a carico del Servizio sanitario nazionale dei
medicinali clorochina, idrossiclorochina, lopinavir/ritonavir,
danuravir/cobicistat, darunavir, ritonavir per il trattamento anche in
regime domiciliare dei pazienti affetti da infezione da SARS-CoV2
(COVID-19), Gazzetta Ufficiale Serie Generale n.69 del 17-03-
[8] Dr B. S. Cacopardo cited. In: D. De Luca, Farmaco contro la
malaria per combattere il Covid-19? L’infettivologo Cacopardo: «I
primi risultati sono buoni», Meridionews, 27 March 2020. See at
the URL:
[9] A. R. Surrey, 7-chloro-4-[5-(n-ethyl-n-2-hydroxyethylamino)-2-
pentyl] aminoquinoline, its acid addition salts, and method of
preparation, US2546658A, 1950.
[10] Government of India, Ministry of Commerce & Industry, Notification
No.54/2015-2020, New Delhi, 25 March 2020. See at the URL:
[11] Bangladesh Among 13 Nations To Get Anti-Malarial Drug From
India,, April 12, 2020. See at the URL:
[12] R. Barbosa Esper, R. Souza da Silva, F. T. Costa Oikawa, M.
Machado Castro, A. Razuk-Filho, P. B. Batista Junior, S. W. Lotze,
C. Nunes da Rocha, R. de Sá Cunha Filho, S. E. Barbosa de
Oliveira, P. Leitão Ribeiro, V. C. Vigar Martins, F. Silva Braga
Bueno, P. Ligeiro Gonçalves Esper, E. Fagundes Parrillo,
Empirical treatment with hydroxychloroquine and azithromycin for
suspected cases of COVID-19 followed-up by telemedicine,
Dropbox, 2020. See at the URL:
[13] A. Savarino, J. R. Boelaert, A. Cassone, G. Majori, R. Cauda,
Effects of chloroquine on viral infections: an old drug against
today’s diseases?, Lancet Infect Dis. 2003, 3, 722.
[14] M. J Vincent, E. Bergeron, S. Benjannet, B. R. Erickson, P. E.
Rollin, T. G. Ksiazek, N. G. Seidah, S. T, Nichol, Chloroquine is a
potent inhibitor of SARS coronavirus infection and spread, Virology
2005, 2:69.
Preprints ( | NOT PEER-REVIEWED | Posted: 21 April 2020 doi:10.20944/preprints202004.0381.v1
[15] M. Wang, R. Cao, L. Zhang, X. Yang, J. Liu, M. Xu, Z. Shi, Z. Hu,
W. Zhong, G. Xiao, Remdesivir and chloroquine effectively inhibit
the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell.
Res. 2020, 30, 269.
[16] J. Andreani, M. Le Bideau, I. Duflot, P. Jardot, C. Rolland, M.
Boxberger, J. Y. Bou Khalil, J.-P. Baudouin, J.-M. Rolain, P.
Colson, B. La Scola, D. Raoult, In vitro testing of
Hydroxychloroquine and Azithromycin on SARS-CoV-2 shows
synergistic effect, 2020. See at the
[17] S. Perinel, M. Launay, É. Botelho-Nevers, É. Diconne, A. Louf-
Durier, R. Lachand, M. Murgier, D. Page, R. Vermesch, G. Thierry,
X, Delavenne, Towards Optimization of Hydroxychloroquine
Dosing in Intensive Care Unit COVID-19 Patients, Clin. Infect. Dis.
2020, ciaa394.
[18] Sermo, Sermo’s COVID-19 Real Time Barometer Study WAVE I:
March 25-27,, 2020. See at the URL: https://public-
[19] Sermo, Sermo’s COVID-19 Real Time Barometer Study WAVE III:
April 7-9,, 2020. See at the URL: https://public-
[20] S. Sandeep, K. McGregor, Energetics Based Modeling of
Hydroxychloroquine and Azithromycin Binding to the SARS-CoV-2
Spike (S)Protein-ACE2 Complex, ChemRxiv 2020, DOI:
[21] K. Kuba, Y. Imai, S. Rao, H. Gao, F. Guo, B. Guan, Y. Huan, P.
Yang, Y. Zhang, W. Deng, L. Bao, B. Zhang, G. Liu, Z. Wang, M.
Chappell, Y. Liu, D. Zheng, A. Leibbrandt, T. Wada, A. S. Slutsky,
D. Liu, C. Qin, C. Jiang, J. M. Penninger, A crucial role of
angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-
induced lung injury, Nat. Med. 2005, 11, 875.
[22] V. Monteil, H. Kwon, P. Prado, A. Hagelkrüys, R. A. Wimmer, M.
Stahl, A. Leopoldi, E. Garreta, C. Hurtado del Pozo, F. Prosper, J.
P. Romero, G. Wirnsberger, H. Zhang, A. S. Slutsky, R. Conder, N.
Montserrat, A. Mirazimi, J. M.Penninger, Inhibition of SARS-CoV-2
infections in engineered human tissues using clinical-grade soluble
human ACE2, Cell 2020, DOI: 10.1016/j.cell.2020.04.004.
[23] D. Zhou, S.-M. Dai, Q. Tong, COVID-19: a recommendation to
examine the effect of hydroxychloroquine in preventing infection
and progression, J. Antimicrob. Chemoth. 2020, dkaa114.
[24] C.-H. Jang, J.-H. Choi, M.-S. Byun, D.-M. Jue,
Chloroquine inhibits
production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated
human monocytes/macrophages by different modes
, Rheumatology
2006, 45, 703.
[25] J. R. Tisoncik, M. J. Korth, C. P. Simmons, J. Farrar, T. R. Martin,
M. G. Katze, Into the eye of the cytokine storm, Microbiol. Mol. Biol.
Rev. 2012, 76, 16.
[26] Q. Ye, B. Wang, J. Mao,The pathogenesis and treatment of the
‘Cytokine Storm’ in COVID-19, J. Infect. 2020, DOI:
[27] E. M. Behrens, G. A. Koretzky, Review: Cytokine Storm
Syndrome: Looking Toward the Precision Medicine Era, Arthritis
Rheumatol. 2017, 69, 1135.
[28] X. Xu, M. Han, T. Li, W. Sun, D. Wang, B. Fu, Y. Zhou, X. Zheng,
Y. Yang, X. Li, X. Zhang, A. Pan, H. Wei,
Effective Treatment of
Severe COVID-19 Patients with Tocilizumab, ChinaXiv:
[29] A. R. Surrey, H. F. Hammer,
The Preparation of 7-Chloro-4-(4-(N-
ethyl-N-β-hydroxyethylamino)-1-methylbutylamino)-quinoline and
Related Compounds, J. Am. Chem. Soc. 1950, 72, 1814.
[30] T. Y. Zhang, B. Zhong, Meeting the Potential Emergency Global
Drug Supply Challenge of Hydroxychloroquine for COVID-19, Med.
Drug Discov. 2020, DOI: 10.1016/j.medidd.2020.100036.
[31] An active pharmaceutical ingredients online database listed more
than 100 hydroxychloroquine trade names as of late April 2020.
See at the URL: https://drugs-
[32] E. Yu, H. P. R. Mangunuru, N. S. Telang, C. J. Kong, J. Verghese,
S. E. Gilliland III, S. Ahmad, R. N. Dominey, B. F. Gupton, High-
yielding continuous-flow synthesis of antimalarial drug
hydroxychloroquine, Beilstein J. Org. Chem. 2018, 14, 583.
[33] Dr M. Seyd cit. In: C. Cuordifede, "Nous constatons une guérison
plus rapide" : Moussa Seydi, le médecin sénégalais qui s'est
inspiré des travaux de Didier Raoult, Marianne, April 1, 2020. See
at the URL:
[34] R. H Laskar, Covid-19: India approves supply of
hydroxychloroquine to 55 countries as commercial sales or grants,
Hindustan Times, 16 April 2020.
[35] B. Mehta, J. Salmon, S. Ibrahim, Potential Shortages of
Hydroxychloroquine for Patients with Lupus During the
Coronavirus Disease 2019 Pandemic, JAMA Health Forum 2020,
1, e200438.
[36] M. A. van der Wal, F. Scheele, J. Schönrock-Adema, A. D. C.
Jaarsma, J. Cohen-Schotanus, Leadership in the clinical
workplace: what residents report to observe and supervisors report
to display: an exploratory questionnaire study, BMC Med. Educ.
2015, 15:195.
[37] R. O. M. A. de Souza, P. Watts, Flow processing as a tool for API
production in developing economies, J. Flow Chem. 2017, 7, 146.
[38] World Health Organization, Model List of Essential Medicines, 18
list, Geneva: 2013. See at the URL:
[39] R. Y. Utomo, M. Ikawati, E. Meiyanto, Revealing the Potency of
Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection,
Preprints 2020, DOI: 10.20944/preprints202003.0214.v1.
[40] F. Meneguzzo, R. Ciriminna, F. Zabini, M. Pagliaro, Accelerated
Production of Hesperidin-rich Citrus Pectin from Waste Citrus Peel
for Prevention and Therapy of COVID-19, Preprints 2020,
[41] P. Demma Carà, R. Ciriminna, M. Pagliaro, Has the time come for
preprints in chemistry?, ACS Omega 2017, 2, 7923.
Preprints ( | NOT PEER-REVIEWED | Posted: 21 April 2020 doi:10.20944/preprints202004.0381.v1
Preprints ( | NOT PEER-REVIEWED | Posted: 21 April 2020 doi:10.20944/preprints202004.0381.v1
... The increasing shortage of APIs, especially of generics, in many developed and developing countries culminated with shortage of hydroxychloroquine (HCQ) used to treat COVID-19 patients. Such situation , which in early 2020 led India to dramatically scale up production for donating the drug to more than 50 countries, 31 has made clear that countries cannot rely any longer on API and fine chemical imports. ...
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The outcomes of the present scientometric analysis of research in catalysis provide chemistry and catalysis scholars with a closer bibliometric knowledge of an old and central field of chemical research which is being reshaped by fundamental and technological advances spanning from single-atom heterogeneous catalysis to flow chemistry. Improving and widening research and education in catalysis is a strategic need for national economies. Four research policy guidelines aimed at fostering progress in catalysis research and education conclude the study.
The limited time indorsed to face the COVID-19 emergency and large number of deaths across the globe, poses an unrelenting challenge to find apt therapeutic approaches. However, lead candidate selection to phase III trials of new chemical entity is a time-consuming procedure, and not feasible in pandemic, such as the one we are facing. Drug repositioning, an exploration of existing drug for new therapeutic use, could be an effective alternative as it allows fast-track estimation in phase II–III trials, or even forthright compassionate use. Although, drugs repurposed for COVID-19 pandemic are commercially available, yet the evaluation of their safety and efficacy is tiresome and painstaking. In absence of any specific treatment the easy alternatives such as over the counter products, phytotherapies and home remedies have been largely adopted for prophylaxis and therapy as well. In recent years, it has been demonstrated that several pharmaceutical excipients possess antiviral properties making them prospective candidates against SARS-CoV-2. This review highlights the mechanism of action of various antiviral excipients and their propensity to act against SARs-CoV2. Though, repurposing of pharmaceutical excipients against COVID-19 has the edge over therapeutic agents in terms of safety, cost and fast-track approval trial burdened, this hypothesis needs to be experimentally verified for COVID-19 patients.
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Cytokine storm is an excessive immune response to external stimuli. The pathogenesis of the cytokine storm is complex. The disease progresses rapidly, and the mortality is high. Certain evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patients has been closely related to the cytokine storm in their bodies. This article reviews the occurrence mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.
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This paper provides an overview of the current global market and manufacturing landscape for hydroxychloroquine (HCQ). The capacity and capabilities of global producers to meet the potential demand for treating patients inflicted with COVID-19 by the novel corona virus SARS-CoV-2, should HCQ's efficacy be established by more definitive clinical trials, is also assessed. Given the large existing manufacturing base and abundance of raw materials for HCQ, the supply challenge can be met with considerable efforts and international cooperation. Preemptive and coordinated emergency efforts among global governments, regulatory agencies, chemical and pharmaceutical industries are imperative for meeting the surge in demand.
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Computational studies suggest that hesperidin, a flavonoid abundant in citrus peel, binding the three main cellular receptors of SARS-CoV-2 virus can act in the prophylaxis and treatment of COVID-19. Herein we urge the uptake of hydrodynamic cavitation industrial-scale reactors based on the low cost, reliable Venturi tube for the extraction of citrus pectin rich in hesperidin (and in other bioflavonoids including naringing) by very fast processing of waste orange peel or waste lemon peel in water only. A device able to process up to 500 kg of waste peels per session, similar to the one lately deployed in Italy for hydrodynamic cavitation-assisted brewing, is capable to provide 36,000 doses of 1000 mg hesperidin per day.
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The use of hydroxychloroquine to aid in the disruption of the SARS-CoV-2 virus and to cure or at least treat the COVID-19 disease is recently being reviewed in various clinical trials worldwide, but with insufficient examination of the binding of human ACE2 to the viral spike. In order to understand and assess the efficacy of the drug or drug combination, this paper looks at the effect of the pharmaceutical drug hydroxychloroquine, as well as a common co-drug, azithromycin, on the SARS-CoV-2 spike-ACE2 complex by using virtualized quantum mechanical modeling to better characterize binding sites on the complex, assess the binding between these sites and the drug compounds, and enhance community PDB files. <br
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COVID-19 pandemic is a serious problem in the world today. The SARS-CoV-2 virus that causes COVID-19 has important proteins used for its infection and development, namely the protease and spike glycoprotein. The RBD (Receptor Binding Domain) of spike glycoprotein (RBD-S) can bind to the ACE2 (Angiotensin Converting Enzyme-2) receptor at the protease domain (PD) (PD-ACE2) of the host cell, thereby leading to a viral infection. This study aims to reveal the potential of compounds contained in Curcuma sp., Citrus sp., Alpinia galanga, and Caesalpinia sappan as anti SARS-CoV-2 through its binding to 3 protein receptors. The study was conducted by molecular docking using the MOE 2010 program (licensed from Faculty of Pharmacy UGM, Indonesia). The selected protein targets are RBD-S (PDB ID:6LXT), PD-ACE2 (PDB ID: 6VW1), and SARS-CoV-2 protease (PDB ID:6LU7). The affinities of bonds formed is represented as a docking score. The results show that hesperidin, one of the compounds in Citrus sp., has the lowest docking score for all three protein receptors representing the highest affinity to bind the receptors. Moreover, all of the citrus flavonoids possess good affinity to the respected receptors as well as curcumin, brazilin, and galangin, indicating that those compounds perform inhibitory potential for the viral infection and replication. In general, the results of this study indicate that Citrus sp. exhibit the best potential as an inhibitor to the development of the SARS-CoV-2, followed by galangal, sappan wood, and Curcuma sp. that can be consumed in daily life as prophylaxis of COVID-19.
We have previously provided the first genetic evi- dence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 pro- tects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 in- fections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000–5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS- CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
Hydroxychloroquine (HCQ) appears to be a promising treatment for COVID-19. However, all ongoing clinical trials with HCQ use different dosing regimens, resulting on various concentrations PK studies are therefore needed to define the optimal dosing regimen.
A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.
BACKGROUND Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. PATIENTS AND METHODS French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. RESULTS Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. CONCLUSION Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.