Potential Drugs for the Treatment of COVID-19:

Synthesis, Brief History and Application

Ekhlass Uddin1, Raisul Islam1, Ashrafuzzaman1, Nur Amin Bitu1, Md.Saddam Hossain2,
ABM Nazmul Islam3, Ali Asraf1, Faruk Hossen1, Ranjan K Mohapatra4, Md.Kudrat-E-
Zahan1*
1
Department of chemistry, Rajshahi University, Rajshahi 6205, Bangladesh.
2
Department of Chemistry, Begum Rokeya University, Rangpur, Bangladesh.
3
Chemistry Discipline, Khulna University, Khulna-9208, Bangladesh
4
Department of Chemistry, Government College of Engineering, Keonjhar, Odisha, India

*
Corresponding Author: Professor, Department of Chemistry, Rajshahi University,
Bangladesh. Email: kudrat.chem@ru.ac.bd
E-mail adresses of the contributing authors:
EU: ekhlassuddin@gmail.com
RI: raisul.chem@gmail.com
AF: ashrafchem568@gmail.com
NAB: nabitu.ru@gmail.com
MSH: saddamru4535@gmail.com
ANI: nazmulchem@ku.ac.bd
AA: asraf.chem@ru.ac.bd
FH: fhossen.chem@ru.ac.bd
RKM: ranjank_mohapatra@yahoo.com
KZ: kudrat.chem@ru.ac.bd

Abstract
Coronaviruses (CoVs) belong to the Betacoronavirus group, an unusually large RNA
genome, are characterized by club-like spikes that project from their surface. An outbreak of
a novel coronavirus 2019 (nCOVID-19) already showed a unique replication strategy and
infection has posed significant threat to international health and the economy around the
globe. Scientists around the world are investigating few previously used clinical drugs for the
treatment COVID-19. This review provides synthesis and mode of action of recently
investigated drugs like Chloroquine, Hydroxychloroquine, Ivermectin, Selamectin,
Remdesivir, Baricitinib, Darunavir, Favipiravir, Lopinavir/ritonavir and Mefloquine
hydrochloride that constitute an option for COVID-19 treatment.

Graphical abstracts

Cholroquine
Hydroxychloroquine
Remdesivir
Favipiravir
Interferring with the
FDA
glycosylation
approved
of cellular receptors

Interferring with the

Ivermectin Investigational
reproduction of RdRp

Interferring with the FDA

viral replication approved
Interferring with the
viral entry of
endocytosis regulators
Barictinib
FDA
SARS-CoV-2
approved
Interferring with the
viral load reduced
cytopathic effect
Investigational
Selamectin FDA Interferring with the
Mefloquine approved virus replication

Interferring with the Japan

Lopinavir
viral entry approved
Ritonavir
Darunavir
Camostat
mesylate

The potent antiviral drugs for targeting COVID-19 treatment

Keywords: Coronavirus; nCOVID-19; Drug synthesis; Antiviral therapies; Pandemic disease

List of abbreviations:
Coronaviruses (CoVs)
Chloroquine (CQ)
Hydroxychloroquine (HCQ)
Alkylated 4-aminoquinolines (4AQs)
Cepharanthine (CEP)
AP2-associated protein kinase 1 (AAK1)
Darunavir (DRV)
Favipiravir (FPV)
Lopinavir (LPV)
mefloquine hydrochloride (MFH)
1. Introduction
Coronaviruses (CoVs) are named so because of their crown-like structure (Latin word
“corona” means crown or “halo”) [1-3]. According to the characteristics of serotype and
genome, the coronavirus subfamily is divided into four genera: α, β, γ and δ [4].
Coronaviruses (CoVs) can cause respiratory illnesses in humans and gastrointestinal illnesses
in animals. World Health Organization (WHO) has recognized COVID-19 as a pandemic on
March 11th 2019, caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus
2) [5, 6]. Generally, previous knowledge in pandemics help to take treatment strategies
against a new pandemic. We urgently need to investigate an effective vaccine for the
treatment of the COVID-19, although the first human coronaviruses were pointed out in the
1960s. Specially, people living in under developing country is at risk of severe COVID-19
disease, either because of consciousness or an underlying health condition due to malnutrition
or lack of proper treatment facilities. The risk of this virus infection will remain for a long
time. On this basis, many groups are working to find an alternative strategy to control the
replication and spreading of the virus. Recently, few drugs have shown promising results to
fight against COVID-19 [2, 7-9]. We have explored different scientific databases searching
for the most promising options for the treatment of COVID-19 and provide an overview of
our findings. We are going to review the synthesis of few drugs which are already approved
or under clinical trial, their brief history and application.
2. Synthesis, brief history and application of drugs for the treatment of COVID-19
2.1 Chloroquine and Hydroxychloroquine:
Chloroquine (CQ) is well known as a first-line drug for the treatment and prevention of
malaria and is one of the most established drugs globally [10]. Chloroquine and its analogue
hydroxychloroquine (HCQ) (Figure 1) both are organic compounds as well as alkylated 4-
aminoquinolines (4AQs) [11, 12]. Also, these drugs are soluble in water but chloroquine is
less soluble than hydroxychloroquine [13]. Chloroquine is less polar, more lipophilic and has
less difficulty diffusing across cell membranes [12, 14, 15].
 Figure 1: Structure of Chloroquine and Hydroxychloroquine.
Chloroquine was first synthesized in 1934 by Hans Andersag [16]. He condensed m-
chloroaniline with oxaloacetic acid diethylester and then steps; saponification and thermal
decarboxylation as well as the reaction with POCl3 were performed to form chloroquine
(Figure 2).

Figure 2: Synthesis of chloroquine by Andersag

Conversely, hydroxychloroquine was synthesized in 1946 and suggested as a better
alternative to chloroquine in 1955 [17]. The historical developmental pathways of
hydroxychloroquine from methylene blue is shown in Figure 3 [18].
 Figure 3: Synthetic pathways of Hydroxychloroquine.
However, chloroquine (CQ) and hydroxychloroquine (HCQ) have been used for the treatment
of malaria since the1940s and also for the remedy of rheuma-toid arthritis, systemic lupus
erythematosus , immunological, infectious and other autoimmune diseases since 1950s [18,
19]. HCQ and QC have the same mechanisms of action as a weak base to prevent malaria,
viruses, and autoimmune conditions , in spite of this HCQ was found to be much less ( about
40%) harmful than CQ [20, 21]. In addition, HCQ has been displayed to have an anti-SARS-
CoV activity in vitro [22]. Chloroquine and hydroxychloroquine have been recommended as
possible drugs for the treatments of COVID-19. Shortly, at least 80 trials of chloroquine,
hydroxychloroquine, or both, sometimes in combination with other drugs, are approved
worldwide. [23, 24].
2.2 Ivermectin:
Ivermectin (Figure 4) was introduced in 1981 by William C. Campbell and Satoshi Omura
and received the Noble Prize in Medicine for their discovery and isolation [25]. At room
temperature, Ivermectin has the form of yellow or light crystalline hygroscopic powder and
photosensitive in polar solvents [26]. It is not soluble in water but soluble in organic solvents
like methanol, ethanol and acetone [27]. Ivermectin is a drug mainly used in veterinary to
treat animals and in humans it is used to treat scabies, river blindness, elephantiasis and
rosacea [28-30].

Figure 4: Chemical structure of Ivermectin.

Ivermectin is synthesized (Figure 5) from avermectin by adding two hydrogen atoms to
reduce a C=C bond using hydrogen gas with Wilkinson’s catalyst, RhCl(PPh3)3 [31].

Figure 5: Synthesis route of Ivermectin.

Finny S. Varghese et al. reported the potency of Ivermectin and it is considered to be an
antiviral agent against the Chikungunya and yellow fever [32]. It inhibits the replication of
SARS-CoV-2 in monkey kidney cell culture with an IC50 of 2.2 - 2.8 µM making it more
potential for COVID-19 drug research [33, 34]. The doses used in cell culture showed the
deviation of an effective treatment for COVID-19 in humans [35]. Moreover, the cell culture
experiments also exhibited the expectancy for treating Dengue but failed in animals [36].
Food and Drug Administration (FDA) approved Ivermectin for the treatment of COVID-19 in
humans on April 2020 and which is under development [37].
2.3 Selamectin:
Selamectin is an interim and anthelmintic parasiticide that controls many ecto- and
endoparasites on pets such as cats, dogs and red pandas etc. It is effective against fleas and a
range of mites [38-41]. B.F. Bishop et al. showed the isopropyl alcohol based structure of
Selamectin (Figure 6). The compound is not miscible in water [42]. Again, it shows the
significant physicochemical characteristics to the host for preventing infections having no
toxic side effects at low concentration [43, 44].

Figure 6: The chemical structure of Selamectin.

The synthesis of Selamectin (Figure 7) was assessed for the commercial viability of
monosaccharides with C-5-oximes by B. J. Banks et al. [42]. Over and above, the unique
properties of Selamectin make it more potent and less-time consuming remissive than other
analogous parasiticide [45, 46]. It exhibited the noteworthy antibacterial potential in vitro
against Mycobacterium ulcerans due to strong pharmacological properties [47]. After all, the
macrocyclic lactone selamectin has shown its availability on an average seven years and
established the potential spot-on treatment for endo- and ectoparasites most likely for cats
and dogs [48, 49].

In May 5, 2020, it is recommended that selamectin along with cepharanthine (CEP) and
mefloquine hydrochloride can be a potential drug for treating 2019-nCoV infection [50].
They have used these drugs against 2019-nCoV-related pangolin coronavirus GX_P2V to
identify drug candidates for treating COVID-19 infection. The spike protein of coronavirus
GX_P2V is very similar (amino acid identity; 92.2%) with that of 2019-nCoV. These drugs
showed remarkable inhibition of cytopathic effects in cell culture at 10 µmol/L.
 Figure 7: Preparation of Selamectin.

2.4 Remdesivir
Remdesivir (RDV, with a development code GS-5734) (Figure 8) is a phosphoramidate
prodrug, an antiviral drug and also a novel adenosine analog drug that acts as an RNA-
dependent RNA polymerase (RdRp) restraint [51-54]. Besides, RDV is an investigational
drug that exhibits antiviral activity against a series of viruses including; middle east
respiratory syndrome coronavirus [MERS-CoV], SARS-CoV, Ebola virus, Marburg virus,
respiratory syncytial virus (RSV), Hendra virus, Junin virus and Lassa fever virus. Moreover,
this compound displayed strong antiviral activity against Nipah virus [55-59].
 Figure 8: Chemical structure of Remdesivir.

At the beginning, RDV was synthesized and developed by Gilead Sciences in 2017 as the
therapatic agent for the treatment of Ebola and Marburg virus disease but was an inefficient
drug against these viral diseases [60, 61]. The synthesis of Remdesivir was done successively
in several steps and synthetic pathways were developed by Chun and coauthors from Gilead
Sciences [62], the steps as follows (Figure 9). At present, Remdesivir is being checked out as
a candidate for the treatment of COVID-19 [63-65].

Remdesivir is suggested on a compassionate-use basis to patients hospitalized with COVID-

19. Clinical improvement is observed in 36 of 53 patients (68%) after treating with
Remdesivir [66]. In-vitro investigation showed that remdesivir can inhibit coronaviruses such
as MERS-CoV and SARS-CoV replication. In an in-vitro test utilizing epithelial cell cultures
of a primary human airway, remdesivir was effective against prepandemic Bat-CoVs, Bat-
CoVs, and circulating contemporary human-CoV in primary human lung cells[67, 68].
Figure 9: Synthetic routes of Remdesivir.
2.5 Baricitinib:
Baricitinib (Oluminant) (Figure 10) is used as a drug fundamentally for the handling of
rheumatoid arthritis (RA), atopic dermatitis and systemic lupus erythematosus and also acts
as an oral, selective, reversible and an ATP competitive kinase inhibitor of Janus kinase 1
(JAK1) and Janus kinase 2 (JAK2) but it has nether effectivity against Tyk2, JAK3, c-MET
and Chk2 kinases [69-74]. As well, it has potent antiviral, anti-inflammatory activity and
high affinity for AP2-associated protein kinase 1 (AAK1) [75]. Additionally, it is an aromatic
polyheterocyclic and poorly permeable compound which is more soluble in organic solvents
but badly soluble in water and ethyl alcohol [76]. This drug has been approved to use for the
treatment of RA first in Europe, then in the United States of America, Japan as well as in
other countries and also the European Medicines Agency approved it for application in 2017
[77-80].

Figure 10: Chemical structure of Bariticinib

There are two routes for the synthesis of bariticinib. Rodgers et al. have described the first
synthetic route of bariticinib (Figure 11) [81]. The reactions were performed to produce
bariticinib through the Horner–Emmons reaction, deprotection of the N-Boc group, a
sulfonamidation reaction, a nucleophilic addition reaction and then a Suzuki coupling
reaction and a hydrolysis reaction where tert-butyl 3-oxoazetidine-1-carboxylate (1) and 4-
chloro -7H-pyrrolo[2,3-d]pyrimidine (5) were used as the starting materials.
 Figure 11: The reported synthetic route to bariticinib.

This synthetic pathway was highly expensive with very low yield and hard operating
conditions. As a result, the method was developed to obtain a better product. Besides, a novel
synthetic route for the synthesis of baricitinib was done as follows in Figure 12.
 Figure 12: The novel synthetic route to baricitinib
The overall yield of this procedure was 49%. Furthermore, this procedure has very easy
operating requirements and not costly and is appropriate for industrial production [81]. With
the emergence of the novel human respiratory coronavirus known as SARS-CoV-2, COVID-
19, we require effective and available therapeutic drugs to halt the current pandemic. Several
studies suggested utilizing bariticinib for the medication of SARS-CoV-2 infections and this
drug is predicted to diminish the capability of virus to affect lung cells. Additionally, this
drug has antiviral activity and also it lessens SARS-CoV-2 endocytosis [82-85].

2.6 Darunavir
Darunavir (DRV; formerly known as, TMC-114) the advanced protease inhibitor (PI) [86],
was the outcome of unique research and development program that declared it (DRV) as an
effective drug by the evaluation of antiviral activity after several thousand clinical trials [87].
First clinical upliftment of DRV was administrated by Tibotec-Virco, Belgium and US Food
and Drug Administration (FDA) and approved it (Figure-13) as potential candidate of PIs for
the treatment of HIV patients in 2006 [88-90]. Improved activity of darunavir caused by the
high binding affinity due to slow dissociation rate [91], responsible for sustained virological
suppression as compared to other PIs [92].

Figure 13: Structure of Darunavir

Rajesh Kumar Rapolu et al. reported an advanced and novel method of Darunavir drug
synthesis procedure by utilizing 4-(1,3-dioxoisoindolin-2-yl)benzene-1-sulphonyl chloride
intermediate, owing to eliminate the possible critical furan dimer impurity [93]. Reaction
conditions and reagents have been mentioned in Figure -14 and 15 and this method provides
more than 90% pure compound.

Figure 14: Preparation of sulphonyl chloride intermediate

 Figure 15: Synthesis of Darunavir
Darunavir (TMC114) is an off white powder in physical appearance with appreciable water
solubility (0.15 mg/mL at 20 °C ), has been licensed for the treatment against both wild-type
and multidrug-resistant viruses [87, 94]. In vitro studies of darunavir has demonstrated high
class of efficiency against wild-type HIV-1 and HIV-2, with an EC50 value of 1 to 5 nM and
an EC90 of 2.7 to 13 nM, without any sort of cytotoxicity at concentrations up to 100 µM
[95]. Moreover, studies have advocated that darunavir has revealed extensive commutations
in plasma HIV-RNA (below 50 copies/mL) and increased in CD4 counts over the active
controls in patients with significant PI resistance [96]. Furthermore, Darunavir co-
administered with ritonavir 600/100 mg twice daily has found to be safe, tolerable, with
immunological benefits [89, 97]. This drug works by selectively inhibiting the cleavage sites
of HIV-1-encoded Gag-Pol polypeptides (at the position of 167 and 168) in infected cells,
thereby preventing the formation of mature infectious virus, HIV-1 particles [98]. Recently,
Darunavir formulated with cobicistat (Darunavir/cobicistat) has been subjected to clinical
trials to treat Pneumonia caused by COVID-19 over 30 participants, which was sponsored by
Shanghai Public Health Clinical Center, China [99]. Efficiency of Darunavir in that case still
on investigation due to some limitations.
2.7 Favipiravir:
Favipiravir introduced as T-705 (trade name: AVIGAN), is a novel RNA dependent RNA
polymerase inhibitor having broad spectrum antiviral potency dispensed for the treatment of
new and recurrent influenza developed by Japan Toyama Chemical Co., Ltd [100, 101]. The
tautomeric structures of favipiravir (Figure 16) favor the mechanistic stabilization energy for
the required complex formation in accordance with the phase viability [102, 103]. T-705 is a
potent mutagenic agent possessed low toxicity [104, 105], high fluidity [106] and auspicious
sensitivity [107] to the significant literature on cell membranes.

Figure 16: The tautomeric structures of favipiravir represented by the H atom

movement.
Qi Guo et al. prepared the better and facile synthetic route of favipiravir (Figure 17) from the
first accessible root material, 2-aminopyrazine explored the allergy-causing dichloro
intermediate [108].
 Figure 17: The synthetic approach to favipiravir in the preferred route.
Favipiravir (FPV) has shown to reduce mortality against Ebola virus during the 2014 West
Africa Ebola virus outbreak [109]. It also showed in vitro activity against Influenza virus
[110], Rift Valley fever virus [111], Bourbon virus [112], Hantavirus [113], Poliovirus [114],
Chikungunya virus [115], Phlebovirus [116], Juninvirus [117], Rabiesvirus [118], and
Arenavirus [119]. Further, it has been used to relieve respiratory symptoms, fever, cough,
dyspnea and pneumonia for the current worldwide outbreak of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2). FPV has begun conducting clinical trials to be a
more likely potent drug against COVID-19 reported by Yin-Xiao Du et al.[120]. It was
approved as an experimental treatment for COVID-19 and exhibited promising mild to
moderate cases of infections [121].

2.8 Lopinavir/ritonavir
With the development of highly active antiretroviral therapy (HAART), the overall life
expectancy of HIV-infected patients has greatly improved since morbidity and mortality
related to HIV significantly continues to attenuate [122]. Lopinavir (LPV) is a protease
inhibitor (PIs) formulated with Ritonavir (RTV) is highly effective component of HAART
regimens for HIV-1 infection ascertained by several clinical trials [123]. Lopinavir/ritonavir
(LPV/r, Kaletra ), uniquely developed by Abbot Laboratories (AL, USA) (Figure 18), was
approved for development in December of 1995 and FDA approve for sale in September of
2000 [124-127].
 Figure-18: Structure of lopinavir and Ritonavir
Coupling of vaniline with phenylchloroformate to produce carbamate derivative was the
preliminary step of lopinavir synthesis initiated from the Abbott Laboratories (USA) [128].
The derivative was subsequently treated with 3-chloropropylamine and NaOH followed by t-
BuOK to produce the target acid, A (Figure 19).

Figure 19: Intermediate product in the synthesis of lopivarin

Obtained acid product was then treated with thionyl chloride in THF to convert into
corresponding acid chloride for coupling with the hydroxyethylene isostere. Coupling with
isostere was accomplished using three equivalents of imidazole in ethyl acetate and
dimethylformamide followed by subsequent debenzylation under transfer hydrogenation
conditions. Obtained crude product crystalized with 2-pyrrolidone-5-carboxylic acid (L-
pyroglutamic acid) for purification (pure up to 80%) (Figure 20).
 Figure 20: Intermediate product in the synthesis of lopivarin
Final synthesis step has been illustrated in Figure 21 and this process provide 89% yield
along with 99% purity end of recrystallization.

Figure 21: Synthesis of lopivarin

Synthesis of HIV protease inhibitor has been reported by H. L. Sham et al [129]. Interaction
of the cyanomethyl ketone with a Grignard reagent to give the corresponding enaminone was
the key reaction, for benzyl Grignard yield become 94%. On the contrary, yield ranged from
81-92% for alkyl Grignards. Reduction of enamione followed by the amines protection,
catalytic debenzylation, coupling with 2,6-dimethylphenoxyacetic acid and removal of
protecting agent have been included in Figure-22 & 23.

Figure 22: Synthetic scheme for the core unit, R= benzyl, butyl, isopropyl, isobutyl
 Figure 23: Reduction of enaminone and synthesis of lopinavir

The synthesis route of lopinavir has been elucidated by Ambati V et al. In this process
(2S,3S,5S)-5-Amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol has (2) activated with N,N-
carbonyldiimidazole through the condensation with (2S)-3-methyl-2-(2-
oxotetrahydropyrimidin-1(2H)-yl)butanoic acid (3) in order to formulate (2S)-N-[(2S,4S,5S)-
5-(dibenzylamino)-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-
(2oxotetrahydropyrimidin-1(2H)-yl)butanamide (4). Compound 4, followed by debenzylation
in the presence of ammonium formate and palladium on charcoal, to give (2S)-N-
[(2S,4S,5S)-5-amino4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-
oxotetrahydropyrimidin-1(2H)-yl)butanamide (5). Compound 5, was further allowed to react
with L-pyroglutamic acid , gave pure (2S)-N[ (2S,4S,5S)-5-amino-4-hydroxy-1,6-
diphenylhexan-2-yl]-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide (S)-
pyroglutamic acid salt 6. Finally, compound 6 was condensed with (2,6-
dimethylphenoxy)acetic acid to obtain lopinavir (Figure-24) . lopinair was obtained from the
above synthesis procedure has purity of 99.5% [130].
Figure 24: Synthesis of Lopinavir and conditions (a) N,N-Carbonydimidazole, ethylacetate;
(b) ammonium formate, palladium on charcoal, methanol; (c) L-pyroglutamic acid, acetone,
DMF; (d) 2,6-dimethylphenoxyaceticacid, thionyl chloride, dichloromethane

Combination of Lopinavir-ritonavir (LPV/r, Kaletra), enriched with supreme potency,

resistive genetical barrier, able to diminish HIV replication [131], enhanced and sustained
plasma levels [132] and has become an effective candidate for HIV treatment. LPV/r,
monotherapy for HIV-HCV coinfected patients declared as safe and effective than
nucleoside-containing HAART regimens [133].Tolerability and potency has been
documented by A. Hermes et al for women infected with HIV-1 based on LPV/r antiviral
therapy with auspicious outcome regardless of age and body mass index [134].
Administration of LPV/r twice daily (400 mg LPV and 100mg RTV) prolonged protein
binding-corrected concentration about to 75 times needed to inhibit 50 percent replication of
wild type HIV and >100-fold increased area under the plasma concentration-time curve
(AUC) [135-137]. Lopinavir, in the form of prodrugs has advanced bioavailability due to
better solubility, metabolism incorporatd with intestinal permeability that augmented the
effect on both the drug delivery and therapeutic efficiency in HAART [138]. Rosario Palacios
et al. have predicted that HIV patients co-infected with Hepatitis C or B (HBV/HCV) treated
with LPV/r has a risk of hepatotoxicity less than 10% [139]. Apparently, kaletra show
significant virologic and immunologic response to the patients were severely antiretroviral
pretreated [140]. Precisely, it considered as a prominent substitution of nucleoside reverse
transcriptase inhibitors (NRTIs) on the basis of durability [141], moreover it has no adverse
impact on patients glucose metabolism [142]. Lopinavir/ritonavir, HIV protease inhibitor has
been taken under multiple trials for COVID-19 treatment in comparison with other drugs [99,
143].
Very recently, May 7, 2020, it is disclosed that lopinavir–ritonavir treatment did not
significantly accelerate clinical improvement, lessen mortality, or diminish throat viral RNA
detectability in patients with severe Covid-19 [144]. They recommend to further studies to
assess these drugs for the treatment of infection with SARS-CoV-2. Combining lopinavir–
ritonavir with other antiviral drugs has been used in SARS[145, 146] and is also investigated
in MERS-CoV[147] and enhanced antiviral effects. Some other reports shows that
lopinavir/ritonavir was can reduce viral loads and improved clinical symptoms during the
treatment. Thus, lopinavir/ritonavir can be suggested to comparatively high-risk groups of
COVID-19 pneumonia (aged patients or patients with underlying diseases) from the early
stage [148-150]. At the same time, they recommend to get more evidence to prove the
clinical efficacy of lopinavir/ritonavir based on well controlled clinical trials.

2.9 Mefloquine hydrochloride

Malaria is one of the most important infectious diseases in the world. Thereby, mefloquine
hydrochloride (MFH) established in the 1970s, is used to relieve malaria on cell membrane
[151]. Thiago Eichi Goto et al. proposed the chemical conformation of MFH (Figure 25)
possesses the significant criteria such as polarity, neutrality etc. varied with pH confirmed it
as a curative drug for malaria medication [152]. The drug is a white crystalline compound
and slightly soluble in water [153]. This quinoline derivative is a racemic mixture of 2-
erythro enantiomers whose differential parameters involved in absorption, transportation,
degradation and elimination [154-156].
 Figure 25: Chemical structure of the antimalarial agent mefloquin hydrochloride.

M. Suresh Kumar et al. prepared a convenient and facile synthesis (Figure 26) of mefloquine
hydrochloride from the condensation of 2,8-bis(trifluoromethyl)-4-bromoquinoline with p-
toluenethiol in presence of potassium hydroxide and chloroform [157].

Figure 26: Synthesis route of mefloquine hydrochloride.

Although MFH clinically used is the best for malaria treatment, it preferentially marked for
side effects such as stomach pain, loss of appetite, nausea, headache, muscle pain or diarrhea
[158-160]. Again, the active mechanism clarified the drug more potent to eliminate the germs
from the patient's body and prevented neurological deterioration [161, 162]. The drug now
appears to have benign importance for lasting behavioral effects from other antimalarial
medications under development [163-165].
Mefloquine hydrochloride combining with cepharanthine, selamectine have been established
to be cytopathic to viral cultures of SARS-CoV-2, but their detailed mechanisms of action are
not clear [166].

Although there are currently no specific established treatments for COVID-19. Treatment of
coronavirus disease 2019 (COVID-19) with clinical trials of few above mentioned synthesis
drugs have been reported recently[167, 168]. However, the potent antiviral drugs with
mechanism of therapy for targeting to treat COVID-19 is shown in Figure 27.

Spike protein
Envelope protein SARS-CoV-2
Membrane glycoprotein
Nucleocapsid protein
(COVID-19)
Selamectin
cytopathic to viral culture
ACE2 Mefloquine
TMPRSS2
Endocytosis Cholroquine Remdesivir
Camostat
Hydroxychloroquine Favipiravir
mesylate
Lopinavir
Ritonavir Uncoating
Endosome
(-) sgRNAs
Darunavir
Translation + Proteolysis UUUUU
Ivermectin UUUUU
UUUUU
UUUUU
on
pti
n s cri
Nonstructural proteins
Tra (+) sgRNAs
Replicase-transciptase complex AAAAA
AAAAA
AAAAA
(+) gRNA AAAAA
AAAAA

N S E M
Double-membrane vesicles
RNA Replication (-) gRNA Translation
UUUUU
(+) gRNA AAAAA

Nucleocapsid

S
E M Golgi

Assembly
and budding
Vesicle
Exocytosis ERGIC
Barictinib
ER

Cell Cytoplasm
Nucleus

Virion
release

Figure 27: The potent antiviral drugs with mechanism of therapy for targeting COVID-19
3. Conclusion
COVID-19 appears more virulent than recent SARS and MERS coronaviruses, and it is
associated with significant mortality among susceptible individuals with comorbidities.
Worldwide, death rate for COVID-19 is increasing in a daily basis. Therefore, the current
nCoV-19 epidemic is related to social rather than the viral catastrophe. The control of the
outbreaks of nCoV-19 is now world challenge. Development of drug for prevention and
controlling remedies of COVID-19 are urgent needed for survival of mankind. Presently,
countries worldwide are taking strategies against the COVID-19 pandemic and vaccination
research against the SARS-CoV-2 virus are of great significance. This review is mainly based
on some previously reported drugs which can be considered for treatment of COVID-19
diseases. This review reveals that the existing data are not sufficient and more research needs
to be done to propose any specific drug for the treatment of COVID-19.The information
provided in this review may be helpful to synthesis drugs for the treatment of COVID-19 and
its management.
Consent for publication
Not applicable.
Funding
None.
Conflict of interest
The authors declare no conflict of interest, financial or otherwise.
Acknowledgement
The authors are thankful to the Chairman, Department of Chemistry, Rajshahi University,
Bangladesh for providing online facilities.

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