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Annals of Medicinal Chemistry
Antiviral Compounds: A Road to Quest for Novel Antiviral
Drugs
OPEN ACCESS
*Correspondence:
Asraf MA, Department of Chemistry,
Rajshahi University, Bangladesh, E-
mail: asraf.chem@ru.ac.bd
Received Date: 14 May 2020
Accepted Date: 21 Jul 2020
Published Date: 24 Jul 2020
Citation:
Asraf MA, Hossen MF, Bitu NA, Uddin
ME, Islam MR, Zamir R, et al. Antiviral
Compounds: A Road to Quest for
Novel Antiviral Drugs. Ann Med Chem.
2020; 1(1): 1004.
Copyright © 2020 Asraf MA. This is
an open access article distributed
under the Creative Commons
Attribution License, which permits
unrestricted use, distribution, and
reproduction in any medium, provided
the original work is properly cited.
Remedy Publications LLC.
Review Article
Published: 24 Jul, 2020
Asraf MA*, Hossen MF, Bitu NA, Uddin ME, Islam MR, Zamir R and Zahan MK
Department of Chemistry, Rajshahi University, Bangladesh
Abstract
Viruses exemplify the most common reason of infectious diseases worldwide and those with prompt
propagation and high infection rates cause animal and human pandemics. These rapid-spreading
diseases are usually treated with antiviral drugs but, often, drug resistance occurs because of the
capability of the pathogens to mutate quickly and become less vulnerable to the treatments. Several
compounds have been developed and some of them have exposed good antiviral activity. This review
provides an overview on some already known compounds, pointing the attention on the running
progresses in identifying and designing novel compounds with outstanding antiviral activity.
Keywords: Severe acute respiratory syndrome; Hepatitis C virus; Herpes simplex virus-2;
Organophosphorus compounds; Thiazole; Human immunodeficiency virus
Abbreviations
COVID-19: Coronavirus Desease-19; SARS: Severe Acute Respiratory Syndrome; MERS-
CoV: Middle East Respiratory Syndrome Coronavirus; AIDS: Acquired Immunodeficiency
Syndrome; HSV: Herpes Simplex Virus; HSV-1: Heres Simplex Virus type 1; HSV-2: Herpes
Simplex Virus type 2; HCV: Hepatitis C Virus; HBV: Hepatitis B Virus; OPs: Organophosphorus
Compounds; HIV; Human Immunodeficiency Virus; CMV: Cytomegalovirus; FDA: The Food
and Drug Administration; WHO: World Health Organization; NNRTI: Non-Nucleoside Reverse
Transcriptase Inhibitors; RT: Reverse Transcriptase; ED50: Effective Dose 50; SI: Selectivity Index;
RNA: Ribonucleic Acid; YFV: Yellow Fever Virus; CVB-5: Coxsackievirus B5; VSV: Vesicular
Stomatitis Virus; DNA: Deoxyribonucleic Acid; EC50: 50% Effective Concentration; BHK: Baby
Hamster Kidney; IC50: Half Maximal Inhibitory Concentration; RSV: Respiratory Syncytial Virus;
SAR: Structure-Activity Relationship; CC50: 50% Cytotoxic Concentration; FRET: Fluorescence
Resonance Energy Transfer; HRV: Human Rhinovirus; TMV: Tobacco Mosaic Virus; FMDV: Foot-
And-Mouth Disease Virus; CRFK: Crandell-Rees Feline Kidney; HEL: Human Embryonic Lung;
ACV: Acyclovir; CrFK: Cranell Feline Kidney; MNC: Maximal Nontoxic Concentration; MIC:
Minimum Inhibitory Concentration; pen: Penciclovir; MDCK: Madin Darby Canine Kidney
Introduction
There are several viral diseases like Coronavirus Desease-19 (COVID-19), Severe Acute
Respiratory Syndrome (SARS) [1], Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
[2], Ebola virus disease [3], Dengue fever [4], Acquired Immunodeficiency Syndrome (AIDS) [5],
Herpes Simplex Virus-1 (HSV-1) and Herpes Simplex Virus-2 (HSV-2) infection [6], Hepatitis C
Virus (HCV) or Hepatitis B Virus (HBV) infection [7,8] lead to human life threatening complications,
being the foremost global public health issues. In spite of the availability of numerous antiviral drugs
in the market, there is no complete cure for HIV infection and no specific treatment for dengue
[4,5]. Currently, scientists are looking for an effective drug for the treatment of COVID-19 and also
to save the world but no vaccine approved by WHO is reported. To date, antiviral drugs have shown
a noteworthy reduction in the spread of epidemics but at the same time, their unremitting usage has
resulted in the development of drug-resistant mutants over the time [9-18]. Many antiviral drugs
display pronounced side-effects and are too expensive to be affordable [19-23]. Consequently, the
discovery of novel, safe and effective antiviral drug is urgently needed for the treatment of viral
infections.
Organophosphorus compounds (OPs) are a broad class of chemical compounds having organic
moieties generally bonded directly to phosphorus or bonded through a heteroatom (S, O or N).
These are the most common compounds in the human environment [24]. They have mainly been
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Asraf MA, et al., Annals of Medicinal Chemistry

NH2 O

N O P O
N
H H O
O N O N O
O
O O
O O O O P O H
N N P O N
N
P O N O O
HN O
O O O O
O P O F
HO P O N
F
OH NH 2 HO O O
O
OH
F
5
N HO
N
NH2
1 4
N N N
O 6
N
NH2
O NH2
O P
O N NH2
N N O N N
O O O N
N
O P NH O N
N N
O O O O O O N O
N
O O P N O O O
N
O P
O O
O
O
P P P
O O O
O
O
O O
O O O

2
3 8 9
7
Figure 1: Transformation of tenofovir DF 2 and GS-7340 3 to tenofovir 1.
Figure 2: Mechanism of activation of sofosbuvir 4 and adefovir 7.

used in industrial (manufacture of lubricants, hydraulic fluids, and

plastics materials) [25], agricultural (pesticides) [26], medicinal
(drugs against osteoporosis, antiviral and anticancer compounds)
[27,28] or veterinary (anthelmintics) applications [29] due to their
exclusive properties and high biological activity. Additionally, OPs
have essentially contributed to the considerable benefits for the
effective food manufacture and the combat against numerous serious
diseases, such as yellow fever, malaria, smallpox [28] or typhus [30].
Thiazole containing compounds (thiazoles) have a broad range
of applications as medicinal agents. It was first reported by Hantzsch
and Weber in 1887 [31]. These compounds have shown It has shown
numerous biological activities like anticancer [32], antibacterial
[33], antiallergic [34], antihypertensive [35], antioxidant [36], anti-
inflammatory [37], antimalarial [38], antifungal [39], antipsychotic
[40] and analgesic [41]. It has also displayed neuroprotective [42],
hypnotic [43], and diuretic [44] activities.
Recently, the use of metal coordination compounds has improved
considerably in clinical therapy, since viruses contain proteins and
nucleic acid units, some atoms of which are excellent coordinating
agents for metal ions [45]. Platinum-based drugs (cisplatin,
carboplatin, and oxaliplatin) have a wide use in the treatment of
human distortions, such as ovarian, testicular, head and neck, and
lung cancers. Following the discovery of the anti-tumor properties
of cisplatin and related complexes, interest for the discovery of other
more efficient complexes of other metals and ligands grew. Due to
the similar chemistry of Palladium (Pd) with Platinum (Pt), the Pd
(II) complexes have been used for clinical trials against tumors. Both
Pd(II) and Pt(II) are soft Lewis acids and form stronger bonds with
nitrogen or sulphur donors (soft bases) than oxygen donors (hard
bases). It has been observed that Pd(II) complexes with inert ligands
exhibited to be more effective anti-viral agents than other metals
[46]. The use of Pd(II) complexes as antiviral agent may always be
promising and encourages further works in the field. Metals have
been used in the treatment of diseases of humans since ancient
times. The Chinese were using elemental gold for the treatment of
diseases, a practice known as chrysotherapy, as far back as 2500 BC
[47]. Complexes containing gadolinium, cobalt, lithium, bismuth,
iron, calcium, lanthanum, gallium, tin, arsenic, rhodium, copper,
zinc, aluminum and lutetium have all been used in medicine [48].
Recently, cobalt, copper and nickel based complexes have been found
to possess antiviral and antibacterial activities [49-51] and also they
have significant catalytic applications [52-54]. Metal coordination
compounds (exogenous complexes) are closest to the metal species
found in biological systems (endogenous complexes). That is why they
are always less toxic than their inorganic and organic compounds.
Therefore, the search for new antiviral agents among metal complexes
is crucial and confirms that they are promising medicines [55].
Phosphorus compounds with antiviral activity
Discovery of novel antiviral therapy is essentially needed to treat
viral infections especially for those infections where vaccination has
not been developed. The opening of the antiviral period is noticed by
the report in 1959 of the synthesis of 5-Iodo-2'-Deoxyuridine (IDU)
[56]. IDU was truly produced as a potential antitumor agent, but later
commercially introduced as the first antiviral drug to be deployed in
the current treatment of herpetic eye contagions. Currently, among
the drugs utilized in treatment of several viral infections [e.g. Hepatitis
C Virus (HCV), Hepatitis B Virus (HBV), Human Immunodeficiency
Virus (HIV), smallpox (variola virus), Cytomegalovirus (CMV),]
there are several compounds having a phosphorus atom.
De Clercq et al. [57] reported in 1985, the activity of 9-(R)-(2-
phosphonomethoxypropyl) adenine (tenofovir) 1 against HIV in
cell culture. Tenofovir is a nucleotide (nucleoside monophosphate)
analogue has a remarkable activity against retroviruses, such as HIV-
1, HIV-2 and hepadnaviruses. Tenofovir is directed to patients in the
form of a prodrug - tenofovir disoproxil fumarate (tenofovir DF) 2.
Tenofovir DF is quickly transformed to tenofovir (Figure 1) which is
digested intracellularly to its active form, anabolite, which is a very
competitive inhibitor of HIV-1 reverse transcriptase and terminates
the growing DNA chain [58].
GS-7340 3 is a prototype molecule and a new type of tenofovir
mono-phosphonoamidate prodrugs. GS-7340 has phenol and alanine
isopropyl ester group as the phosphonate masking groups which
is the difference from tenofovir. GS-7340 shows 500 to 1000 fold
improved activity against HIV-1 in T-cells, activated peripheral blood
mononuclear lymphocytes and macrophages [59].
Up till now, there are a large number of agents reported for
the treatment of HCV infections. Nucleoside/nucleotide analogs is
one class of them which is promising candidate for in vitro results.
These compounds can share the properties with the intracellular
nucleoside substrates of the target HCV enzymes associated with
the transcription of the viral genome and, when phosphorylated to
the nucleoside triphosphate, lead to premature termination of the
growing HCV RNA chain during viral replication [60]. Sofosbuvir
4 ,one of nucleotide analog, is a phosphoramidate prodrug that is
metabolized within the liver into the active antiviral agent 2′-deoxy-
2′-α-fluoro-β-C-methyluridine-5′-monophosphate 5 which is
again phosphorylated to the active 2′-deoxy-2′-α-fluoro-β-C-
methyluridine-5′-triphosphate 6 (Figure 2) [61]. The triphosphate

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Asraf MA, et al., Annals of Medicinal Chemistry

NH2
Phenylethylthiazolylthiourea derivatives as a new type of Non-
NH2
Nucleoside Reverstranscriptase Inhibitors (NNRTI) discovered
O
by Ahgren et al. [66] through systematic bond disconnection of
N N

P O O N O O N O
the known HIV-1 Reverse Transcriptase (RT) inhibitor R82913
OH C
OH O P
OH
O P
3
(Figure 4). The compound 13 displayed activity with ED50 of 1.33 μM
OH O(CH2 )3 O(CH2 )15 CH
OH OH
concentration and Selectivity Index (SI) >286 in the cell-based anti-
HIV examination. At micromolar concentration, it was surprisingly
OH
OH
10 11 12
inactive against HIV-2 or simian immunodeficiency. Stefanska et
Figure 3: Molecular structures of foscarnet 10, cidofovir 11 and CMX-001 12. al. [67] further synthesized a plenty numbers of thiazolyl thiourea
compounds with different alkyl and aryl substitution at one of the
S S
nitrogen atoms of thiourea and examined them for activity against
HN HN
various Ribonucleic Acid (RNA) virus [(bovine viral diarrhea virus,
S
NH HN N Yellow Fever Virus (YFV), Coxsackievirus B5 (CVB-5), poliovirus
N
CH3
CH3 type-1, Vesicular Stomatitis Virus (VSV) and reovirus type-1)] and
NH HN
Cl
N
HIV-1 and Deoxyribonucleic Acid (DNA) viruses [Vaccinia Virus
S Cl
(VV), HSV-1)]. The compound 14 exhibited anti-CVB activity
13 R= phenylethyl and anti-HIV-1 with EC50 of 36 EC50 μM concentration and 14 μM
14 R= cyclohexyl R82913 concentration, respectively and no cytotoxicity for BHK and MT4
15 R= benzoyl cell lines were found. Compound 15 displayed anti-CVB activity with
Figure 4: Mono substituted antiviral thiazole derivatives (13–15) derived EC50=40 μM. Its anti-HIV-1 activity was detected to be very weak
from R82913. (EC50>100 μM).
Thiazolyl ketone-containing peptidic compounds reported by
assists as a substandard substrate for the NS5B protein and it is Regnier et al. [68] as Severe Acute Respiratory Syndrome Coronavirus
the viral RNA polymerase and can act as an inhibitor of viral RNA protease (SARS-CoV 3CL) inhibitors where the compound 16 was
synthesis [62]. The Food and Drug Administration (FDA) accepted the most potent compound (Ki value of 2.20 μM and IC50 of 9.5 μM).
sofosbuvir in combination with ribavirin in 2013 for oral dual therapy Based on the molecular docking studies on dimeric chymotrypsin-
of HCV genotypes 2 and 3, and for triple therapy with injected like protease, Konno et al. [69] optimized the molecular structural
pegylated interferon and ribavirin for treatment-naive patients with requirements for the compound 16. Aliphatic and aromatic
HCV genotypes 1 and 4. A combination of sofosbuvir and the viral
carbamates and acyl substitution at P4 (17–22) (Figure 5) did not
NS5A inhibitor ledipasvir was approved in 2014.
show activity (IC50s=13–280 μM) comparable to 16. Phenoxymethyl
Hepatitis B virus attacks the liver and can lead to both acute carbonyl substitution (23) displayed a little improved activity with an
and chronic disease. Adefovir 7 is a drug usually used to treat IC50 of 6.8 μM. 4,5-dimethylthiazole (24) substitution at P1' improved
infections with HBV. Adefovir 7 is a nucleotide analog with reverse activity (IC50=2 μM). Benzothiazole (25 and 26) substitution at P1'
transcriptase inhibitor activity. Adefovir is orally administrated as a exhibited 4 to 5 fold improvement in the potency (IC50s=1.7 μM and
prodrug – adefovir dipivoxil 8. It is hydrolyzed after administration
to adefovir and phosphorylated to its active diphosphorylated form H
N
P1 H
N
P1
P3
adefovir dipivoxil 9 (Figure 3). Adefovir DP competes with dATP
P3 O
O

upon phosphorylation for the incorporation by the HBV reverse

O
O S S
H
H R N
R N

transcriptase. When adefovir is incorporated into viral transcripts, it

N N
N N N H H N
H H P4 O
P4
O
P1'
O O

causes chain-termination due to the lack of a 3′-hydroxyl group [63].

P1'

P2
P2

Adefovir dipivoxil can considerably improve biochemical, histological O

O
O
O
O O

O
O

and virological outcomes in HBeAg-positive and –negative patients,

O
O O

O
O
O
25 26 O
27 28
O O

and serological outcomes in HBeAg-positive patients [64]. 17 18 O O

16
O2 N O
O O O

O
O O
29 OH
30 N
31
R= R=
The compound foscarnet 10 and cidofovir 11 is used to treat
O O O O
O
19 20 21 N
O
O O

O
32 33 34
CMV infections. Foscarnet and cidofovir both attack at the viral
O O
HOOC O2 N

23
O O
22 H

DNA polymerase. Foscarnet interacts with the pyrophosphate

O N O
H
N

N
35 36 37
binding site of the DNA polymerase directly, whereas cidofovir first P3 O
H
N
P1

phosphorylated to its diphosphate derivative, which then interact as O

O S

competitive inhibitor/alternate substrates [65].

H
N
O N N N
H H
P1'
O O

In 1980, World Health Organization (WHO) declared that

P4
P2

24
smallpox had been eliminated from the earth. But, the bad news for
H
H N
N
O

the human is that variola virus may emerge again from biological O
O S
H
O
N
S
R

weapon and it may happen by the terrorists. CMX-001 12 could be a

H N
N
N N N
O N N H H
N
H H
O

possible candidate for such type of scenario in the earth. CMX-001 12

O
O
R
O

is the hexadecyloxypropyl ester of cidofovir and it has been reported O

O
O
O

as an active antiviral drug against vaccinia virus. R=

COOH
R= O
O

38 42 43 44
39 40 41
Thiazole compounds as antiviral agents
Figure 5: Mono substituted antiviral thiazole scafolds 16–44.
Mono substituted thiazole derivatives:

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Asraf MA, et al., Annals of Medicinal Chemistry

N N OH
Cl

O
H2 N S NH
N N S NH N

N HN Ac
N N N H2 N Ac
N S
N HN
N N R
O S O
47 48 R1 = (CH2)4 NH2 (Lys)
O N
H
N 50
49 R1 = CH2-imidazole (His) H
OH OH N
H H O
N N
O O

45 46 NH NH
N
NH

N N
N
N N
AV IC50 13 nM AV IC50 58 nM S
S
rat pharmacokinetics rat pharmacokinetics S
LE 0.38 LE 0.35 OH
Clint 61 mL/min/kg Clint 48 mL/min/kg 53
LipE 5.5 LipE 5.3 51 52
F 13% F 34%
logD 1.7 logD 1.3 OH
Vdss 0.5 L/kg Vdss 3.5 L/kg
HLM<8 mL/min/mg HLM<8 mL/min/mg
T1/2 0.4h T1/2 1.5h COOH
RRCK= 14x10-6cm/s RRCK= 4x10-6cm/s COOH
COOH
COOH
N
Figure 6: Monosubstituted antiviral thiazole compounds 45 and 46. N
N NH
N NH
NH O
NH O S
O O
S
2.3 μM, respectively). Substitution with electron donating groups on S
S
H2 N
54 H2 N CH3 H2 N 57
H2 N
the phenyl ring of P4 again improved the antiviral potency (27–34) 55
56
S

(IC50s=0.6 μM to non-toxic). In the case of isosteric replacement of OH O

phenyl with pyridinyl (35) at P4 faintly decreased the activity to IC50 O R1 R2

of 2.9 μM. On the other hand, the replacement with phenylamino S

OH

(36) improved the potency (IC50=1.5 μM). The activity was decreased
N OH

to an IC50 of 7.5 μM by increasing the chain length (37). Drastically 58 (R) R1 = OH R2 = H

the activity was reduced (IC50>1600 μM) when reversing the
stereochemistry at P2 in 38. Substitution with polar groups did not
increase the activity of the compounds 39–41 (IC50s>1600 μM to
non-toxic). Cyclic amide substitution at P1 was found to be very
important for activity enhancement (42–44) (IC50s=210 to >1600
μM).
Bristol-Myers Squibb group reported that the compound 45
(Figure 6) was a highly selective and strong inhibitor of Respiratory
Syncytial Virus (RSV) against several clinical isolates with an average
EC50 of 20.4 nM [70]. To improve the activity, several derivatives of
benzimidazole were synthesized by Pryde et al. [71] Replacement of
benzimidazole to thiazole-imidazole 46 showed good antiviral activity
(IC50=58 nM) against RSV and also showed good pharmacokinetic
profile in the rat model.
Disubstituted thiazole derivatives: The compound 47 (Figure
7), nucleosides with modified nucleobase, was a new type of HIV-
1 TAR RNA binding agents [72]. Nucleobase containing thiazole
motif can recognize AU base pair in a sequence selective manner.
Joly et al. [73] claimed that due to labile ester bond, these modified
nucleosides degrade in biological media and did not display any
anti-HIV-1 potency. Moreover, they synthesized 47- amino acid
conjugates and these were stable in biological media and exhibited
anti-HIV-1 potency in the submicromolar range. Conjugates 48 and
49 displayed IC50 of 0.63 and 0.41 μM, respectively, in cellular anti-
HIV-1 evaluation. The ester group of 3,4-dihydropyrimidin-2(1H)-
one HIV-1 replication inhibitors was replaced by Kim et al. [74] and
resulted in a metabolically stable similar compound of 50. The anti-
HIV-1 potency of 50 was 78 nM (EC50) and it was very comparable to
the parent compound.
Distinto and his coworkers carried out virtual a screening and
identified (3Z)-3-(2-[4-(3,4-dihydroxyphenyl)-1,3-thiazol-2-yl]
hydrazin-1-ylidene)-2,3-dihydro-1H-indol-2-one (51) as a new
generation dual inhibitor of HIV-1 RT associated ribonuclease
H (RNase H) and DNA polymerase (DP) function. 51 exhibited
inhibition in the low micromolar range (RNase H IC50=2 μM, DP
IC50=1.4 μM). It was also revealed that RNase H inhibitory potency
59 (S) R1 = H R2 = OH
Figure 7: Disubstituted antiviral thiazole derivatives 47–59.
was not associated to binding with Mg2+ ion in the catalytic site.
Activity profile of 51 was not same against two common NNRTI
resistant mutants (Lys103Asn and Tyr181Cys). The compound 51
was 3- and 9- fold less active in terms of the DP and RNase H function,
respectively, of the Lys103Asn mutant. But this compound was as
active on wild type RT and 6-fold less potent on the DP and RNase
H function, of the Tyr181Cys mutant. The binding site of diketo acid
derivative RDS1643 (i.e. RNase H catalytic site) and efavirenz (i.e. DP
catalytic site) did not overlap with the binding site of 51 but binding
of 51 reduces the binding of efavirenz and, vice versa [75]. (3Z)-3-
(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1-ylidene)-2,3- dihydro-1H-
indol-2-one derivatives were synthesized by Meleddu et al. [76]
and examined them for RT potency. These investigations proposed
a critical role of nature of the substituent's in the 4-phenylthiazole
system. The compound 53 without substitutes at the 4-phenylthiazole
moiety did not display any activity.
Some completely new Influenza Neuraminidase (NA) inhibitors
were designed based on the studies of NA active site and Structure-
Activity Relationship (SAR) of the reported NA inhibitors by Liu et
al. [77 ] The compounds 54–57 owned IC50 values of 3.43, 4.27, 10.4
and 7.78 μM, respectively which were compared with oseltamivir
carboxylate (IC50=0.17 μM). Barbier et al. [78] prepared sixteen novel
noricumazole A derivatives (including thiazole derivatives) which
were verified in the HCV inhibitory assay. Most of the compounds
were moderate to strong HCV inhibitors (350–6 nM) but these
compounds also showed pronounced cytotoxicity. The compound
58, the thiazole analog of noricumazole A exhibited a robust HCV
inhibitory potency along with moderate cytotoxic activity (IC50=16
nM, CC50=347 nM). Remarkably, R stereoisomer was more potent
than the S (59, IC50=275 nM, CC50=1259 nM) [79].
Faldaprevir (60) (Figure 8), an anti-HCV compound produced
by Boehringer-Ingelheim extended phase III clinical trials but was
not submitted for FDA certification [80]. Bailey et al. [81] developed
novel P2 motifs to further improve the activity and efficacy. They

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H
S N
Br

O N O
N O
O O N N
N N N

S
HN N O
O N H
HN N O
H

72
N S

O S
N O N
H
O
N
O
N H
O
R
71 EC 50 = 0.21 mM
S
OH
N SI = 47.19
NH
O O NH O EC 50 = 1.67 mM F NH2
NH
O O O SI = 37.40
O
NH2

R1 N
P3 P2 P1
60 R = H
N
H
N
H
N N S

61 62 R = CH3 N
H
N
S N
S O
O HN
O N

R1 S R2 O
74 R1 = 4-OMeC6H4CH2-
73 -
S
H
N O N
N
75 R1 = 2-ClC 6H4 N

76 R1 = 4-NH2C 6H4CH2-
O N
N N O

O NH2 77
O
O O R1
NH
N O
O H
N S N O
NH O N S S
O
X1
O O
N H N O
O O
N O

OH O HN N
NH
O 64 R1 = F, R2 = iso-propyl
HN
79 R = CH3 N
O
65 R1 = Cl, R2 = iso-propyl 80 R= H
S
66 S N
R1 = CH3, R2 = iso-propyl N
O
67 R1 = F, R2 = CN
63 68 R1 = CH3, R2 = CF3
HN

Boc
R N 78 R
81-91
O N S
R1 X1 R1 X1
Compound Compound

O 81 NH S
87 NH
O
N
N O F
O H
S
NH
N
82
O
NH F
88 NH
N O
F3C

83 O
NH
69 R = CH3
70 R = Cl 89 O
84 NH
Figure 8: Disubstituted antiviral thiazole derivatives 60–70.
90 F3C O

found that the 2,4-disubstituted thiazole core exhibited the most 85 NH

exciting activity. The compounds 61 and 62 were the most active and
displayed IC50 of 0.9 nM, and 1.1 nM, respectively and EC50 of 16 nM 91
O

and 9 nM, respectively.

86 NH
The first HCV protease inhibitor was the BILN-2061 (63, IC50=0.8
nM, in HCV NS3/4A protease inhibition assay and EC50=2.8 nM in
the cell-based anti-HCV assay) (Figure 8) and was used for clinical Figure 9: Disubstituted antiviral thiazole compounds 71–91.

trials but terminated due to its cardiac poisonousness in animal

(such as amide or ester group) at the C-3 position of quinoxalin-
studies [82]. Parsy et al. [83] prepared analogous of 63 containing
2(1H)-one and NH group of lactam moiety were beneficial for the
urea moiety within the macrocycle to improve its activity. The
antiviral potency. A robust electron withdrawing group on the
compound 64 showed outstanding biochemical potency (IC50=3.5
benzene ring of the thiazole-phenyl moiety decreased the activity. The
nM) in Fluorescence Resonance Energy Transfer (FRET) assay but
compound 71 (EC50=1.67 μM and SI=37.40) (Figure 9) resulted in the
lower activity (EC50=538 nM) in the cell-based assay (HCV replication
development of anti-HCV compound 72 which showed EC50 of 0.21
inhibition in GS4.1 cells), whereas 65 and 66 with a chlorine or methyl
μM and SI of 47.19.
group at position 8 confirmed decent activity in the biochemical assay
with IC50 of 2.3 nM and 1.8 nM, respectively, and 7 to more than Lin et al. [86] separated 25 compounds from a library of 35,000
9-fold improved activity in the cell-based assay. The carbonitrile compounds using a cell-based HCV replicon system. These 25
group substituted compound 67 exhibited an IC50 of 10 nM and an candidates efficiently inhibited HCV1b replicon activity (EC50<1.5
EC50 of 89 nM. The compound 68 with trifluoromethyl substitution μM) and owned lower intrinsic cytotoxicity. The compound 73
at thiazole was the most active and displayed an IC50 value of 0.5 nM, was an inhibitor of HCV against genotype 1b and 2a replicons and
EC50 value of 13 nM and a CC50 value of >75 μM. Replacing proline also against 2a infectious virus with EC50s of 4.1, 807.6, and 175.6
ring of 63 with azetidine ring gave slightly less active compounds 69 nM, respectively and SI of more than 12,195 and 284, respectively.
(IC50=6.6 nM and EC50=45 nM) and 70 (IC50=2.1 nM and EC50=60 Compounds 74–76 showed robust antiviral activities against four
nM) [83,84]. dengue serotypes (74–76: EC50=0.9, 1.7 and 4.1 μM against Dengue
Thirty five new quinoxalinone derivatives for anti-HCV Virus (DENV1); EC50=7.6, 4.1 and 6.2 μM against DENV2; EC50=2.6,
effectiveness were studied by Zhong et al. [85] SAR studies exposed 2.3 and 1.0 μM against DENV3 and EC50=5.0, 5.0 and 7.2 μM against
that 4-arylsubstituted thiazol-2-amine moiety, the H-bond acceptor DENV4).

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Asraf MA, et al., Annals of Medicinal Chemistry

O
against HRV 14, HRV 16, HRV 1a, HRV 2, HRV 8, HRV 54, HRV
H
89, HRV 45 and HRV 5, respectively [87]. El-sabbagh et al. published
R2 N N R3
X2 thiazole derivatives of 1,2-benzisothiazole-3(2H)-one-1,1-dioxide
O S
as antiviral drugs. Compound 79 and 80 exhibited potency against
92-100
Varicella-zoster virus (TKϸ VZV strain OKA and TK_VZV strain 07-
Compound R2 R3 X2 Compound R2 R3 X2
1), cytomegalovirus (AD-169 strain and Davis strain), HSV-1 (KOS),
HSV-2(G), VV, VSV and HSV-1 TK_KOS ACVr with an EC50 of 20
F
μM [88]. Novel 2-amino-1,3-thiazole-4-carboxylic acid derivatives
92 C2H5 O 97 NH
were prepared by Li et al. and were examined their activity against
N N
N N F
F3C F3C

C2H5
Tobacco mosaic virus (TMV) at 100 μg/mL. Compounds 85, 87, 88, 91
O
and 96 exhibited greater than 50% inhibition for curative activity and
N
93 N 98 N NH
Br N N
F3C

it was greater than the positive control ningnanmycin. Inactivation

Cl

94 N H O 99 N
N
O potency (>50% inhibition) of 81, 83, 85–88, 90, 96, 94, 97 and 100
F3C
(Figure 9 and 10) was also found to be higher than the positive control
N
F3C

N N
95 H O 100
N N
N Br N F
Br
Cl
96 NH
F3C N
N
Figure 10: Disubstituted antiviral thiazole compounds 92–100.
To find new Human Rhinovirus (HRV) pan-active inhibitors,
Decor et al. screened 98,000 compounds from the Boehringer
Ingelheim collection by means of a phenotypic antiviral screening
strategy. They found a strong antiviral compound 77 with EC50 of
640, 630, 1600, 790, 210, 1300, 790, 1200 and 660 nM against HRV
14, HRV 16, HRV 1a, HRV 2, HRV 8, HRV 54, HRV 89, HRV 45 and
HRV 5, respectively. Additional optimization gave the compound 78
with EC50 of 220, 1400, 1200, 915, 130, 395, 890, 430 and 535 nM
F
ningnanmycin (Table 1). Compounds 83–85, 91, 95 and 96 displayed
NH
decent induction activity with >80% inhibition (greater than positive
Cl
control tiadinil). Protection activity was also outstanding for 82–85,
88, 89–91 and 94–98 being higher than the positive control virazole
(Table 1) [89].
Jeong et al. screened out 2-amino-4-arylthiazole derivative (101;
IC50=6.8 µM) (Figure 11) from 50,000 compounds (chemical library
of the Bio-Center of the Gyeonggi Institute of Science Technology
Promotion) against 3Dpol of Foot-and-Mouth Disease Virus
(FMDV). Ring A and B of 101 was tuned to examine the SAR for the
optimization of toxicity, activity and chemical stability. Elimination
of either 3-OH (102) or 3,4-diOH (104, 106) caused the complete
loss of potency and elimination of 4-OH provided moderately strong
compound 103. Substitution of either 3,4-diOH (105) or 4-OH
(108) with the methoxy group reduced the 3Dpol inhibition potency.

Table 1: Antiviral potency against TMV at 100 µg/mL. % inhibition @100 µg/mL.
Compound Curative Inactivation Induction Protection

81 49.17 ± 0.83 69.23 ± 2.56 71.00 ± 5.00 14.29 ± 5.72

82 31.67 ± 6.44 29.49 ± 1.28 79.33 ± 6.87 60.95 ± 7.54

83 49.17 ± 4.17 60.68 ± 8.76 83.33 ± 3.13 89.52 ± 4.15

84 47.50 ± 2.50 33.33 ± 2.57 81.00 ± 3.00 68.57 ± 2.86

85 55.83 ± 2.5 53.85 ± 5.13 88.00 ± 2.00 87.62 ± 6.83

86 29.17 ± 0.83 54.70 ± 5.25 60.00 ± 2.00 41.43 ± 4.29

87 63.33 ± 3.33 66.67 ± 2.56 38.00 ± 6.00 47.14 ± 1.43

88 53.33 ± 5.00 63.25 ± 5.49 36.67 ± 3.23 74.29 ± 2.86

89 41.50 ± 8.17 28.21 ± 2.56 61.00 ± 7.00 62.86 ± 2.86

90 47.50 ± 2.50 62.39 ± 7.06 78.00 ± 4.00 58.57 ± 4.29

91 55.00 ± 5.00 26.92 ± 3.85 86.00 ± 2.00 82.86 ± 2.86

92 27.50 ± 0.83 53.85 ± 2.57 33.00 ± 3.00 20.00 ± 5.71

93 33.10 ± 2.50 21.21 ± 2.57 30.35 ± 3.23 22.55 ± 2.86

94 45.00 ± 4.41 68.38 ± 5.42 56.00 ± 2.00 84.29 ± 1.43

95 30.83 ± 2.50 76.92 ± 6.98 80.00 ± 7.68 67.14 ± 1.43

96 56.11 ± 2.76 12.82 ± 2.56 89.33 ± 3.65 47.14 ± 4.29

97 35.00 ± 1.67 25.65 ± 2.57 54.00 ± 6.00 90.48 ± 3.88

98 28.33 ± 1.67 53.85 ± 6.08 25.00 ± 1.00 77.14 ± 1.91

99 33.33 ± 3.33 53.85 ± 5.13 62.00 ± 4.00 77.14 ± 8.20

100 30.56 ± 5.29 76.92 ± 2.21 78.00 ± 4.00 30.00 ± 1.43

Tiadinil 29.17 ± 4.17 23.57 ± 3.08 63.00 ± 3.00 40.84 ± 5.07

Ningnanmycin 45.00 ± 4.84 45.64 ± 2.35 28.36 ± 2.99 43.19 ± 3.54

Virazol 35.39 ± 5.00 41.21 ± 4.21 32.50 ± 7.50 28.53 ± 4.56

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Asraf MA, et al., Annals of Medicinal Chemistry

The compound 119 (Figure 12) noticeably inhibited virus-

B induced cell death with EC50 of 5.8 ± 1 µM and SI of 25 in CPE-
A
R2 reduction assay. Moreover, 119 exhibited potency in virus yield and
N
R1 NH plaque reduction assay with EC50 of 1.32 ± 0.41 µM and 1.39 ± 0.06
S µM, respectively. Molecular docking studies of 119 into the β-OG
101-117
pocket of DENV E protein exhibited that 4-chlorophenyl ring of
OH the thiazole involve into a π–π staking interaction with PHE193 and
HO
PHE279, and hydrophobic interaction with LEU207 [91].
O

F
N
NH
Dawood et al. prepared and investigated a series of new bis-1,3-
S
thiazole derivatives against Influenza A (H1N1) virus, Poliovirus,
HCV and HBV. Their studies confirmed that the compound 121 was
118
active against HCV in sub-micromolar range with an EC50 of 0.56 µM
IC 50= 0.57 μM
(3Dpol. inhibition assay) as compared to the standard drug IFNa-2b (EC50=0.1 µM). Similar
to 121 with para-substituted phenyl ring at N3 of thiadiazole showed
IC 50= 13.0 μM
(cell based FMDV inhibition assay) poor activity (122–124, EC50=1.12, 1.04 and 2.80 µM, respectively).
Figure 11: Disubstituted antiviral thiazole compounds 101–118. The SI of 121–123 (>36, >18 and >19, respectively) was superior to
the drug IFNa-2b (SI>20). Compound 130 containing isosterically
thiazole showed poor anti-HCV activity (EC50=12.7 µM). The
O
activity of the compounds 120 and 125–128 were decreased by 20-
O S N
S
R2 fold (EC50>20 µM). HCV strains, 2a (JFH-1), 1a/2a (H77/JFH-1)
N
N
N
S
N
X
and (H77, Genotype-1a) exhibited strong resistance toward 121 while
HO
N R1 1b/2a (CON-1/JFH-1), 2a/2a (J6/JFH-1) and (CON-1, Genotype-1b)
N NH
Compound R1 R2 X exhibited strong activity with EC50 1.09, 1.54 and 0.46 µM, respectively.
S
N
120
121
C6H5
C6H5
C6H5
COMe
N
N
Furthermore, 130 also showed activity against influenza virus H1N1
122 4-Cl C6H4 COMe N (EC50=24 and 23 µg/mL in visual and neutral red assays, respectively)
119 123 4-Me C6H4 COMe N
124 4-OMeC6H4 COMe N and it was comparable to antiviral drug Ribavirin (EC50=22 µg/mL)
Cl
125
126
C6H5
4-Cl C6H4
COOEt
COOEt
N
N
[92].
127 4-Me C6H4 COOEt N
128 4-OMeC6H4 COOEt N 5-Methyl-4-thiazolidinone skeleton is a crucial pharmacophoric
129 C6H5 COOEt CMe
character for antiviral property which was reported to bind flavivirus
O
NH
E protein [93]. Moreover, Pacca et al. [94] examined the anti-YFV
S N
O

N
N
N
and SLEV activity of two phthalyl-thiazoles (131 and 132) through
O

plaque flow cytometry, reduction assay, and cellular viability and

S S

N
N
immunofluorescence tests. Compounds 131 and 132 were active only
N S
N O
O
N R 131 R = F
132 R = Cl R
against SLEV at non-cytotoxic concentration (Figure 12).
R = C6H5
130
Madni et al. [95] synthesized a series of (5-(4-chlorophenyl)-3-
Cl phenyl-4,5-dihydropyrazol- 1-yl)thiazole-4-carbohydrazide Schiff
S
NH
bases based on the bioisosteric principle. Compounds 133 and
O
N 134 were found to have strong activity against HIV-1 replication
N

N
N
O
(IC50=0.50, 0.45 µM, SI=3 and 5, respectively). 133 and 134 were not
active against HIV-2. Osman et al. [96] prepared thiazole containing
S HN N O

R 135
133 R = F
134 R = Cl coumarin compounds. Compound 135 containing methylamino
group inhibited the replication of H1N1 influenza A virus with an
Figure 12: Disubstituted antiviral thiazole compounds 119–135.
IC50 value of 4.84 µg/mL in MDCK cells (Figure 12).
Nevertheless, 4-hydroxy-3-methoxy incorporation (107) of the ring Trisubstituted thiazole derivatives: Zhou et al. [91] curtained
A was more potent than 101 with an IC50 of 3.7 µM. N-substituted three National Cancer Institute (NCI) libraries with ~142,000
amide on the B ring showed a critical role in 3Dpol inhibition potency compounds by means of a computational high-throughput screening
(111–113) because of the steric effect of that amide group. H-bond procedure targeting the BOG pocket of the E protein on the dengue
donor at ring B is also needed for activity (110 compared with 114– virus surface and acknowledged the compound 136 (Figure 13)
117). Substitution at position 3 of ring B (114 and 115) provided with an IC50 of 31 µM and TI of 1.96 against YFV-IRES-Luc virus
more active compound as compared to substitution at position 4. The in viral growth assay. Though the host cell cytotoxicity was higher, it
compound 116 showed greater activity (IC50=0.79 µM). Replacement was the first proof that a BOG pocket (N-octyl-β-D-glucoside) was
of 3-OMe with 3-Cl gave 117 which was the strong inhibitor of 3Dpol an effective target for antiviral treatment. Li et al. [93] planed and
with IC50=0.39 µM in the series. The compound 118 showed the most prepared several similar compounds of 136 based on the binding
effective antiviral activity in cell-based FMDV inhibition assay with model derived from molecular docking findings and found 137 with
EC50 of 13.0 µM and it was several folds greater than the positive an EC50 of 0.9 µM and TI of 170 in YFV inhibition assay. Compound
control (Ribavirin; EC50=1367.0 µM). It was also found that the 137 examined at the primary 50 µM concentration displayed 99%
metabolic stability of 118 was enhanced and at the same time, half- inhibition of YFV and DENV replication. Mayhoub et al. published
life was extended as compared with 101 [90]. the activity of 137 as EC50=2.8 µM and TI=78 against YFV luciferase

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Asraf MA, et al., Annals of Medicinal Chemistry

thiazolylthioacetamides derivatives 143 and 144 exhibited EC50 of

NH2 O
X Br
O

HN
0.73 and 0.97 µM and TI of 58 and 52, respectively against influenza
A/H1N1 virus. Antiviral activity displayed by 143 and 144 was 10
Br O NH2

N S
S HN

to 183 fold higher than reference drugs oseltamivir carboxylate,

N S
O
N
S

amantadine, ribavirin, and rimantadine. Antiviral activity of 143

H2N S
HN
N S
N R

and 144 was very specific to influenza A/H1N1 virus and they were
R

Compound R X N S
Br
137
inactive against Influenza A/H3N2, Influenza B, HIV-1 IIIB, and
Cl O n-Bu
138 Br O Br

139 141 143

HIV-2 ROD. Compounds 143 and 144 exhibited poor activity in
CF3 O R = NO2
Cl 140 Cl S
144 R = NO2
136 n-Bu
the neuraminidase (H1N1) inhibition assay. Compounds 145, 146
142
and 147 exhibited EC50 of 2.67, 3.33 and 2.09 µM, respectively, and
R

O
Cl N
S
O
TI of 9, 38 and 52, respectively against HIV-1 IIIB in the cell-based
Cl S
Cl
S S
HN N
HN
antiviral assay. Compounds 145, 146 and 147 also exhibited antiviral
activity against some key mutant strains (E138K, K103N, and L100I)
O2N
N

Br
Br
of HIV-1 with EC50 values in the micromolar range.
Br
Br

145
146 R = CH3 Xu et al. [100] examined 2,4,5-trisubstituted thiazole derivatives
147 R=H
(148–179) (Figure 14) as a new class of HIV-1 (wild type and NNRTI-
Figure 13: Trisubstituted antiviral thiazole compounds (136–147). resistant strains) replication inhibitors. The compound 176 was the
most active compound and exhibited IC50 of 0.046 µM against wild
R2 type HIV-1 in cell-based antiviral assay. Compounds 173, 175 and
S N 176 were also examined on seven NNRTI- resistant HIV-1 strains
and they showed several fold fluctuations in the IC50 (from 2.6 to
NH
R3 S
R1
N
N
111-fold), which were superior to those of nevirapine (from 15.6 to
371-fold). Another finding is the substitution at position 2 of thiazole
R1
O nucleus which plays a critical role for the activity as displayed by
Compound R1 R2 R3 IC50 (μM)
Compound R1 IC50 (μM) the activity result of compounds 148, 149 and 151. Compound 148
148
149
OMe
OMe
CH3
CH2CH3
CH3
CH2CH3
no activity
2.2
152
153
154
C6H5
o-OMeC6H4
m-OMeC6H4
0.65
6.97
0.82
with dimethylamino substitution was completely inactive while
150
151 OMe
OH CH2CH3
H
CH2CH3
CH2 C6H5
4.4
0.65
155
156
p-OMeC6H4
p-OHC6H4
0.31
0.64 149 with diethylamino substitution exhibited an IC50 of 2.2 µM.
157 p-N(CH3)2C6H4 0.87
S NH 158
159
p-FC6H4
p-NO2 C6H4
0.66
0.80
Moreover, compound 151 with benzylamino substitution exhibited
R1 m-NO2 C6H4
higher activity with an IC50 of 0.65 µM. The study on the steric and
160 1.47
161 p-CNC6H4 0.45
N 162 2,6-diClC6H3 7.21

hydrophobic plots on position 2 in 3D-QSAR (three dimensional

163 2-OH 5-NO2 C6H3 5.20
164 3-OMe 4-OHC6H3 0.33
O 165 3,4,5-triOMeC6H2 >10

quantitative structure–activity relationships) also support the fact

166 2-furanyl 1.00
S NH
167 3-pyridyl 4.67
168 2-naphthyl 0.96

O
R1 N that bulky group substitution at position 2 increases the activity.
Compound R1 IC 50 (μM)
Compound R1 IC 50 (μM) Compound R1 IC 50 (μM)
O Substitution at position 2 (compounds 152–168) provided compound
169 CH3 9.59
170
171
p-NO2 C6H4
p-FC6H4
>10
>10
173
174
o-F C6H4
p-F C6H4
0.062
1.21
177
178
2,4-diCl C6H3
2-furanyl
0.14
6.20
155 with an IC50 of 0.31 µM. The optimization of substitution at
position 3 and 4 of 155 gave the compounds 169 to 179 and led to the
172 p-OMe C6H4 >10 175 2,4-diF C6H3 0.064 179 C6H5 0.18
176 o-Cl C6H4 0.046

Figure 14: Trisubstituted antiviral thiazole compounds 148–179.

strongest antiviral compound 176.
Fused thiazole derivatives: Atamanyuk et al. [101] reported
cellular assay. They emphasized on two main problems in 137 i.e. the antiviral activity of thiopyrano[2,3-d][1,3]thiazole derivative 180
potential of simple methyl ester to be converted into inactive free acid (Figure 15) against coronavirus SARS using visual system (EC50vis=1.7
in the plasma (rat plasma t1/2=1.4 h) and reactive dibromomethyl μM and SIvis=14) and neutral red dye (EC50-NR=6 μM and SINR=5.4).
group which was expected to cause in vivo toxicity. Compounds Barradas et al. [102] studied antiviral activity of imidazo[2,1-b]
with F and OCH3 in place of Cl on the phenyl ring were found to thiazole carbohydrate derivatives against Junin virus (strain IV4454)
be inactive while 138 and 139 containing Br and CF3 substitution in monkey Vero cells. The most active compound against Junin
exhibited EC50 of 3.3 µM and 6.6 µM, respectively, displaying the virus was 181 (EC50=0.8 µM, SI=463) and it was superior to the
significance of both the electronegativity and size on C-4 position of reference ribavirin (EC50=18.5 µM, SI=21.6). By the replacement of
the phenyl ring. Altering the substitution from para to ortho or meta
also provided inactive compounds confirming the fact that para- R2
Cl Br
substitution on phenyl ring is critical for the activity. Compound 140
with methylthioester exhibited the maximum activity with EC50 of 1.4
µM and TI of 256. After replacing dibromomethyl group of 138 with O O
S O O
5
methyl and changing substitution at phenyl ring usually produced S N 3 S
O
inactive compounds but 141 containing 4-n-butyl substitutions S
N
N
N
N
N
exhibited an EC50 of 2.8 µM, which exposed a new path to synthesize O O
3
OR1
5
derivatives without the reactive dibromomethyl moiety. Moreover,
S
O O CH3 O O CH3
O
O O

replacement of metabolically labile methyl ester with hydrazine 180 O

O O
O
carboximidamide derivative (142) improved the activity to EC50 of 2.4 O O

181 R1 = CH3, R2 = Cl
µM and TI of 147 [97,98]. 182 R1 = CH3, R2 = Br 184 185
183 R1 = COCH3, R2 = Cl
Zhan et al. [99] reported that thiazolylthioacetamides compounds
Figure 15: Antiviral fused thiazole compounds 180-185.
are a new class of potential antiviral compounds. 2-Amino substituted

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R1 S
rings increased (194–197), similar results with the SAR observed
in the bicyclic compounds. A little enhancement in the activity was
N

N O
R2 H S

H S
N
found when the saturated rings fused on the imidazo[2,1-b]thiazole
Cl N N O

N O N
N

O
scaffold were substituted by a benzene ring in 198 (EC50=0.092 μM),
whereas substitution at benzene rings provided less active analogs
Cl N

Cl
199–202 [105]. Changing cyclopentyl on piperazine ring with the
N N O
193
Compound R1 R2 EC50 (μM) EC50 = 0.079 μM
N O
186
187
H
CH3
H
H 46%@10μM
>10 192
EC50 =0.89 μM
dehydrocyclopentyl group also gave an active analog 203 with an EC50
188
189
H
iso-propyl
CH3
H
53%@10μM
1.32 of 0.031 μM.
190 H cyclo-propyl 0.016 S
191 H 0.74
An encouraging inhibitor was prepared by Ghosh et al. [106]
2-Methyl propane N
n(H2C)
S N O
N
which maximized the active site hydrophobic interactions and aid a
O Cl
robust network of H-bonding interactions with backbone atoms of
N N
R

N O
Cl
wild-type HIV-1 protease. This approach led to the further design of
N

inhibitors that would slow down the growth of drug-resistant HIV-1

N O

194 n=1; EC50 =0.13 μM

Compound R EC50 (μM)

195 n=1; EC50 =0.19 μM
196 n=1; EC50 =0.94 μM
variants because of their possible lessening of catalytic fitness. The
198 H 0.092 S inhibitor 204 (Figure 16) contains 6−5−5 ring-fused crown-like
199 OCH3 8.63 N
200
201
Cl
Br
1.85
1.79 N O tetrahydropyranofuran on the P2 ligand and an aminobenzothiazole
202 CH3 0.30
Cl N
on the P2′ ligand with the (R) hydroxylethyl sulfonamide isostere.
S
N O
Compound 204 exhibited strong antiviral activity (HIV-1NL43,
IC50=0.39 nM) with greater antiviral activity compared with the FDA
N

N O 197
EC50 = 0.026 μM

Cl N
approved drug darunavir (IC50=3.8 nM) and lopinavir (IC50=20 nM).
N O
N
Moreover, compound 204 inhibited the replication of all three DRV-
NH

resistant variants (HIV-1DRVRP20, HIV-1DRVRP30, and HIV-1DRVRP51).

H
O N N
203 S S

EC50 = 0.031 μM O
O O
Furthermore, it strongly blocked and maintained better activity
P2'
O
P2
204
against all seven HIV-1 variants (HIV-1APV5μM, HIV-1SQV5μM, HIV-
Cl N
N N
1NFV5μM, HIV-1LPV5μM, HIV- 1IDV5μM, HIV-1ATV5μM and HIV-1TPV15μM).
X-ray crystallographic data of the inhibitor 204 exhibited that it
H
N Cl
S

Cl occupied the protease active site in two distinct conformations.

205 R1 = Cl , R2 = Cl
R1 = H , R2 = OH
206
207 R1 = OCH3, R2 = OH Ulusoy Guzeldemirci et al. [107] assessed the antiviral activity of
Figure 16: Antiviral fused thiazole compounds 186–207. the compounds 205–206 against RNA and DNA viruses in Madin-

–Cl group at the C-4 position of aromatic ring formed slightly less R1 , R2
R2
S O

active compound 182 (EC50=1.1 µM, SI=268). Activity decreased N N

significantly when the methoxy group of the carbohydrate moiety N N S N

R1

was replaced by the more polar acetoxy group in 183 (EC50=7.5 µM, O R3
OCH3
Compound R1 R2 R3
SI=9.3). Additionally, position switching of carbohydrate from 3 to 5 208 H H H
also decreased activity (184, EC50=18.5 µM, SI=21.6). The compound 209
210
H
H
2-Cl
4-Cl
H
H
H3CO

185 similar to Pyrrolo[2,1-b]thiazole exhibited 98.1% inhibition in 211

212
H
2-Cl
2-Cl
6-Cl
OCOCH 2CH 3
CH 3
Compound R1 R2
214
virus yield at 10 µM concentration [103]. 213 2-Cl 6-F CH 3
215
3-F-Ph
3-Cl-4-F-Ph
H
H
216 3-Cl-Ph COCH3
Wang et al. [104] revised the structure of imidazo[1,2-a]pyridine R2
S
derivatives and reported by GlaxoSmithKline to notice imidazo[2,1-b] N
O

thiazole derivatives 190 and 203 (EC50=16 nM and 31nM, respectively) N

R1 N

(Figure 16) as new inhibitors of HCV Non-Structural 4B (NS4B),

O

O N N
NH

examined using GT 1b subgenomic replicon assay. Resistance profile Compound R1 R2 S O 2S NH

O

analysis exhibited that they aim the second amphipathic α helix of 217 3-Cl-4-F-Ph COCH3

NS4B (i.e. 4BAH2). These 4BAH2 inhibitors did not show any cross-
resistance to other direct-acting antiviral compounds targeting at 218

NS5B, NS3/4A and NS5A. Compound 190 exhibited synergism with

NS3/4A inhibitor. Compound 186 containing no substituent on the
R2
thiazole ring showed no inhibitory activity while a small substituent H O
H
N

like methyl at C2- (187) or C3-position (188) gave poor inhibitory S N N N

O

activity. The compounds 189 and 190 with isopropyl or cyclopropyl O S S O

(189, EC50=1.32 μM; 190, EC50=0.016 μM) exhibited a noteworthy H

N S

R3
increase in the activity, whereas 191 with isobutyl at C3-position R
R1 N

(EC50=0.74 μM) led to a 46-fold reduction in activity, signifying that Compound R1 R2 R3

3 carbon substituents at C3-position were best for antiviral activity. Compound
4-OCH3
R
222 Cl C3H7 CH 3
219 223 H CH2 -CH=CH 2 CH 3
Additional replacement of cyclopentyl did not show better potency 220 4-BzO 224 Cl CH 3 CH 3
221 4-tert-butylphenyl
(192, EC50=0.89 μΜ; 193, EC50=0.079 μΜ). Tricyclic compounds
were not very active and activity dropped as the size of the fused Figure 17: Antiviral fused thiazole compounds 208–224.

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X X
numerous bioisosteres of thiazolone compounds and exposed their
antiviral activity in cell-based anti-HCV activity (genotype b).
O Me Compound 218 exhibited EC50 of 0.79 µM and SI of 94.3 [111].
OY HO
N OH YO Lozynskyi et al. [112] synthesized novel rel-(6R,7R)-2-oxo-7-
S phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazole-6-
N
carbaldehyde derivatives as active antiviral agents. Compound
O
S
X X 219 displayed encouraging activity against Epstein-Barr virus
Compound X Y
(EBV) (EC50=0.07 μM, SI=3279) in viral capsid antigen Elisa test
Ph 226 SO 3 Na H
N 227 SO 3 Na Btz and moderate activity against HSV-1 and VZV in viral cytopathic
228 H Btz(COONa)2
S 229 C(CH3) 3 Btz(COONa)2 effect test. Compound 220 exhibited moderate activity against
N 230 CH2COONa H HCV (EC50=12.6 μM, SI=43.1) and compound 221 was moderately
231 CH2COONa Btz
O Me
232 CH2COONa Btz(COONa)2 active against VZV in human foreskin fibroblasts cell culture assay
233 CH2P(O)(OH)ONa H
234 CH2P(O)(OH)ONa Btz (EC50=23.4 μM, SI=27.2).
N N
Ph Me
Guzeldemirci et al. [113] prepared 4-thiazolidinone derivatives and
assessed them against several DNA- and RNA- viruses in mammalian
225
cell cultures. 3-Propyl-2-[((6-(4- chlorophenyl)imidazo[2,1-b]
Figure 18: Antiviral bisthiazole compounds 225–234. thiazol-3-yl)acetyl)hydrazono]-5-methyl-4-thiazolidinone (222)
showed moderate activity against influenza A/H1N1 subtype
Darby Canine Kidney, Vero, Crandell-Rees Feline Kidney (CRFK), (A/PR/8/34 and A/Virginia/ATCC/3/2009), influenza A/
Human Embryonic Lung (HEL) and HeLa cells. Compound 205 H3N2 subtype (A/HK/7/87) with EC50 ranging from 56–79 µM and
displayed antiviral activity against feline coronavirus in CRFK cell cytotoxicity >100 µM. Compounds 223 and 224 showed antiviral
cultures (EC50=7.5 μM and SI>13). Compounds 206 and 207 showed activity against vesicular stomatitis virus in HeLa cells with EC50
activity against HSV-1 and VV in HEL cell cultures (EC50=9, 16 and values of 9 µM and 2 µM and cytotoxicity of 100 µM and 20 µM,
20, 14 μM, respectively). respectively. All the synthesized 4-thiazolidinone derivatives were
inactive against HIV.
Miscellaneous thiazole derivatives: Chen et al. [108] presented
that thiazolidin-4-one derivatives 202–205 (Figure 16) were poten in Dawood et al. [92] prepared and assessed numerous bisthiazole
HIV-RT inhibitory assay with IC50 of 4.66, 2.91, 3.13 and 2.95 µM, analogs in in-vitro antiviral assay against four viruses (Poliovirus,
respectively. Methyl substitution at position 5 decreased the activity Influenza A (H1N1) virus, Hepatitis B virus, and Hepatitis C
(206, IC50=17.23 µM; 207, IC50=11.86 µM). Saeed et al. [109] studied virus). Analog 225 (Figure 18) displayed potent anti-HCV activity
thiazol-2-ylidene-benzamide derivatives 214 and 215 as HIV-2 (strain with an EC50 of 0.56 µM in luciferase reporter gene assay. The SAR
ROD) inhibitors with IC50 of 2.02 and 0.40 µg/mL, and SI of >52 and study specified that thiadiazole analogs have improved activity as
>313, respectively. Another studies revealed that trimethoxyphenyl compared to thiazole analogs at C5 and hydrophobic phenyl at N3
substitution (210) and t-butyl substitution (217) give somewhat of thiadiazole potentiated the activity. Furthermore, the presence of
less active compounds with EC50 of 2.44 and 1.89 µg/mL, and SI of large hydrophobic group at C5 of thiadiazole was not preferred and
>25 and >26, respectively [110]. Ghada et al. designed and prepared acetyl group at C5 gave a marked increase in the activity compared
Table 2: Disubstituted antiviral thiazole compounds.
Compound R1 R2 3Dpol. Inhibition, IC50 (µM)

101 3,4-diOH 4-NHAc 6.8

102 4-OH 4-NHAc NC

103 3-OH 4-NHAc 18.3

104 H 4-NHAc NC

105 3,4-dimethoxy 4-NHAc 26.4

106 3,4-difluoro 4-NHAc NC

107 4-hydroxy-3-methoxy 4-NHAc 3.7

108 3-hydroxy-4-methoxy 4-NHAc 7.8

109 3,4-dihydroxy 3-NHAc 5.8

110 3,4-dihydroxy H 10.8

111 3,4-dihydroxy 4-NHCOEt 9.2

112 3,4-dihydroxy 4-NHCOiPr 11.3

113 3,4-dihydroxy 4-NHCOPh 32.8

114 3,4-dihydroxy 3-COOH 0.8

115 3,4-dihydroxy 4-COOH 1.6

116 4-hydroxy-3-methoxy 3-COOH 0.79

117 3-chloro-4-hydroxy 3-COOH 0.39

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Table 3: Most active thiazole derivatives displaying antiviral activities.

Sl. No. Compound Activity Assay Virus/target

1 14 EC50: 14 µM Plaque reduction assay CVB -5

2 31 IC50: 0.65 !M Fluorescence -based peptide cleavage assay SARS-CoV3CL protease

3 46 IC50: 58 nM Viral replication assay RSV A2

4 68 IC50: 0.5 nM, EC50: 13 nM FRET assay Cell based assay in GS4.1 cells HCV

5 78 EC50: 130-1400 nM Viral cell replication assay HRV (pan -activity)

TK+ VZV strain OKA and TK- VZV strain
6 79 & 80 EC50: 20 µM Plaque forming units assay
07 -1
7 97 90.48 ± 3.88% % inhibition of TMV @ 100 µg/mL TMV

8 118 EC50: 13 µM Cell -based FMDV inhibition assay FMDV

EC50: 5.8 µM CPE -reduction assay

9 119 EC50: 1.32 µM Virus yield assay DENV

EC50: 1.39 µM Plaque reduction assay

10 137 EC50: 0.9 µM YFV inhibition assay YFV

Cell -culture based assay in Madin -Darby canine kidney
11 143 EC50: 0.73 !M A/H1N1
cells
12 176 IC50: 0.046 µM Cell based antiviral assay wild type HIV -1

13 181 EC50: 0.8 µM Virus yield inhibition assay Junin Virus (strain IV4454)

14 204 IC50: 0.39 nM P24 assay in MT-4 cells HIV-1NL43

Cell -culture based assay in human embryonic lung
15 206 EC50: 9 µM HSV-1
fibroblast cells
Cell -culture based assay in human embryonic lung
16 207 EC50: 14 µM VV
fibroblast cells
17 219 EC50: 0.07 µM Inhibition of viral CPE EBV

H H H
N NH 2 M/L N NH 2
N Li2PdCl4/MeOH N
Li 2PdCl 4/MeOH N S N Pd S
L2
N N N N
HN N N NH
H 2N NH2 Cl
H 2N NH2 Pd
S S 236
S S M/2 L
L1 235 K 2PdCl4/MeOH/H2O M/2 L
Li2PdCl4/MeOH
Figure 19: Pd(II) complex (235) with benzyl bis(thiosemicarbazone) (L1).
H
H
N NH 2
N
to ethoxycarbonyl group. Mourer et al. [114] prepared nine anionic N
N
N NH 2

Pd S
water-soluble calix [4] arene analogs (226–234) (Figure 18), N
Pd
S
S H H Cl 2
incorporating sulfonate, carboxylate or phosphonate groups, six of H2N
S N
them incorporating two 2,2’-bithiazole subunits in alternate position N N N
N
N N
at the lower rim. Synthesized compounds were checked for antiviral H
H H H

activity against various HIV strains (HIV-1 IIIB/MT4, HIV-1 LAI/ 238 237
CEM-SS, HIV-1 Bal/PBMC). Most of the compounds possessed Figure 20: Complexes of Pd(II) with FoTsc (L2) : [Pd(FoTsc)Cl] (236),
antiviral activity in the range of 10 µM to 50 µM. [Pd(FoTsc)(H2FoTsc)]Cl2 (237), and [Pd(FoTsc)2] (238).

Summarization of the most active thiazole compounds having

antiviral activities against various strains along with the assay type is
given in Table 3.
Pd complexes with antiviral activity: Antiviral activity of Pd(II)
complex (235) of benzyl bis(thiosemicarbazone) (L1) (Figure 19) was
evaluated against the replication of four HSV 1 and HSV 2 strains, two
of them wild type and two resistant mutants to ACV with different
TK gene mutations. The data were compared to the effect: (i) against
ACV sensitive wild strains Victoria (HSV 1) and BJA (HSV 2), and
(ii) against ACV resistant mutants R-100 (HSV 1) and PU (HSV 2).
The complex displayed remarkable activity against acyclovir-resistant
viruses. The data also suggested that the activity is dependent on virus
and on compound specificities as well [115].
The antiviral experiments of Pd (II) complexes with pyridine-
2-carbaldehyde thiosemicarbazone (HFoTsc) (Figure 20) were
evaluated by other researchers performed on continuous M.D.B.K.
cells with four HSV-1 and HSV-2 strains (two sensitive to acyclovir
and two resistant mutants). The complexes showed considerable
antiviral activity against HSV (Human Simplex Virus) replication
[116]. It has been observed that the ligand (L2), [HFoTsc] exhibits
poor activity than Pd (II) complexes against HSV. In addition, the
complexes of formula [Pd(FoTsc)(H2FoTsc)]Cl2 (237) is more
effective inhibitors of HSV replication than [Pd(FoTsc)Cl] (236)
followed by [Pd(FoTsc)2] (238), which could be useful in the treatment
of HSV infections, especially that resistant to acyclovir [117]. The data
obtained here show that when ligand is coordinated to a metal ion the
complex showed antiviral activity which depends on the metal ion
and the ligand specificities [116].

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Table 4: Antiviral activity of Pd (II) complexes.

Complex Bio-activity Virus tested
Victoria (HSV-1), BJA (HSV-2),
Benzyl bis(thiosemicarbazonate)Pd(II), IC50 = 0.3, 3, 0.01, 0.01 µM, IC50 = 0.4, 0.04, 1,
R-100 (HSV-1),
1,2,4-triazole bis(4 methylthiosemicarbazonate)Pd(II) 0.1 mM
PU (HSV-2)
[Pd(HFoTsc)2]Cl2, IC50 = 10 µM
[Pd(FoTsc)Cl], IC50 = >1.0 µM
HSV-1
[Pd(FoTsc)2], IC50 = 0.06 µM
pyridine-2-carbaldehyde thiosemicarbazone [HFoTsc] IC50= 0.001µM
IC50= 10, 0.01, 0.1, 0.1 µM
[Pd(FoTsc)(H2FoTsc)]Cl2,
IC50 =NA, ND, ND, ND µM Victoria (HSV-1),
[Pd(FoTsc)Cl],
IC50= 0.06, 1, 1, 1 µM BJA (HSV-2),
[Pd(FoTsc)2],
IC50 = 0.001, 0.1, 1, 1 µM R-100 (TKA, HSV-1),
[HFoTsc],
IC50 = 0.0002, 0.002, 0.02, 0.02 µM, PU (TKN, HSV-2)
ACV
NA: not active; ND: not done
cis-[(nucl)2Pd(pen)2]Cl2, >400, 240, >400 MIC (µg/ml) Vesicula stomatitis virus,
nucl = guanosine, >400, >400, >400 MIC (µg/ml) Coxsaekie virus B4,
inosine, 240, 240, >400 MIC (µg/ml) Respiratory syncytial
cytidine, or penciclovir >400, >400, >400 MIC (µg/ml)
L4 >40, >40, >40, >40, >40 MIC (µg/ml) Parainfluenza-3 virus, Reovirus-1,
L5 >200, >200, >200, >200, >200 MIC (µg/ml) Sindbis,
Pd[L1]Cl2, >40, >40, >40, >40, >40 MIC (µg/ml) Coxsackie virus B4,
Pd[L2]Cl2 >40, >40, >40, >40, >40 MIC (µg/ml) Punta toro virus
[C12H10N3S2Cl2Pd] IC50 = >100, 13.3, 91.9, 22, 34µM MDCK,
[C12H9N3S2Cl3Pd] IC50 = >100, 42.8, >100, 180, 60µM HEL,
[C18H14N3S2Cl2Pd] IC50 = 100, 100, >100, 254, 168µM CrFK,
[C12H9N4OS2Cl2Pd] IC50 = 55.3, 14.6, 39.1, 21, 30µM HeLa,
[C12H9N4OS2Cl2Pd] IC50 = >100, 51.7, >100, 385, 152µM CEM

OH OH CH 3 CH3
O O
9 1N 2 N
8 3 H H
MeOH
CH2OH CH 2OH
R N
N O CH2 OH Br 7 5
N4 Na2PdCl4 Br N
O 6 Cl
2' Pd
3'
N 1' N
N N 4' Cl
HN
6 N 6'
1 5 7 5'
2 8 L4 240
4 9
3 N O
H2N N
Pd CH 3 CH3
1' O O
9 1N 2 N
2' O 8 MeOH : CH2Cl2 H
3 H
1:1
CH2OCOCH 3 CH 2OCOCH3
3' Br 7 N4 Na2PdCl4 Br N
N 6 5 Cl
N 2' Pd
4' 4' 3' N
N 1'
4' Cl
OH OH
N 6'
R N O CH2OH 5'
L3 L5 241

OH
239
Figure 21: Molecular structure of Penciclovir (L3) and cis-[(nucl)2Pd(pen)2]
Cl2(239).
In order to improve and extend the antiviral activity of drugs
penciclovir (pen) (L3), Garoufis et al. [118] reported in 2001, the
activity of mixed nucleoside complexes of Pd(II) of formulae cis-
[(nucl)2Pd(pen)2]Cl2 (239) (Figure 21), where nuclear guanosine,
inosine, cytidine or penciclovir, against HSV-1 and HSV-2 strains.
It had been observed that the complexes displayed a similar activity
as penciclovir, but were not superior to the parent compound. In
addition, the complex with nuclear PEN showed highest activity due
to its four penciclovir molecules for each Pd atom in this case.
It was reported that the transition metals with cyclam ions strongly
and can potentially form a range of trans- and cis-configurations,
which may be recognized directly by co-receptor proteins. The Pd(II)-
cyclam complexes exhibited poor activity as anti-HIV agents, owing to
the inability of Pd(II) to bind to axial ligands and inability to espouse
configurations except trans one [119]. The square-planar Pd(II)
complexes (240 and 241) (Figure 22) with 7-bromo-1,3-dihydro-3-
Figure 22: Pd (II) complexes (240 and 241) with ligands L4 and L5, Pd[L4/
OH
L5]Cl2.
hydroxymethyl-1-methyl-5-(2'-pyridyl)-2H-1,4-benzodiazepin-2-
one ((+)-L4), and 3-acetoxymethyl-7-bromo-1,3-dihydro-1-methyl-
5-(2'-pyridyl)-2H-1,4-benzodiazepin-2-one ((±)-L5) were prepared.
The complexes were evaluated for their in vitro anti-viral activity
in different assay systems and complexes showed none or marginal
activity [120].
Gómez-Segura et al. [121] in 2009 were investigated the antiviral
activity of Pd (II)-ACV complex cis-[PdCl2(H2O)(N7-ACV)]
ACVxH2O (242) (Figure 23) assayed against HSV-1 strains. Herein
ACV is bind with Pd(II) through N(7) position and a pseudo-chelate
N7/O6 Pd(II) complex involving H-bonds with the cis H2O molecule
[122,123]. The recognition of secondary ACV molecules by the Pd(II)
derivative promotes cooperatively potent HSV-1 inhibitory activity
which, in turn, strongly depends on concentration conditions. In
the range of concentrations that is examined, the Pd(II) complex
under study was not cytotoxic to normal cells. The ACV molecule
in the outer coordination sphere did not revealed antiviral activity
regardless of that linked to Pd though cooperatively. The recognition
of free ACV by the complex can be hence attributed to hydrogen-

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O NH 2
Cl
H 2COH 2CH2COC C CH(CH 3)2

Cl
Pd O
N H
H NO3
H 2N N O N
N
Cu
N 6 N
7 5 1 NH N
NO3
O N NH 2
H
8 2 H
HO 9 4 N

N 3 (H3C) 2HC C COCH 2CH2OCH 2

N NH2
O NH2 O
249
242 Figure 26: Structure of Cu(II) complex (249) of valacyclovir.
Figure 23: Pd (II)-ACV complex (242).

R
H
N O OH2
N N
. nH2 O R= SO2 (1-Ni, 1-Co, 1-Cu, 1-Zn)
S M
N
R' 250 R= CO (3-Ni, 3-Co, 3-Cu)
N O OH2
S Pd
R
Cl
R
Cl R
(243-247) R
O O
N
Figure 24: Pd (II) complexes of thiosemicarbazones [243. R=H, R'=H; 244. 2Na+ R= SO2 (2-Ni, 2-Co, 2-Cu, 2-Zn)
251 M
. nH2O R= CO (4-Ni, 4-Co, 4-Cu)
R=H, R'=Cl; 245. R=H, R'=C6H5; 246. R=H, R'=NO2; 247. R= NO2, R'=H].
N O
O
R
R

Figure 27: Synthesized transition metal complexes.

H
of viral adsorption and viral replication, as there was no observable
Ph reduction of CPE at any of the applied concentrations. The result
P N
N- possibly due to the blockage of virus receptor binding sites on the cell
Ph Pd
surface and decreased viral adsorption in this case.
Cl O

Copper complexes as antiviral agents: Copper is a bio-essential

248
Figure 25: Sructure of Pd (II) complex (248) with 2-(diphenylphosphino)
benzaldehyde-1adamantoylhydrazone.
bonding interactions according to other related complexes of ACV
previously studied. In a first approximation, the combination of
Pd(II) and antiviral nucleoside molecules of ACV can be exploited
to design multifunctional drugs that may possess synergistic antiviral
activities.
Karaküçük-Iyidogan et al. in 2011 synthesized Pd(II) complexes
(243-247) with a series of thiosemicarbazones [124,125]. The
structures of complexes are shown in Figure 24. The antiviral
activities of all compounds have been tested against a wide variety
of DNA and RNA viruses. The antiviral evaluation showed that none
of the compounds evaluated endowed with anti-DNA or -RNA virus
activity at subtoxic concentrations except for the palladium complex
243. This compound exhibited slightly selective inhibition against
cytomegalovirus which may be due to an indirect cytostatic activity
of the compounds rather than a specific antiviral activity.
Simic et al. [126] in 2016 reported the antiviral activity of
Pd(II) complex (248) with the ligand of 2-(diphenylphosphino)
benzaldehyde-1-adamantoylhydrazone against poliovirus type 1
was assessed by examination of the Cytopathic Effect (CPE) in Hep-
2 cells. The result shown that this compound (Figure 25) does not
possess any antiviral activity against poliovirus type 1 at the level
element. Copper plays an important role in the endogenous oxidative
DNA damage associated with aging and cancer [127]. Hunter et
al. [128] reported in 2005, Cu2-xylyl-bicyclam exhibits anti-HIV
activity. It was used Cu2+-cyclam was used as a paramagnetic probe
to investigate interactions of the model protein target with metal-
locyclams in solution. [bis-(2-pyridylcarbonyl)-amido] copper(II)
nitrate dehydrate binds with an inhibition constant of 480 μM is an
example of substrated competitive inhibitors for HIV-1 protease.
Moreover, according to molecular modeling, the catalytic water
between Asp25 and Asp125 of HIV-1 protease is directly coordinated
to the Cu(II) ion [129]. The binding interaction of a water-soluble
Cu(II) complex of an antiviral drug, valacyclovir, (Figure 26) with
Calf Thymus DNA (CT-DNA) showed that Cu(II) complex most
likely interacts with DNA via a groove-binding mode [130].
García-Gallego et al. [131] in 2012, prepared some
aminosulfonated and aminocarboxylated ligands and used in the
synthesis of transition metal complexes (Figure 27) based on Cu(II).
Some of those complexes may constitute an interesting new class of
antiviral agents.
The copper complex with aminosulfonato ligand (Figure 28)
against HIV were observed 70% inhibition in the pre-infected cells
and more than 50% in the post-infected cells [132].
Horton and Varela [133] in 2000 reported antiviral activities
of three 3-deoxy-D-erythro-hex-2-ulose bis(thiosemicarbazone)
complexes of copper(II), ions against poliovirus type 1. [aqua(py
ridoxalthiosemicarbazonato) copper(II)] chloride monohydrate

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Asraf MA, et al.,
SO2
N O
Cu H2O
N OH
O steps of the replicative cycle. On the other hand, Ni(N'-(2-hydroxy-
SO2
252
Figure 28: Copper complex with aminosulfonato ligand.
inhibits HIV-1 replication in primary T cells and in cell line culture,
displaying its antiviral activity during the early post entry step of
HIV-1 replication. Furthermore, it has been proven to act specifically
against HIV-1 and not against other retroviruses such as HTLV [134].
The HIV inhibitory activity of (2-(1H-benzo[d]imidazol-2-yl)-4-
(6-hydroxy-4,7-dimethoxybenzofuran-5-carbonyl)-1H-pyrrol-1-yl)
copper(II) chloride hexahydrate was more potent than atevirdine as
well as the HCV-NS3-4A protease inhibitor activity of the compound
showed high potency [135].
Cobalt complexes as antiviral agents: Examples of cobalt
containing enzymes in biology include Vitamin B12, nitrile hydratase,
prolidase, glucose isomerase, methylmalonyl-CoA carboxytransferase,
aldehyde decarbonylase, lysine-2,3-aminomutase, bromoperoxidase
and methionine aminopeptidase. The structure bis-(6-hydroxy-
4,7-dimethoxybenzofuran-5-carbonyl)-8-oxo-8H-pyrimido[1,6-a]
pyrimidin-6-yloxy)coblt(III) chloridedihydrate have comparable
potency against purified recombinant HIV-1 [135]. Coblat(III)
complex CTC-96 was reported as an effective the treatment of
epithelial herpetic keratitis, one of the major causes of blindness
in industrial nations [136]. Cobalt bis(1,2-carbollides) described as
antiviral therapeutics, specifically against HIV protease [137,138].
{Na2[Co(ethylene-diamine-N,N,N′,N′-tetra-3-propionate ion)]}
• 4H2O inhibit HIV replication when treating both pre- and post-
infected PBMC cells [131]. [{(DES)MeN(CH2)2NMe(DES)}Co(H2O)2]
• 2H2O complex showed dual behavior like anti-HIV activity in
indicative of fusion inhibitor activity and inhibits replication of HIV,
which indicates that they may also act in subsequent steps of the
replicative cycle [132]. npapCo complex mentioned as moderated
active against Herpes simplex virus-1 (KOS), Herpes simplex
virus-2 (G) and Herpes simplex virus-1TK-VMW1837 [139]. Co(II)
complexes with o-diphenols and o-aminophenols ligands exhibited
antiviral activity with low toxicity [140].
Nickel complexes as antiviral agents: Xylylbicyclam
([1,4-phenylenebis-(methylene)]-bis-1,4,8,11-
tetraazacyclotetradecane), AMD3100, Mozobil, is a drug currently
in clinical trials for mobilization of stem cells to restore the
immune systems of cancer patients [141]. The drug has also been
in clinical trials for the treatment of HIV [142,143]. Xylylbicyclam
has been shown to be a highly selective antagonist for the CXCR4
co-receptor protein, which is used by HIV to enter human T cells
[144]. Since nickel has been shown to enhance co-receptor binding
of xylylbicyclam by a factor of 50 relative to the metal-free bicyclam
[145], it was elucidated that the nickel–cyclam complexes enhance
binding to the CXCR4 co-receptor and contribute to the anti-HIV
activity [146]. [bis-(citronellalthiosemicarbazonato)nickel(II)] was
reported as new potential anti-HIV drugs which frequently coinfect
Remedy Publications LLC.
Annals of Medicinal Chemistry
HIV-1 positive patients and interfere with AIDS progression [134].
[{(DES)MeN(CH2)2NMe(DES)}Ni(H2O)2] • 2H2O showed anti-
HIV activity in the pre-infected cell experiment, which indicative of
fusion inhibitor activity [132]. {Na2[Ni(ethylene-diamine-N,N,N′,N′-
tetra-3-propionate ion)]} • 4H2O complexes capable of inhibiting
HIV replication, pointing out that they may also act in subsequent
3-methoxybenzylidene)-2-hydroxybenzoylhydrazone)2 • 2H2O
complex showed very interesting activity against the DNA-viruses
herpes simplex virus (i.e., HSV-1, HSV-2, and an acyclovir-resistant
thymidine-kinase deficient HSV-1 strain) and VV [147]. Recently,
Three nickel complexes containing thiosemicarbazone ligand were
tested on influenza virus plaque formation showed inhibitory effects
on influenza virus plaque formation. Plaque formation by influenza A
viruses was almost completely inhibited by these complexes at 10 µg/
mL concentration [148].
Conclusions
As discussed in this literature review, medicinal applications of
organophosphorus compounds as drugs or drug candidates against
many viral diseases have extended significantly in recent years. OPs
are largely used in clinical practice as agents with antiviral properties.
In the past decade, a large number of thiazole compounds have
been synthesized and evaluated for antiviral activity. Compounds
46, 68, 176, 204 and 219 were the most potent monosubstituted,
disubstituted, and trisubstituted, fused and miscellaneous thiazole
compounds for anti-RSV, anti-HCV, anti-HIV-1, anti-HIV-1NL43,
and anti-EBV activity, respectively. Compounds 14, 31, 46, 68, 78,
79, 97, 118, 119, 137, 143, 181, 204, 206, 207 and 219 were the potent
antiviral against CVB, SARS, RSV, HCV, HRV, VZV, TMV, FMDV,
DENV, YFV, influenza virus, Junin virus, HIV-1, HSV, VV and EBV,
respectively. There is further scope for synthesis and evaluation of
novel thiazole compounds by taking the most active compounds as
lead structures.
Few of the inert Pd(II) complexes reported, some of these showed
considerable activity and some are found in marginal value against
different viruses mentioned in the discussion. All relevant results are
summarized in Tables 1 and comparisons, especially with standard,
can thus be made. It was observed that the antiviral activity depends
on the metal ion and the ligand specificities. This review aims to
encourage further research in the field, in order to discover and
establish new complexes with Pd and other metals as well, to be used
as antiviral agents.
The unique properties result in metal ions and their complexes
having prospective medicinal applications especially in designing
active antiviral drugs. Moreover, metal complexes could be
complementary to organic compounds.
Acknowledgement
Authors would like to acknowledge the International Science
Program (ISP), Uppsala University, Sweden and the Swedish
International Development Cooperation Agency (SIDA) for partial
financial support to conduct this investigation. The authors also
acknowledge the infrastructure and support of the Faculty of Science,
Rajshahi University, Bangladesh. The authors are also thankful to
Department of Chemistry, Rajshahi University, Bangladesh for
providing laboratory facilities to conduct this works.
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Asraf MA, et al.,
References
1. Severe Acute Respiratory Syndrome (SARS).
2. Middle East Respiratory Syndrome Coronavirus (MERS-CoV)
3. Number of Cases and Deaths in Guinea, Liberia, and Sierra Leone during
the 2014-2016 West Africa Ebola Outbreak.
4. WHO. Dengue and severe dengue.
5. HIV/AIDS
6. h. w. w. i. m. n. r. h. e. a. J. 2018.
7. Global hepatitis report. 2017.
8. Hepatitis.
9. Baldanti F, Underwood MR, Stanat SC, Biron KK, Chou S, Sarasini A, et
al. Single amino acid changes in the DNA polymerase confer foscarnet
resistance and slow-growth phenotype, while mutations in the UL97-
encoded phosphotransferase confer ganciclovir resistance in three
double-resistant human cytomegalovirus strains recovered from patients
with AIDS. J Virol. 1996;70(3):1390-5.
10. Chou S, Guentzel S, Michels KR, Miner RC, Drew WL. Frequency of
UL97 phosphotransferase mutations related to ganciclovir resistance in
clinical cytomegalovirus isolates. J Infect Dis. 1995;172(1):239-42.
11. Ghany MG, Doo EC. Antiviral Resistance and Hepatitis B Therapy. J
Hepatol. 2009;49:S174-S84.
12. Zoulim F. Hepatitis B virus resistance to antiviral drugs: Where are we
going? Liver Int. 2011;31(1):111-16.
13. Morfin F, Thouvenot D. Herpes simplex virus resistance to antiviral
drugs. J Clin Virol. 2003;26(1):29-37.
14. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350(10):1023-
35.
15. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T.
Efavirenz plasma levels can predict treatment failure and central nervous
system side effects in hiv-1-infected patients. AIDS. 2001;15(1):71-75.
16. Martinez JP, Sasse F, Brönstrup M, Diez J. A meyerhans antiviral
drug discovery: Broad-spectrum drugs from nature. Nat Prod Rep.
2015;32(1):29-48.
17. Wiehe A, Brien JMO, Senge MO. Trends and targets in antiviral
phototherapy. Photochem Photobiol Sci. 2019;18(11):2565-12.
18. Ansari A, Ali A, Asif M. Review: Biologically active pyrazole derivatives.
New J Chem. 2017;41:16-41.
19. Ammassari A, Murri R, Pezzotti P, Trotta MP, Ravasio L, De PL, et al.
Self-reported symptoms and medication side effects influence adherence
to highly active antiretroviral therapy in persons with HIV Infection. J
Acquir Immune Defic Syndr. 2001;28(5):445-9.
20. Ewers EC, Shah PA, Carmichael MG, Ferguson TM. In Concurrent
systemic chemo immunotherapy and sofosbuvir-based antiviral
treatment in a hepatitis C virus-infected patient with diffuse large B-cell
lymphoma. Open Forum Infect Dis. 2016;3(4):ofw223.
21. Fried MW. Side effects of therapy of hepatitis C and their management.
Hepatology. 2002;36:S237-S244.
22. Hanson KE, Swaminathan S. Cytomegalovirus antiviral drug resistance:
Future prospects for prevention, detection and management. Future
Microbiol. 2015;10(10):1545-8.
23. BrennanT, Shrank W. New expensive treatments for hepatitis C infection.
JAMA. 2014;312(6):593-94.
24. Demkowicz S, Rachon J, Daśko M, Kozak W. Selected organophosphorus
compounds with biological activity. Applications in medicine. RSC
Advances. 2016; 6:7101-12.
Remedy Publications LLC.
Annals of Medicinal Chemistry
25. Marklund A, Andersson B, Haglund P. Screening of organophosphorus
compounds and their distribution in various indoor environments.
Chemosphere. 2003;53:1137-46.
26. Singh BK, Walker A. Microbial degradation of organophosphorus
compounds. FEMS Microbiology Reviews. 2006;30:428-471.
27. Hudson HR, Wardle NJ, Bligh SWA, Greiner I, Grun A, Keglevich G.
N-heterocyclic dronic acids: Applications and synthesis. Mini Rev Med
Chem . 2012;12(4):313-25.
28. De Clercq E. Antivirals: Past, present and future. Biochem Pharmacol.
2013;85(6):727-44.
29. McKellar QA, Jackson F. Veterinary anthelmintics: Old and new. Trends
Parasitol. 2004;20(10):456-61
30. Terry Jr AV. Functional consequences of repeated organophosphate
exposure: Potential non-cholinergic mechanisms. Pharmacol Ther.
2012;134(3):355-65.
31. Hantzsch A, Weber J. Ueber verbindungen des thiazols (pyridins der
thiophenreihe). Berichte der Deutschen Chemischen Gesellschaft.
1887;20:3118-32.
32. Bishayee A, Karmakar R, Mandal A, Kundu S, Chatterjee M. Vanadium-
mediated chemoprotection against chemical hepatocarcinogenesis in
rats: Haematological and histological characteristics. Eur J Cancer Prev.
1997;6(1):58-70.
33. Laczkowski Z, Biernasiuk K, Baranowska-Laczkowska A, Misiura A,
Malm K, Plech A. Synthesis, antibacterial activity, interaction with
nucleobase and molecular docking studies of 4-formylbenzoic acid based
thiazoles. Med Chem. 2016;12(6):553-62.
34. Hargrave KD, Hess FK, Oliver JT. N-(4-Substituted-thiazolyl) oxamic
acid derivatives, new series of potent, orally active antiallergy agents. J
Med Chem. 1983;26(8):1158-63.
35. Patt WC, Hamilton HW, Taylor MD, Ryan MJ, Taylor Jr DG, Connolly
CJ, et al. Structure-activity relationships of a series of 2-amino-4-thiazole-
containing rennin inhibitors. J Med Chem. 1992;35(14):2562-72.
36. Jubie S, Gowramma B, Nitin K, Jawahar N, Kalirajan R, Gomathy S, et al.
Synthesis and biological evaluation of some 3-(methoxy phenyl)-2-aryl-
thiazolidin-4-one derivatives. Indian J Pharm Sci. 2009;1;32-38.
37. Muhammad ZA, Masaret GS, Amin MM, Abdallah M, Farghaly
AT. Anti-inflammatory, analgesic and anti-ulcerogenic activities of
novel bis-thiadiazoles, bis-thiazoles and Bis-formazanes. Med Chem.
2017;13(3):226-38.
38. Karade HN, Acharya B, Sathe M, Kaushik M. Design, synthesis, and
antimalarial evaluation of thiazole-derived amino acids. Med Chem Res.
2008;17:19-29.
39. Vengurlekar S, Prachand S, Jain S, Gupta R. Synthesis and evaluation
of some thiazole derivatives as an antifungal agent. Int J Pharm Life Sci.
2014;5(5):3526-3520.
40. Pattan SR, Dighe N, Nirmal S, Merekar A, Laware R, Shinde H, et al.
Synthesis and biological evaluation of some substituted amino thiazole
derivatives. Asian J Res Chem. 2009;2(2):196-201.
41. Gurupadayya BM, Gopal M, Padmashali B, Manohara Y. Synthesis and
pharmacological evaluation of azetidin-2-ones and thiazolidin-4-ones
encompassing benzothiazole. Indian J Pharma Sci 2008;70(5):572-7.
42. Koufaki M, Kiziridi C, Nikoloudaki F, Alexis MN. Design and synthesis
of 1, 2-dithiolane derivatives and evaluation of their neuroprotective
activity. Bioorg Med Chem Lett . 2007;17(15):4223-7.
43. Ergenç N, Çapan G, Günay NS, Özkirimli S, Güngör M, Özbey S,
et al. Synthesis and hypnotic activity of new 4-thiazolidinone and
2-thioxo-4, 5-imidazolidinedione derivatives. Arch Pharm (Weinheim).
1999;332(10):343-7.
15 2020 | Volume 1 | Issue 1 | Article 1004
Asraf MA, et al.,
44. Andreani A, Rambaldi M, Mascellani G, Rugarli P. Synthesis and diuretic
activity of imidazo [2, 1-b] thiazole acetohydrazones. Euro J Med Chem.
1987;22:19-22.
45. Frezza M, Hindo S, Chen D, Davenport A, Schmitt S, Tomco D, et al.
Novel metals and metal complexes as platforms for cancer therapy. Curr
Pharm Des. 2010;16(16):1813–25.
46. Das M, Livingstone S. Cytotoxic action of some transition metal chelates
of schiff bases derived from S-methyldithiocarbazate. Br J Cancer.
1978;37(3): 466–69.
47. Merchant B. Gold, the noble metal and the paradoxes of its toxicology.
Biologicals. 1998;26(1):49-59
48. Bertini G, Gray H, Gray HB, Stiefel E, Valentine JS, Stiefel EI. Biological
inorganic chemistry: Structure and reactivity. University Science Books.
2007.
49. Asraf MA, Rahman MM, Kabiraz DC, Ansary RH, Hossen MF, Haque
MF, et al. Structural elucidation, 3D molecular modeling and antibacterial
activity of Ni (II), Co (II), Cu (II) and Mn (II) complexes containing
salophen ligand. Asian J App Chem Res. 2019;3(3):1-15.
50. Sarker D, Karim MR, Haque MM, Zamir R, Asraf MA. Copper (II)
complex of salicylaldehyde semicarbazone: Synthesis, characterization
and antibacterial activity. Asian J Chem Sci. 2019;16(4)1-8.
51. Sarker D, Reza MY, Haque MM, Zamir R, Asraf MA. Synthesis,
characterization, antibacterial and thermal studies of Cu (II) complex
of thiophene-2-aldehyde semicarbazone. Asian J App Chem Res.
2019;4(4):1-10.
52. Asraf MA, Ezugwu CI, ZakariaC, Verpoort F. Homogeneous
photochemical water oxidation with metal salophen complexes in neutral
media. Photochem Photobiol Sci. 2019;18:2782-91.
53. Asraf MA, Younus HA, Ezugwu CI, Mehta A, Verpoort F. Cobalt
salophen complexes for light-driven water oxidation. Catal Sci Technol.
2015;5:4901-25. 2016;6(11):4271-82.
54. Asraf MA, Younus HA, Yusubov M, Verpoort F. Earth-abundant
metal complexes as catalysts for water oxidation; is it homogeneous or
heterogeneous? Catal Sci Technol. 2015;5:4901-25
55. Loginova NV, Tat’yana V, Zheldakova RA, Chernyavskaya AA, Osipovich
NP, Glushonok GK, et al. Copper (II) complexes of sterically hindered
o-diphenol derivatives: Synthesis, characterization and microbiological
studies. Central Euro J Chem. 2006;4:440-57.
56. Prusoff WH. Synthesis and biological activities of iododeoxyuridine, an
analog of thymidine. Biochim Biophys Acta. 1959;32(1):295-6.
57. Pat U. 4724233A 1985.
58. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate. Clinical
Pharmacokinetics. 2004;43(9):595-612.
59. Lee WA, He GX, Eisenberg E, Cihlar T, Swaminathan S, Mulato A, et
al. Selective intracellular activation of a novel prodrug of the human
immunodeficiency virus reverse transcriptase inhibitor tenofovir leads
to preferential distribution and accumulation in lymphatic tissue.
Antimicrob Agents Chemother. 2005;49(5):1898–06.
60. Eldrup AB, Prhavc M, Brooks J, Bhat B, Prakash TP, Song Q, et al.
Structure− activity relationship of heterobase-modified 2 ‘-C-methyl
ribonucleosides as inhibitors of hepatitis C virus RNA replication. J Med
Chem. 2004;47(21):5284-97.
61. Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, et al.
Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide
prodrug (PSI-7977) for the treatment of hepatitis C virus. J Med Chem.
2010;53(19);7202–18.
62. Fung A, Jin Z, Dyatkina N, Wang G, Beigelman L, Deval J. Efficiency of
incorporation and chain termination determines the inhibition potency
Remedy Publications LLC.
Annals of Medicinal Chemistry
of 2′-modified nucleotide analogs against hepatitis C virus polymerase.
Antimicrob Agents Chemother. 2014;58(7):3636–45.
63. Ray AS, Vela JE, Olson L, Fridland A. Effective metabolism and long
intracellular half life of the anti-hepatitis B agent adefovir in hepatic cells.
Biochem Pharmacol. 2004;68(9):1825-31.
64. Dando TM, Plosker GL. Adefovir dipivoxil: A review of its use in chronic
hepatitis B. Drugs. 2003;63(20):2215-34.
65. De Clercq E. New inhibitors of Human Cytomegalovirus (HCMV) on the
horizon. J Antimicrob Chemother. 2003;51(5):1079-83.
66. Ahgren C, Backro K, Bell F, Cantrell A, Clemens M, Colacino J, et al. The
PETT series, a new class of potent nonnucleoside inhibitors of human
immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents
Chemother. 1995;39(6):1329–35.
67. Stefanska J, Nowicka G, Struga M, Szulczyk D, Koziol AE, Augustynowicz-
Kopec E, et al. Antimicrobial and anti-biofilm activity of thiourea
derivatives incorporating a 2-aminothiazole scaffold. Chem Pharm Bull
(Tokyo). 2015;63(3):225-36.
68. Regnier T, Sarma D, Hidaka K, Bacha U, Freire E, Hayashi Y, et al. New
developments for the design, synthesis and biological evaluation of potent
SARS-CoV 3CLpro inhibitors. Bioorg Med Chem Lett. 2009;19(10):2722-
7
69. Konno S, Thanigaimalai P, Yamamoto T, Nakada K, Kakiuchi R,
Takayama K, et al. Design and synthesis of new tripeptide-type SARS-
CoV 3CL protease inhibitors containing an electrophilic arylketone
moiety. Bioorg Med Chem. 2013;21(2):412-24.
70. Cianci C, Yu KL, Combrink K, Sin N, Pearce B, Wang A, et al. Orally
active fusion inhibitor of respiratory syncytial virus. Antimicrob Agents
Chemother. 2004;48(2):413-22.
71. Pryde DC, Tran TD, Gardner I, Bright H, Stupple P, Galan S, et al. Non-
benzimidazole containing inhibitors of respiratory syncytial virus. Bioorg
Med Chem Lett. 2013;23(3):827-33
72. Duca M, Malnuit V, Barbault F, Benhida R. Design of novel RNA ligands
that bind stem–bulge HIV-1 TAR RNA. Chem Commun (Camb).
2010;46(33):6162-4.
73. Joly JP, Mata G, Eldin P, Briant L, Fontaine-Vive F, Duca M, et al.
Artificial nucleobase–amino acid conjugates: A new class of TAR RNA
binding agents. Chemistry. 2014;20(7):2071-9.
74. Kim J, Ok T, Park C, So W, Jo M, Kim Y, et al. A novel 3,
4-dihydropyrimidin-2 (1H)-one: HIV-1 replication inhibitors with
improved metabolic stability. Bioorg Med Chem Lett. 2012;22(7):2522-6.
75. Distinto S, Esposito F, Kirchmair J, Cardia MC, Gaspari M, Maccioni
E, et al. Identification of HIV-1 reverse transcriptase dual inhibitors by
a combined shape-, 2D-fingerprint-and pharmacophore-based virtual
screening approach. Eur J Med Chem. 2012;50:216-29.
76. Meleddu R, Distinto S, Corona A, Bianco G, Cannas V, Esposito F,
et al. (3Z)-3-(2-[4-(aryl)-1, 3-thiazol-2-yl] hydrazin-1-ylidene)-2,
3-dihydro-1H-indol-2-one derivatives as dual inhibitors of HIV-1 reverse
transcriptase. Eur J Med Chem. 2015;93:452-60.
77. Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, et al.
BCX-1812 (RWJ-270201): Discovery of a novel, highly potent, orally
active, and selective influenza neuraminidase inhibitor through structure-
based drug design. J Med Chem. 2000;43(19):3482-6.
78. Liu Y, Zhang L, Gong J, Fang H, Liu A, Du G, et al. Design, synthesis, and
biological activity of thiazole derivatives as novel influenza neuraminidase
inhibitors. J Enzyme Inhib Med Chem. 2011;26(4):506-13.
79. Barbier J, Wegner J, Benson S, Gentzsch J, Pietschmann T, Kirschning
A. Total synthesis of a noricumazole a library and evaluation of HCV
inhibition. Chem–A Euro J. 2012;18(29):9083-90.
16 2020 | Volume 1 | Issue 1 | Article 1004
Asraf MA, et al.,
80. Kanda T, Yokosuka O, Omata M. Faldaprevir for the Treatment of
Hepatitis C. Int J Mol Sci. 2015;16(3):4985–96.
81. Goudreau N, Llinas-Brunet M. The therapeutic potential of NS3
protease inhibitors in HCV infection. Expert Opin Investig Drugs.
2005;14(9):1129-44.
82. Brunet LM, Bailey MD, Bolger G, Brochu C, Faucher AM, Ferland JM, et
al. Structure− activity study on a novel series of macrocyclic inhibitors of
the hepatitis C virus NS3 protease leading to the discovery of BILN 2061.
J Med Chem. 2004;47(7):1605-8.
83. Parsy C, Alexandre FR, Brandt G, Caillet C, Cappelle S, Chaves D, et
al. Structure-based design of a novel series of azetidine inhibitors of
the hepatitis C virus NS3/4A serine protease. Bioorg Med Chem Lett.
2014;24(18):4444-49.
84. Parsy CC, Alexandre FR, Bidau V, Bonnaterre F, Brandt G, Caillet C,
et al. Discovery and structural diversity of the hepatitis C virus NS3/4A
serine protease inhibitor series leading to clinical candidate IDX320.
Bioorg Med Chem Lett. 2015;(22):5427-36.
85. Zhong QF, Liu R, Liu G. Structure–activity relationship studies on
quinoxalin-2 (1H)-one derivatives containing thiazol-2-amine against
hepatitis C virus leading to the discovery of BH6870. Mol Divers.
2015;19(4):829-53.
86. Lin HM, Wang JC, Hu HS, Wu PS, Yang CC, Wu CP, et al. Resistance
analysis and characterization of a thiazole analogue, BP008, as a potent
hepatitis C virus NS5A inhibitor. Antimicrob Agents Chemother.
2012;56(1):44-53.
87. Décor A, Grand-Maître C, Hucke O, O’Meara J, Kuhn C, Constantineau-
Forget L, et al. Design, synthesis and biological evaluation of novel
aminothiazoles as antiviral compounds acting against human rhinovirus.
Bioorg Med Chem Lett. 2013;23(13):3841-7.
88. El-Sabbagh OI. Synthesis of some new benzisothiazolone and
benzenesulfonamide derivatives of biological interest starting from
saccharin sodium. Arch Pharm (Weinheim). 2013;346(10):733-42.
89. Li FY, Guo XF, Fan ZJ, Zhang YQ, Zong GN, Qian XL, et al. Synthesis
and biological activities of novel 2-amino-1, 3-thiazole-4-carboxylic acid
derivatives. Chin Chem Lett. 2015;26(10):1315-18.
90. Jeong Kw, Lee Jh, Park Sm, Choi JH, Jeong DY, Choi DH, et al. Synthesis
and in-vitro evaluation of 2-amino-4-arylthiazole as inhibitor of 3D
polymerase against Foot-and-Mouth Disease (FMD). Eur J Med Chem.
2015;102:387-97.
91. Zhou Z, Khaliq M, Suk JE, Patkar C, Li L, Kuhn RJ, et al. Antiviral
compounds discovered by virtual screening of small−molecule libraries
against dengue virus E protein. ACS Chem Biol. 2008;3(12):765-75.
92. Dawood KM, Eldebss TM, El-Zahabi HS, Yousef MH. Synthesis and
antiviral activity of some new bis-1, 3-thiazole derivatives. Eur J Med
Chem. 2015;102:266-76.
93. Li Z, Khaliq M, Zhou Z, Post CB, Kuhn RJ, Cushman M. Design, synthesis,
and biological evaluation of antiviral agents targeting flavivirus envelope
proteins. J Med Chem. 2008;51(15):4660-71
94. Pacca CC, Marques RE, Espindola JWP, Oliveira Filho GB, Leite
ACL, Teixeira MM, et al. Thiosemicarbazones and Phthalyl-Thiazoles
compounds exert antiviral activity against yellow fever virus and Saint
Louis encephalitis virus. Biomed Pharmacother. 2017;87:381-87.
95. Madni M, Hameed S, Ahmed MN, Tahir MN, Al-Masoudi NA,
Pannecouque C. Synthesis, crystal structure, anti-HIV, and
antiproliferative activity of new pyrazolylthiazole derivatives. Med Chem
Res. 2017;26:2653-65.
96. Osman H, Yusufzai SK, Khan MS, Razik BMA, Sulaiman O, Mohamad S,
et al. New thiazolyl-coumarin hybrids: Design, synthesis, characterization,
X-ray crystal structure, antibacterial and antiviral evaluation. J Mol
Structure. 2018;1166:147-54.
Remedy Publications LLC.
Annals of Medicinal Chemistry
97. Mayhoub AS, Khaliq M, Botting C, Li Z, Kuhn RJ, Cushman M. An
investigation of phenylthiazole antiflaviviral agents. Bioorg Med Chem.
2011;19(12):3845-54.
98. Mayhoub AS, Khaliq M, Kuhn RJ, Cushman M. Design, synthesis, and
biological evaluation of thiazoles targeting flavivirus envelope proteins. J
Med Chem . 2011;54(6):1704-14.
99. Zhan P, Wang L, Liu H, Chen X, Li X, Jiang X, et al. Arylazolyl (azinyl)
thioacetanilide. Part 9: Synthesis and biological investigation of
thiazolylthioacetamides derivatives as a novel class of potential antiviral
agents. Arch Pharm Res. 2012;35(6):975-86.
100. Zhongliang Xu, Ba M, Zhou H, Cao Y, Tang C, Yang Y, et al. 2, 4,
5-Trisubstituted thiazole derivatives: A novel and potent class of non-
nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase.
Eur J Med Chem. 2014;85:27-42.
101. Atamanyuk D, Zimenkovsky B, Atamanyuk V, Lesyk R.
5-Ethoxymethylidene-4-thioxo-2-thiazolidinone as versatile building
block for novel biorelevant small molecules with thiopyrano [2, 3-d][1, 3]
thiazole core. Synthetic Communications. 2014;44:237-44.
102. Barradas JS, Errea MI, D'Accorso NB, Sepúlveda CS, Damonte EB.
Imidazo [2, 1-b] thiazole carbohydrate derivatives: Synthesis and antiviral
activity against Junin virus, agent of Argentine hemorrhagic fever. Eur J
Med Chem . 2011;46(1):259-64.
103. Barradas JS, Errea MI, Sepúlveda C, Damonte EB, D'accorso NB.
Microwave-assisted synthesis of pyrrolo [2, 1-b] thiazoles linked to a
carbohydrate moiety. J Heterocyclic Chem. 2014;51(1):96-100.
104. Shotwell JB, Baskaran S, Chong P, Creech KL, Crosby RM, Dickson
H, et al. Imidazo [1, 2-a] pyridines that directly interact with hepatitis
C NS4B: Initial preclinical characterization. ACS Med Chem Letters.
2012;3(7):565-69.
105. Wang NY, Xu Y, Zuo WQ, Xiao KJ, Liu L. Discovery of imidazo [2, 1-b]
thiazole HCV NS4B inhibitors exhibiting synergistic effect with other
direct-acting antiviral agents. J Med Chem. 2015;58(6):2764-78.
106. Ghosh AK, Rao KV, Nyalapatla PR, Osswald HL, Martyr CD, Aoki M, et
al. Design and development of highly potent HIV-1 protease inhibitors
with a crown-like oxotricyclic core as the P2-ligand to combat multidrug-
resistant HIV variants. J Med Chem. 2017;60(10):4267-78.
107. Ulusoy Güzeldemirci N, Karaman B, KÜÇÜKBASMACI Ö.
Antibacterial, antitubercular and antiviral activity evaluations of some
Arylidenehydrazide derivatives bearing imidazo [2, 1-b]thiazole moiety.
Turk J Pharm Sciv. 2017;14(2);157-63.
108. Chen H, Guo Z, Yin Q, Duan X, Gu Y, Li X. Design, synthesis and HIV-
RT inhibitory activity of novel thiazolidin-4-one derivatives. Front Chem
Sci Eng. 2011;5:231-37.
109. Saeed A, Al-Masoudi NA, Ahmed AA, Pannecouque C. New substituted
thiazol-2-ylidene-benzamides and their reaction with 1-Aza-2-
azoniaallene salts. Synthesis and anti-HIV activity. Zeitschrift für
Naturforschung B. 2011;66(5):512-20.
110. Saeed A, Al-Masoudi NA, Pannecouque C. In-vitro anti-HIV activity
of new thiazol-2-ylidene substituted benzamide analogues. Der Pharma
Chemica. 2012;4(1):106-15.
111. Sithambaresan M, Kurup MP. 2-(3-Ethoxy-2-hydroxybenzylidene)-
N-phenylhydrazinecarboxamide. Acta Crystallographica Section E:
Structure Reports Online. 2011;67(11):o2972-o2972.
112. Lozynskyi A, Golota S, Zimenkovsky B, Atamanyuk D, Gzella A, Lesyk
R. Synthesis, anticancer and antiviral activities of novel thiopyrano [2,
3-d] thiazole-6-carbaldehydes. Phosphorus, Sulfur, and Silicon and the
Related Elements. 2016;191(9):1245-49.
113. Güzeldemirci NU, Pehlivan E, Naesens L. Synthesis and antiviral activity
evaluation of new 4-thiazolidinones bearing an imidazo [2, 1-b] thiazole
moiety. Marmara Pharm J. 2018;22:237-48.
17 2020 | Volume 1 | Issue 1 | Article 1004
Asraf MA, et al.,
114. Mourer M, Psychogios N, Laumond G, Aubertin AM, Regnouf-de-Vains
JB. Synthesis and anti-HIV evaluation of water-soluble calixarene-based
bithiazolyl podands. Bioorg Med Chem. 2010;18(1):36-45.
115. Genova P, Varadinova T, Matesanz AI, Marinova D, Souza P. Toxic
effects of bis(thiosemicarbazone) compounds and its palladium (II)
complexes on herpes simplex virus growth. Toxicol Appl Pharmacol.
2004;197(2):107-12.
116. Varadinova T, Kovala-Demertzi D, Rupelieva M, Demertzis M, Genova
P. Antiviral activity of platinum (II) and palladium (II) complexes
of pyridine-2-carbaldehyde thiosemicarbazone. Acta Virologica.
2001;45(2):87-94.
117. Kovala-Demertzi D, Varadinova T, Genova P, Souza P, Demertzis M.
Platinum (II) and palladium (II) complexes of pyridine-2-carbaldehyde
thiosemicarbazone as alternative antiherpes simplex virus agents.
Bioinorg Chem Appl. 2007;2007:56165.
118. Garoufis A, Hadjikakou S, Hadjiliadis N. Palladium coordination
compounds as anti-viral, anti-fungal, anti-microbial and anti-tumor
agents. Coord Chem Rev. 2009;253:1384-97.
119. Hunter T, Paisey SJ, Park Hs, Cleghorn L, Parkin A, Parsons S, et al.
Configurations of metallocyclams and relevance to anti-HIV activity. J
Inorg Biochem . 2004;98(5):713-9.
120. Višnjevac A, Tušek-Božić L, Majerić-Elenkov M, Hameršak Z, Kooijman
H, De Clercq E, et al. Synthesis, structural characterisation and biological
activity of Zn (II) and Pd (II) complexes of 3-substituted 5-(2′-pyridyl)-1,
4-benzodiazepin-2-one derivatives. Polyhedron. 2002;21:2567-77.
121. Gómez-Segura J, Caballero S, Moreno V, Prieto M, Bosch A. Palladium
(II) binding to N (7) of acyclovir: DNA interaction and Herpes Simplex
Virus (HSV-1) inhibitory activity. J Inorg Biochem. 2009;103(1):128-34.
122. Matsumoto H, Kaneko C, Mori T, Mizuno Y. A series of novel acyclic
nucleosides. II. Synthesis of acyclic nucleosides bearing an imidazo [4,
5-d][1, 3] oxazine ring. J Heterocyclic Chem. 1990;27:1307-11.
123. Sletten E. Crystal structure of a copper–nucleoside analogue. J Chem
Society D: Chem Commun. 1971;558.
124. Ari E, Bedir H, Yildirim S, Yildirim T. Androgenic responses of 64
ornamental pepper (Capsicum annuum L.) genotypes to shed-microspore
culture in the autumn season. Turk J Biol. 2016;40(3):706-17.
125. Karaküçük-İyidoğan A, Taşdemir D, Oruç-Emre EE, Balzarini J. Novel
platinum(II) and palladium(II) complexes of thiosemicarbazones derived
from 5-substitutedthiophene-2-carboxaldehydes and their antiviral and
cytotoxic activities. Eur J Med Chem. 2011;46(11):5616-24.
126. Šmidling D, MITIć-ćULAfIć D, VUkOVIć-GAčIć B, Simić D, Knežević-
Vukčević J. Evaluation of antiviral activity of fractionated extracts of sage
Salvia officinalis L. (Lamiaceae). Arch Biol Sci. 2008;60:421-29.
127. Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the
degenerative diseases of aging. Proc Natl Acad Sci. 1993;90(17);7915-22.
128. Hunter TM, McNae IW, Liang X, Bella J, Parsons S, Walkinshaw MD,
et al. recognition of macrocycles: Binding of anti-HIV metallocyclams to
lysozyme. Procd Natl Acad Sci. 2005;102(27):2288-92.
129. Meggers E. Exploring biologically relevant chemical space with metal
complexes. Curr Opin Chem Biol. 2007;11(13):287-92.
130. Shahabadi N, Fatahi P. DNA interaction studies of a platinum(II) complex
containing l-histidine and 1,10-phenanthroline ligands. DNA Cell Biol.
2012;31(5):1328-34.
131. García-Gallego S, Rodríguez JS, Jiménez JL, Cangiotti M, Ottaviani
MF, Muñoz-Fernández MÁ, et al. Polyanionic N-donor ligands as
chelating agents in transition metal complexes: Synthesis, structural
characterization and antiviral properties against HIV. Dalton Trans.
2012;41(21):6488-99.
Remedy Publications LLC.
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132. García-Gallego S, Serramía MJ, Arnaiz E, Díaz L, Muñoz-Fernández MA,
Gómez-Sal P, et al. Transition-metal complexes based on a sulfonate-
containing N-donor ligand and their use as HIV antiviral agents. Eur J
Inorg Chem. 2011;201(10):1657-65.
133. Horton D, Varela O. Cu, Pt, and Pd complexes of the 3-deoxy-1,2-
bis(thiosemicarbazone) derived from D-glucose. Carbohydr Res.
2000;328(3):425-29.
134. Pelosi G, Bisceglie F, Bignami F, Ronzi P, Schiavone P, Re MC, et al.
Antiretroviral activity of thiosemicarbazone metal complexes. J Med
Chem . 2010;53(24):8765-9.
135. Galal SA, El-All ASA, Hegab KH, Magd-El-Din AA, Youssef NS, El-
Diwani HI. Novel antiviral benzofuran-transition metal complexes. Eur
J Med Chem. 2010;45(7):3035-46.
136. Asbell PA, Epstein SP, Wallace JA, Epstein D, Stewart CC, Burger RM.
Efficacy of cobalt chelates in the rabbit eye model for epithelial herpetic
keratitis cornea. 1998;17(5):550-7.
137. Kaya M, Yenikaya C, Colak AT, Colak F. Synthesis, spectral, thermal and
biological studies of Co(III) and binuclear Ni(II) complexes with a novel
amine-imine-oxime ligand. Russ J Gen Chem. 2008;78:1808-15.
138. Chang EL, Simmers C, Knight DA. Cobalt complexes as antiviral and
antibacterial agents. Pharmaceuticals. 2010;3(6):1711-28.
139. Abdel-Rahman LH, Abu-Dief AM, Newair EF, Hamdan SK. Some new
nano-sized Cr(III), Fe(II), Co(II), and Ni(II) complexes incorporating
2-((E)-(pyridine-2-ylimino)methyl)napthalen-1-ol Ligand: structural
characterization, electrochemical, antioxidant, antimicrobial, antiviral
assessment and DNA Interaction. J Photochem Photobiol B. 2016;160:18-
31.
140. Jurca T, Marian E, Vicaş LG, Mureşan ME, Fritea L. Spectroscopic
analyses developments and applications. 2017.
141. De Clercq E. The design of drugs for HIV and HCV. Nat Rev Drug discov.
2007;6(12):1001-18.
142. De Clercq E, Yamamoto N, Pauwels R, Baba M, Schols D, Nakashima H,
et al. Potent and selective inhibition of Human Immunodeficiency Virus
(HIV)-1 and HIV-2 replication by a class of bicyclams interacting with
a viral uncoating event. Proc Natl Acad Sci U S A. 1992;89(12):5286–90.
143. Bridger GJ, Skerlj RT, Thornton D, Padmanabhan S, Martellucci SA,
Henson GW, et al. Synthesis and structure-activity relationships of
phenylenebis (methylene)-linked bis-tetraazamacrocycles that inhibit
HIV replication. Effects of macrocyclic ring size and substituents on the
aromatic linker. Med Chem. 1995;38(2):366-78.
144. E De Clercq. Inhibition of HIV infection by bicyclams, highly potent and
specific CXCR4 antagonists. Mol Pharmacol. 2000;57(5):833-39.
145. Gerlach LO, Jakobsen JS, Jensen KP, Rosenkilde MR, Skerlj RT, Ryde
U, et al. Metal ion enhanced binding of amd3100 to asp262 in the cxcr4
receptor. Biochem. 2003;42(3):710-17.
146. Hunter TM, McNae IW, Simpson DP, Smith AM, Moggach S, White F,
et al. Configurations of nickel–cyclam antiviral complexes and protein
recognition. Chem Eur. 2007;13(1):40-50.
147. Rogolino D, Carcelli M, Bacchi A, Compari C, Contardi L, Fisicaro E,
et al. A versatile salicyl hydrazonic ligand and its metal complexes as
antiviral agents. J Inorg Biochem. 2015;150:9-17.
148. Guveli S, Turan K, Ulkuseven B. Nickel(II)-PPh3 complexes with ONS
and ONN chelating thiosemicarbazones: Synthesis and inhibition
potential on influenza A viruses. Turk J Chem. 2018;42:371–84.
18 2020 | Volume 1 | Issue 1 | Article 1004