Efficient synthesis and anti-bovine viral diarrhea virus evaluation of 5-(aryldiazo)salicylaldehyde thiosemicarbazone derivatives

Article abstract of DOI:10.1080/00397911.2019.1626893

An efficient procedure for the synthesis of 5-(aryldiazo)salicylaldehyde thiosemicarbazone derivatives 1-25 was achieved via the condensation of 5-(aryldiazo)salicylaldehyde derivatives I–V with N-(4)-substituted thiosemicarbazide derivatives. Antiviral a

Full text of DOI:10.1080/00397911.2019.1626893

Synthetic Communications
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Efficient synthesis and anti-bovine viral diarrhea
virus evaluation of 5-(aryldiazo)salicylaldehyde
thiosemicarbazone derivatives
Samir Y. Abbas, Wahid M. Basyouni, Khairy A. M. El-Bayouki, Reham M.
Dawood, Tawfeek H. Abdelhafez & Mostafa K. Elawady
To cite this article: Samir Y. Abbas, Wahid M. Basyouni, Khairy A. M. El-Bayouki, Reham M.
Dawood, Tawfeek H. Abdelhafez & Mostafa K. Elawady (2019): Efficient synthesis and anti-bovine
viral diarrhea virus evaluation of 5-(aryldiazo)salicylaldehyde thiosemicarbazone derivatives,
Synthetic Communications, DOI: 10.1080/00397911.2019.1626893
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https://doi.org/10.1080/00397911.2019.1626893
Efficient synthesis and anti-bovine viral diarrhea virus
evaluation of 5-(aryldiazo)salicylaldehyde
thiosemicarbazone derivatives
Samir Y. Abbasa, Wahid M. Basyounia, Khairy A. M. El-Bayoukia, Reham M.
Dawoodb, Tawfeek H. Abdelhafezb, and Mostafa K. Elawadyb
aOrganometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt;
bMicrobial Biotechnology Department, National Research Centre, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 17 April 2019
An efficient procedure for the synthesis of 5-(aryldiazo)salicylaldehyde
thiosemicarbazone derivatives 1-25 was achieved via the condensation
of 5-(aryldiazo)salicylaldehyde derivatives I–V with N-(4)-substituted
thiosemicarbazide derivatives. Antiviral activity of the synthesized
compounds was carried out. From the obtained results, it was
noticed that compound 11 has a strong antiviral activity.
KEYWORDS
Salicylaldehydes;
N-(4)-substituted
thiosemicarbazides;
thiosemicarbazones;
anti-bovine viral
diarrhea virus
GRAPHICAL ABSTRACT
Introduction
Thiosemicarbazone derivatives were reported as interesting moiety where they displayed
a wide range of biological activities such as antibacterial, antifungal, antiprotozoal, anti-
tumor, and antiviral activities (Figure 1).[1–4]
In 1972, D. J. Bauer stated that the first true antiviral agents discovered were the thio-
semicarbazones.[5] In 1950, p-aminobenzaldehyde thiosemicarbazone was found as the
first antiviral agent to be active against vaccinia virus infection in mice and fertile
CONTACT Samir Y. Abbas
samiryoussef98@yahoo.com; Wahid M. Basyouni
w_basyouni2002@yahoo.com
Organometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, Cairo, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
ß 2019 National research centre

2
S. Y. ABBAS ET AL.
S
CH3
N
N
NH2
N
N
H
N
S
H3C
S
N
N
O
N
N
NH2
N
H
NH2
H
CH3
Methisazone
(antiviral)
Triapine
(anticancer)
Tiacetazone
(turberculostatic)
S
F3CO
NH2
H3CO
H3CO
N
S
N
H
N
N
H
NH2
anti-BVDV
anti-HCV
Figure 1. Some of the known biologically active thiosemicarbazone derivatives.
eggs.[6,7] Then, a wide range of thiosemicarbazones were discovered from which isatin
3-thiosemicarbazone (methisazone) was emerged (Figure 1). Methisazone was used for
man where it had tentative efficacy in the treatment and prophylaxis of smallpox.[8]
Some thiosemicarbazone derivatives (Figure 1) showed potent anti-bovine viral diarrhea
virus activity. The thiosemicarbazones have the potentiality as antiviral agents for the treat-
ment of infections caused by other highly related members of Flaviviridae family such as
hepatitis C virus.[9] Therefore, thiosemicarbazone-related compounds (Figure 1) being
strong inhibitors of HCV replicon replication.[10]
Owing to their versatile chemistry, researches have been progressed to design and synthe-
size broad spectrum of thiosemicarbazone derivatives. Also, thiosemicarbazone derivatives
are versatile scoffed for the syntheses of biologically active heterocyclic compounds.[11]
Today, the chemists, especially the synthetic organic chemists are faced with develop-
ment of new procedures or improvement of old procedures with environmental con-
cerns where energy/cost-effective preparations and minimal waste production should be
taken into consideration.[12–14]
Therefore, the aim of the present work was directed for synthesizing several newer
thiosemicarbazone derivatives and bear structural similarities to the well-known potent
anti-HCV agents.
Result and discussion
The present investigation was directed for synthesizing a new series of 5-(aryldiazo)-salicy-
laldehyde thiosemicarbazone derivatives bearing various substituents at aryldiazo and
N-(4)-substituted thiosemicarbazone moieties. The aryldiazo-salicylaldehyde derivatives I–V
precursors are not commercially available, as far as we are aware and were prepared. Thus,
5-(3-substituted-phenyldiazo)-salicylaldehyde derivatives I–V were prepared according to
the previously reported procedures via reacting salicylaldehyde with the appropriate 3-sub-
stituted-phenyldiazonium chloride (Scheme 1).[15–19] Structural elucidation of compounds
I–V was accomplished by careful inspection of their spectral data.
Many trails were carried out for synthesizing the desired thiosemicarbazone derivatives.
Generally, the N-(4)-substituted thiosemicarbazone derivatives 1–25 were synthesized via

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3
NH2
X
HCl
NaNO2
OH
CHO
X
N
OH
X
N
Cl
N
N
CHO
I,
IV,
V,
X = H
X = CF3
X = NO2
II,
X = Br
III, X = CH3
Scheme 1. Synthesis of 5-(3-substituted-phenyldiazo)-salicylaldehyde derivatives I–V.
S
OH
OH
S
H2N
N
NHR
X
N
N
H
X
N
N
N
H
NHR
N
CHO
1-25
I-V
1 X = H R = H
6 X = Br R = H
11 X = CH3 R = H
12 X = CH3 R = CH3
2 X = H R = CH3
3 X = H R = C2H5
7 X = Br R = CH3
8 X = Br R = C2H5
13 X = CH3 R = C2H5
4
5
9
14
15
X = H R = C6H5
X = H R = C6H4OCH3-4
X = Br R = C6H5
X = Br R = C6H5OCH3-4
X = CH3 R = C6H5
X = CH3 R = C6H4OCH3-4
10
16
21
X = NO2 R = H
X = CF3 R = H
17 X = CF3 R = CH3
18 X = CF3 R = C2H5
19 X = CF3 R = C6H5
22 X = NO2 R = CH3
23 X = NO2 R = C2H5
24 X = NO2 R = C6H5
20 X = CF3 R = C6H4OCH3-4 25 X = NO2 R = C6H4OCH3-4
Scheme 2. Synthesis of 5-(3-substituted-phenylazo)-salicylaldehyde thiosemicarbazones 1–25.
reacting the 5-(3-substituted-phenylazo)-salicylaldehydes I–V with the desired thiosemicar-
bazide derivative (Scheme 2).
Structure of the N-(4)-substituted thiosemicarbazones 1–25 was investigated through
careful study of their spectral data as well as their elemental analyses. IR spectra showed
ꢀ(OH) in the region 3468–3409 cmꢀ1 as characteristic intense bands due tothe phenolic
group. The spectra showed other bands in the region 3300–3100 cmꢀ1 attributed to NH
groups. IR spectra revealed also the presence of bands in 1618–1614 cmꢀ1 and
1281–1223 cmꢀ1 regions for CH ¼ N and C ¼ S diagnostic groups, respectively, for thio-
semicarbazones with the disappearance of carbonyl group bands.
1H NMR spectra of 1–25 were characterized, generally, by the presence of broad sig-
nals integrating as one proton at about d ¼ 10.90 ppm (D2O-exchangeable) assigned to
the OH protons. The spectra of the 4-amino derivatives showed NH2 proton signals at:
d about 8.20 ppm. For other substituted products, NH-R proton signals appeared at
d about 8.60 and 10.20 ppm for alkyl and aryl substituents, respectively. The spectra
revealed also signals due to NH–N ¼ protons at d in the region 11.86–11.48 ppm (D2O-
exchangeable) beside the other characteristic signals. 13C NMR spectral assignments

4
S. Y. ABBAS ET AL.
depended on characteristic signals, where the signals resonated in the deshielded region
about 160 and 177 ppm are assigned to C ¼ N and C ¼ S, respectively.
Anti-viral screening of the new synthesized compounds
Preliminary anti-viral screening of selected examples from the synthesized products was
carried out on the bovine viral diarrhea virus (BVDV), which is a single positive RNA
stranded virus classified as a member of the same family of hepatitis C Virus (HCV),
i.e. flaviviridae. Some of the synthesized compounds were subjected to in vitro testing of
antiviral activity. Viral infectivity assay was carried out using the plaque formation
method.[20] A plaque is a localized focus of virus-infected cells which under optimal
conditions originates from a single infectious virus particle. Counting of these foci for
serial dilution of virus suspension is a highly quantitative method for assay of viral
infectivity. Under these conditions, reduction in virus plaque counts provides a very
sensitive mean for measuring the antiviral activity of a potential antiviral. The results of
the plaque reduction assay are summarized in Table 1. The antiviral effect obtained for
the synthesized compounds suggested that the tested thiosemicarbazone derivatives have
no antiviral activity or have a toxic effect on the cells.
From the results obtained from the Table 1, it was noticed that compound 11 has a
strong antiviral activity. Compounds 9 and 25 have a toxic effect on the cells. The activ-
ity of thiosemicarbazone derivative 11 may be attributed to the presence of the methyl
group at 5-(arylazo)salicylaldehyde moiety and free amino group at N-(4)-thiosemicar-
bazone moiety. The presence of 4-bromo- and 4-nitrophenyl-substituents at arylazo
(9 and 25) showed a toxic effect on the cells.
Conclusion
A new series of novel N-(4)-substituted thiosemicarbazone derivatives bearing N-(4)-
substituted-aryl moieties were synthesized for their expected antiviral activity. The
expected anti-viral properties of selected examples from the synthesized derivatives were
studied. The results indicated that compound 11 is the active one, while the other tested
products were inactive or cytotoxic. Therefore, the present study revealed a new potent
anti-viral agent.
Experimental section
Synthesis of the 5-(aryldiazo) salicylaldehyde thiosemicarbazone derivatives
A mixture of salicylaldehyde derivatives I–V (0.01 mol) and the thiosemicarbazide deriv-
atives
(namely
thiosemicarbazide,
N-(methyl)-thiosemicarbazide,
N-(ethyl)-
TABLE 1. Antiviral Screening of selected examples of the synthesized thiosemicarbazone derivatives.
Sample
Concentration (10 mg/ml)
Notes
9
11
25
Toxic effect
2 ꢁ 10ꢀ4.6 PFU
Toxic effect
—————————————
(Active compound)
—————————————
ꢀ4.6
ꢂ
Positive control
85 10
PFU

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5
thiosemicarbazide, N-(phenyl)-thiosemicarbazide and N-(4-methoxyphenyl)-thiosemicar-
bazide) (0.01 mol) in ethanol (25 mL) was heated under reflux for 1 h and then left to
cool. The solid product obtained was filtered off and crystallized from ethanol to give
the desired thiosemicarbazone 1–25.
2-(5-((3-Bromophenyl)diazenyl)-2-hydroxybenzylidene)-N-ethylhydrazinecarbo-
thioamide (8)
1
Yield 80%; m.p. 224–225 ꢃC; IR: ꢀ/cmꢀ1¼3365, 3259 (NH), 1606 (C ¼ N); H NMR:
d/ppm: 1.12 (t, 2H, J ¼ 7.0 Hz, CH2CH3), 3.57 (q, 2H, J ¼ 7.0 Hz, CH2CH3), 7.02 (d, 1H,
J ¼ 8.8 Hz, Ar–H), 7.53 (t, 1H, J ¼ 9.0 Hz, Ar–H), 7.69 (d, 1H, J ¼ 7.9 Hz, Ar–H), 7.76
(dd, 1H, J ¼ 8.8, 2.2 Hz, Ar–H), 7.86 (d, 1H, J ¼ 7.7 Hz, 1H, Ar–H), 7.93 (s, 1H, Ar–H),
8.40 (s, 1–H, Ar–H), 8.61 (s, 1H, CH ¼ N), 8.66 (br, 1H, NH), 10.97 (br, 1H, OH),
11.48 (br, 1H, NH); 13C NMR: 15.0, 39.8, 117.3, 121.4, 122.9, 123.5, 124.1, 124.6, 131.7,
133.5, 138.9, 145.5, 153.4, 160.1, 176.7; Anal. Calcd. for C16H16BrN5OS (406.3):
C, 47.30; H, 3.97; N, 17.24; Found: C, 47.27; H, 4.01; N, 17.18%.
Funding
Financial support was provided by the Science and Technology Development Fund in Egypt
(STDF) through the project No. 14993.
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