Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.02.037

A series of isatin-β-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-β-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their antiherpetic activity. The synthesis and structure-activity relationship studies are presented.

Full text of DOI:10.1016/j.bmcl.2011.02.037

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1948–1952
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Isatin-b-thiosemicarbazones as potent herpes simplex virus inhibitors
Iou-Jiun Kang a, , Li-Wen Wang a, , Tsu-An Hsu a, Andrew Yueh a, Chung-Chi Lee a, Yen-Chun Lee a,
a,
Ching-Yin Lee b, Yu-Sheng Chao a, Shin-Ru Shih b, , Jyh-Haur Chern
⇑
⇑
a Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
b School of Medical Technology, Chang Gung University, Taoyuan 333, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of isatin-b-thiosemicarbazones have been designed and evaluated for antiviral activity against
herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity
was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-b-thiosem-
icarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that
the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their anti-
herpetic activity. The synthesis and structure–activity relationship studies are presented.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 September 2010
Revised 11 January 2011
Accepted 10 February 2011
Available online 15 February 2011
Keywords:
Herpes simplex virus
HSV-1
HSV-2
Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are dou-
ble-stranded DNA viruses1 and well known for their ability to
cause one of the most common infections in man throughout the
world.2 In both cases, life-long latency is established in sensory
ganglia from which the virus can reactivate to cause recurrent epi-
sodes on the mouth (labial herpes) or genitals (genital herpes) as
often as several times a year.3 HSV infections can also cause serious
systemic illnesses, particularly in the growing immunocompro-
mised population (AIDS patients, organ transplant recipients, che-
motherapy patients) and neonates.4
Most of the existing drugs for treatment of HSV infections have
been dominated by nucleoside derivatives such as acyclovir, ganci-
clovir, penciclovir, valaciclovir (converted to acyclovir) and famci-
clovir (converted to penciclovir).5 Among these drugs, acyclovir is
the most commonly used drug for HSV therapy.6 However, drug-
resistant strains of HSV are emerging7 which is prevalent in the fol-
lowing therapeutic treatment.8 In 1980, it was first reported that
the mechanism of resistance to acyclovir could occur following
mutation in either HSV thymidine kinase (TK) or DNA polymerase.9
The similarity in the mechanism of current anti-herpese drugs sug-
gests that cross-resistance is common among drug-resistant
strains.10 Thus, the discovery of new non-nucleoside anti-HSV mol-
ecules with novel mechanisms of action is an important goal for
antiviral research.
As early as 1946, the discovery of thiosemicarbazones as antitu-
bercular agents was reported by Domagk et al.11 In 1950, thiosemi-
carbazones were first reported to possess antiviral activity in mice
against vaccinia virus.12 Since then, the biological effects of other
thiosemicarbazones have been widely investigated. Results of
these studies have demonstrated that thiosemicarbazone deriva-
tives also possess additional antibacterial,13 anti-fungal,14 antima-
larial,15 antineoplastic,16 antiparasitic,17 anti-HIV,18 anti-HSV19
,
anti-CMV (Cytomegalovirus),20 and anti-MLV (Moloney leukemia
virus)21 activity. Isatin-b-thiosemicarbazone (1, IBT) and N-meth-
ylisatin-b-thiosemicarbazone (2, methisazone, marboran) (Fig. 1)
are extensively studied thiosemicarbazones that demonstrate an
inhibitory effect against the replication of poxviruses.22 Methisa-
zone has also been used in the clinical treatment of smallpox.23
This drug plays an important role as a smallpox chemoprophylactic
agent. The spectrum of antiviral activity of this drug has been ex-
tended by additional in vitro studies to include other groups of
viruses, such as adenovirus, herpesvirus, picornavirus, reovirus,
arbovirus, myxo- and para-myxovirus, and retrovirus.24
The precise viral target and mechanism of action of IBT and its
derivatives remains unknown. The biological properties of thio-
semicarbazones are often related to metal ion coordination. It is
possible that the function of the IBT or thiosemicarbazone is
to act as a carrier for heavy metal, thereby increasing its ability
to penetrate the viral envelope. The ability of thiosemicarbazones
to increase the intracellular copper concentration has been re-
ported.25 Based on the observation that some viral DNA and struc-
tural protein is synthesized in the presence of IBT, the suggestion
had been made that the compound interferes with the maturation
of viral progeny.26 Also, it was reported that the primary effect of
⇑
Corresponding authors. Address: Institute of Biotechnology and Pharmaceutical
Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan Town,
Miaoli County 350, Taiwan, ROC. Tel.: +886 37 246 166; fax: +886 37 586 456.
E-mail address: jhchen@nhri.org.tw (J.-H. Chern).
Authors with equal contribution.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.02.037

I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1948–1952
1949
toward multidrug-resistant cells.33d Evolution of this chemical
family offers the promise of curing those cancers most resistant
to chemotherapy.
R2
R3
X
S
C
N
N
NH
O
NH2
N
NH
O
R4
Recently, an antiviral screening program was initiated to search
for new isatin-b-thiosemicarbazone HSV inhibitors in our labora-
tory. In order to diversify the functional groups on the IBT scaffold,
we synthesized compounds of general structure 3 (Fig. 1) and eval-
uated their anti-HSV activity via plaque reduction assay.29 Interest-
ingly, several derivatives of IBT were identified as potential
antiherpetic agents. In this Letter, we would like to report the syn-
thesis of these isatin-b-thiosemicarbazones and evaluation of their
inhibitory activities against HSV. Details of this investigation will
be described herein.
N
N
R1
R
3
1 : R = H
Isatin-β-thiosemicarbazone
2 : R = CH3 Methisazone
Figure 1. Isatin thiosemicarbazones with previously reported anti-poxvirus activity
(1, 2) and scaffold 3 for anti-HSV activity.
The synthesis of N4-monosubstituted thiosemicarbazones
10–23, 28–33 and semicarbazones 24–27 was described in
Scheme 1. Condensation of aqueous hydrazine (80% in H2O) with
commercially available isothiocyanate 5 or isocyanate 6 gave thio-
semicarbazide 7 or semicarbazide 8. Alternatively, reaction of aryl
amine with thiophosgene in the presence of sodium bicarbonate
gave the isothiocyanate intermediate 4. Subsequent condensation
of 4 with aqueous hydrazine (80% in H2O) afforded thiosemicarba-
zide 7. Condensation of 7 and 8 with isatin 9 in methanol afforded
the desired products 10–33.
the IBT is to enhance viral postreplicative transcription elongation,
either directly or by suppressing termination, resulting in the for-
mation of longer-than-normal transcripts.27 Studies by Katz et al.28
have supported that inhibition of A18R helicase activity on the vir-
al RNA polymerase is one possible mode of action of IBT.
Additionally, the combinatorial optimization and a more in-
depth biological evaluation of isatin-b-thiosemicarbazone deriva-
tives against vaccinia and cowpox virus infections have been
reported in 2005.33a,b This combinatorial library has provided com-
pounds with significantly enhanced potency over IBT in cell-based
activity against vaccinia, and with somewhat enhanced potency
against cowpox. On the other hand, a series of derivatives were
found to possess significant anti-HIV activity with low cytotoxicity
and high selectivity index.33c It was recently reported that some of
isatin-b-thiosemicarbazone derivatives showed selective activity
In addition, N1-substituted thiosemicarbazones 34–37 were
prepared by reacting thiosemicarbazone 10 with alkyl or aryl io-
dide in DMF under microwave irradiation at 100 °C30 (Scheme 2).
The synthesis of N4-substituted thiosemicarbazones 41–49 was
described in Scheme 3. The methyl hydrazinecarbodithioate 38
was prepared by the reaction of carbon disulfide with aqueous
X
NHNH2
N2H4 (aq)
Ar NH
Ar
N
C
X
+
CH Cl , 0 C, 1h
°
2
2
5. X = S
6. X = O
7. X = S
8. X = O
N2H4 (aq)
CH2Cl2, r.t., 1h
NaHCO3
CHCl3-H2O, r.t., 1h
+
CSCl2
Ar NH2
Ar
NCS
4
O
R4
X
NH Ar
O
N
N
NH
O
H
R4
9
MeOH, reflux, 5h
N
H
10-33
22. X = S, R4 = H, Ar = 4-ImidazolylPh
23. X = S, R4 = H, Ar = 4-MorpholinylPh
24. X = O, R4 = H, Ar = Ph
25. X = O, R4 = H, Ar = 3-CH3Ph
26. X = O, R4 = H, Ar = 4-CH3Ph
27. X = O, R4 = H, Ar = 3-OCH3Ph
28. X = S, R4 = F, Ar = Ph
29. X = S, R4 = Cl, Ar = Ph
30. X = S, R4 = Br, Ar = Ph
10. X = S, R4 = H, Ar = Ph
11. X = S, R4 = H, Ar = 2-CH3Ph
12. X = S, R4 = H, Ar = 3-CH3Ph
13. X = S, R4 = H, Ar = 4-CH3Ph
14. X = S, R4 = H, Ar = 2-OCH3Ph
15. X = S, R4 = H, Ar = 3-OCH3Ph
16. X = S, R4 = H, Ar = 4-OCH3Ph
17. X = S, R4 = H, Ar = 4-FPh
18. X = S, R4 = H, Ar = 2-ClPh
19. X = S, R4 = H, Ar = 3-ClPh
20. X = S, R4 = H, Ar = 4-ClPh
21. X = S, R4 = H, Ar = 4-BrPh
31. X = S, R4 = OCH3, Ar = Ph
32. X = S, R4 = OCF3, Ar = Ph
33. X = S, R4 = CH3, Ar = Ph
Scheme 1. General synthetic route to N4-monosubstituted thiosemicarbazones 10–23, 28–33, and semicarbazones 24–27.

1950
I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1948–1952
S
N NH
O
S
NH
NH
N NH
1
K CO , R I
2
3
1
O
34. R = CH
35. R = Et
3
N
N
R
1
DMF, 100 C, 20min
°
H
1
MW Irrad.
1
36. R = Ph
37. R = Benzyl
10
1
34-37
Scheme 2. General synthetic route to N1-substituted thiosemicarbazones 34–37.
S
CH3I
0 C, 1.5h
KOH
CS2 + N2H4 (aq)
H3CS
NHNH2
EtOH, 0 C, 1h
°
°
38
O
R2R3NH
O
S
N
R2
N
R3
39
H
NHNH2
MeOH, reflux, 10h
MeOH, reflux, 5h
40
R2
R3
S
N NH
O
41. R2, R3 = CH3
47. R2 = H, R3 = CH3
48. R2 = H, R3 = Et
49. R2 = H, R3 = n-Pr
N
42. R2, R3 = Et
43. R2, R3 = n-Pr
44. NR2R3 = Pyrrolidine
45. NR2R3 = Piperidine
46. NR2R3 = Morpholine
N
H
41-49
Scheme 3. General synthetic route to N4-substituted thiosemicarbazones 41–49.
hydrazine (80% in H2O) and followed by treatment of methyl io-
dide at 0 °C in ethanol.31 The displacement of the S-methyl group
of methyl hydrazinecarbodithioate 38 by appropriate amine 39
gave the thiosemicarbazide 40.32 Subsequent condensation of 40
with isatin in methanol afforded the desired thiosemicarbazones
41–49 in quantitative yields.
All the isatin-b-thiosemicarbazones described herein were
tested in a plaque reduction assay29 under a standard procedure.
In preliminary SAR studies, a series of compounds 10–27 were syn-
thesized according to Scheme 1 and then submitted for anti-HSV-1
and anti-HSV-2 testing as well as cytotoxicity evaluation in the RD
cell lines. These biological results were summarized in Table 1.
Interestingly, compound 10 exhibited significant activity against
substituents introduced in the N4 phenyl ring of the thiosemicarba-
zone had a pronounced influence on its antiviral activity. The lack
of anti-HSV activity of these thiosemicarbazones is probably asso-
ciated with an increase in lipophilic, steric, and electrostatic prop-
erties caused by the substituents.
Next, replacement of the thiocarbonyl group of compounds 10,
12, 13 and 15 by a carbonyl group gave compounds 24–27, respec-
tively. All of the urea analogues (24–27) were found to be totally
inactive, which revealed that the thiourea moiety is a critical struc-
tural feature required for antiherpetic activity.
As reported in Table 2, when a substituent (F, Cl, Br, OCH3, OCF3,
CH3) was introduced at the C-5 position of indole moiety, to form
compounds 28–33, only 5-methoxy (31) and 5-trifluoromethoxy
(32) analogues showed significant anti-HSV-1 activity
HSV-1 (IC50 = 2.97 0.19
lM) without cytotoxicity up to the con-
centration of 25 M. Surprisingly, it was completely inactive
l
(IC50 = 5.01 0.72 and 5.90 0.06 lM, respectively). It is also inter-
against HSV-2. Introduction of a methyl or methoxy group in the
N4 phenyl ring of compound 10 resulted in compounds (11–16)
with different antiviral activities. The 3-methyl (12), 3-methoxy
(15), and 4-methoxy (16) analogues show similar antiviral activity
esting to note that the halogen (28–30) and methyl (33) groups
were considerably less active than the methoxy (31) and trifluoro-
methoxy (32) groups at the C-5 position. On the other hand, intro-
duction of various substituents (CH3, Et, Ph, Benzyl) at N-1 of
indole moiety, to form compounds 34–37, resulted in a complete
loss of antiherpetic activity as compared with the corresponding
compound 10. These significant results indicated that the NH
group in the indole moiety is critical for antiviral activity against
HSV. This effect might be due to their drastically conformational
change and steric requirement at the N-1 position of indole moiety.
In an attempt to confirm the influence on antiviral activity be-
tween mono- and di-substituents at the terminal (N4) position of
thiourea moiety, a number of thiosemicarbazones (41–49) were
prepared (Table 3). As shown in Table 3, the introduction of a
diethylamine (42) on the thiocarbonyl group showed significant
against HSV-1 (IC50 = 3.84 0.41, 2.64 0.21 and 2.20 0.34 lM,
respectively). However, the 2-methyl (11), 4-methyl (13), and 2-
methoxy (14) analogues exhibit no anti-HSV activity. It is very
interesting to note that compound 12 exhibited significant anti-
HSV-1 activity with no cytotoxicity up to the concentration of
25
compound 10 (17–21) revealed that only 4-chloro (20) and 4-bro-
mo (21) analogues showed activity against HSV-1
l
M. Introduction of a halogen group in the N4 phenyl ring of
(IC50 = 2.69 0.36 and 3.29 0.14 lM, respectively). Of the hetero-
cycles placed in the N4 phenyl ring of compound 10 (22, 23), only
4-imidazole analogue (22) showed anti-HSV-1 activity
(IC50 = 6.21 0.45
l
M). On the basis of these results, the various
and highly selective activity against HSV-2 (IC50 = 1.54 0.21 lM).

I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1948–1952
1951
Table 1
Table 2
Antiherpetic activity and cytotoxicity for compounds 10–27
Antiherpetic activity and cytotoxicity for compounds 28–37
X
H
S
H
N
Ar
N
N
NH
O
N
NH
O
R4
N
H
N
R1
Compound
X
Ar
IC50
HSV-1
(
l
M)a
IC50
HSV-2
(
l
M)a CC50
RDc
(l
M)b
Compound
R1
R4
IC50
HSV-1
(
l
M)a
IC50
HSV-2
(
l
M)a
CC50
RDc
(l
M)b
28
29
30
31
32
33
34
35
36
37
H
H
H
H
H
H
CH3
Et
Ph
F
Cl
Br
OCH3
OCF3
CH3
H
H
H
>25
>25
>25
5.01 0.72
5.90 0.06
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
10
11
S
S
2.97 0.19 >25
>25
>25
H3C
>25
>25
CH3
12
13
14
S
S
S
3.84 0.41 >25
>25
>25
>25
>25
>25
>25
>25
CH3
Benzyl
H
H3CO
a
Mean of triplicate well values. All experiments were performed at least twice.
Plaque reduction assay was employed.
b
Mean of triplicate well values. All experiments were performed at least twice.
RD: human rhabdomyosarcoma cells.
c
OCH3
15
S
2.64 0.21 >25
2.20 0.34 >25
>25
Table 3
16
17
S
S
>25
>25
OCH3
Antiherpetic activity and cytotoxicity for compounds 41–49
>25
>25
>25
>25
F
2
S
R
R
Cl
N
3
18
19
S
S
>25
>25
N
NH
O
Cl
N
>25
>25
H
20
21
S
S
2.69 0.36 >25
3.29 0.14 >25
>25
>25
Cl
Br
N
Compound
–NR2R3
IC50
HSV-1
(
l
M)a
IC50
HSV-2
(
l
M)a
CC50
RDc
(l
M)b
22
S
6.21 0.45 >25
>25
N
41
42
>25
>25
>25
>25
N
N
23
24
S
>25
>25
>25
>25
>25
>25
N
O
>25
>25
1.54 0.21
>25
O
CH3
43
>25
N
25
26
27
O
O
O
>25
>25
>25
>25
>25
>25
>25
>25
>25
CH3
OCH3
44
45
46
>25
>25
5.80 0.52
3.14 0.20
2.74 0.23
>25
>25
>25
N
N
N
a
1.30 0.16
O
Mean of triplicate well values. All experiments were performed at least twice.
Plaque reduction assay was employed.
47
48
49
–NHCH3
–NHEt
–NHn-Pr
>25
>25
>25
0.30 0.04
>25
>25
>25
1.27 0.14
>25
>25
>25
>25
b
Mean of triplicate well values. All experiments were performed at least twice.
c
RD: human rhabdomyosarcoma cells.
Acyclovird
a
Mean of triplicate well values. All experiments were performed at least twice.
However, the dimethylamine (41) and dipropylamine (43) ana-
logues showed poor activity. Additionally, replacement of the dial-
kylamino group with larger heterocycloalkyl groups such as
pyrrolidine (44) and piperidine (45) also led to a significant and
highly selective activity against HSV-2 (IC50 = 5.80 0.52 and
Plaque reduction assay was employed.
b
Mean of triplicate well values. All experiments were performed at least twice.
RD: human rhabdomyosarcoma cells.
c
d
Standard as antiviral agent.
3.14 0.20 lM, respectively). These results demonstrated that
cant activity against both HSV-1 (IC50 = 1.30 0.16
lM) and HSV-
most of compounds in this series were highly selective in inhibit-
ing HSV-2. Interestingly, when a morpholinyl ring was introduced
at the thiocarbonyl group (NR2R3), compound 46 showed signifi-
2 (IC50 = 2.74 0.23 M). It is worthy to note that compound 46
was only slightly less active than acyclovir, one of the most com-
monly-used antiherpetic drugs. This unexpected biological result
l

1952
I.-J. Kang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1948–1952
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our SAR investigation, the thiourea moiety of thiosemicarbazone
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