Methyl-2-arylidene hydrazinecarbodithioates: Synthesis and biological activity

Article abstract of DOI:10.2478/s11696-013-0346-4

Methyl-2-arylidene hydrazine-carbodithioate has not been of particular interest to researchers even though its metal complexes are extensively reported on due to their biological activity. This study examined the cytostatic and antiviral activity of twelve methyl-2-arylidene hydrazinecarbodithioates reported by many researchers as intermediates for the synthesis of thiosemicarbazides and the preparation of their metal complexes. Compounds IIc, IIi, and IIl with tridentate ligand features were found to have the lowest IC₅₀ value (6.5 μM, ≈ 1 μM, and 0.8 μM, respectively) against HL60 human promyelocytic leukemia cells. They were also most inhibitory to human embryonic lung (HEL) fibroblast proliferation (5.3 μM, 17 μM, and 2.6 μM). Compound IIc and IIl show antiviral activity against wild-type herpes simplex virus (HSV), varicella zoster virus (VZV), and acyclovirresistant HSV; however, these activities were observed at concentrations at which the compounds also markedly inhibit HL60 and HEL cell proliferation.

Full text of DOI:10.2478/s11696-013-0346-4

Chemical Papers 67 (6) 650–656 (2013)
DOI: 10.2478/s11696-013-0346-4
ORIGINAL PAPER
Methyl-2-arylidene hydrazinecarbodithioates:
synthesis and biological activity
b
c
aManojkumar Mahapatra, Umasankar Kulandaivelu, Philipp Saiko,
cGeraldine Graser, Thomas Szekeres, Graciela Andrei, Robert Snoeck,
c
d
d
dJan Balzarini, a,eVenkatesan Jayaprakash*
aDepartment of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835 215, India
bMedicinal Chemistry Research Division, Vaagdevi College of Pharmacy,
Hanamkonda, Warangal, Andhra Pradesh 506 001, India
cDepartment of Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna – Medical University of Vienna,
Waehringer Guertel 18-20, A-1090 Vienna, Austria
dRega Institute for Medical Research, KU Leuven, B-3000, Leuven, Belgium
eValens Pharma Services, Regus Citi Centre, Level 6, Chennai Citi Centre, 10/11, Dr.Radhakrishnan Salai,
Chennai, Tamil Nadu 600 004, India
Received 23 September 2012; Revised 29 November 2012; Accepted 13 December 2012
Methyl-2-arylidene hydrazine-carbodithioate has not been of particular interest to researchers
even though its metal complexes are extensively reported on due to their biological activity. This
study examined the cytostatic and antiviral activity of twelve methyl-2-arylidene hydrazinecarbod-
ithioates reported by many researchers as intermediates for the synthesis of thiosemicarbazides and
the preparation of their metal complexes. Compounds IIc, IIi, and IIl with tridentate ligand features
were found to have the lowest IC50 value (6.5 µM, ≈ 1 µM, and 0.8 µM, respectively) against HL60
human promyelocytic leukemia cells. They were also most inhibitory to human embryonic lung
(HEL) fibroblast proliferation (5.3 µM, 17 µM, and 2.6 µM). Compound IIc and IIl show antiviral
activity against wild-type herpes simplex virus (HSV), varicella zoster virus (VZV), and acyclovir-
resistant HSV; however, these activities were observed at concentrations at which the compounds
also markedly inhibit HL60 and HEL cell proliferation.
c
ꢀ 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: Schiff’s base, methyl hydrazinecarbodithioate, HL60 cell line, anticancer, antiviral,
cytotoxicity
Introduction
metal complexes were studied for their biological ac-
tivity (Beraldo & Gambinob, 2004; Ettari et al., 2010;
Jiang et al., 2006; Katz, 1987; Liberta & West, 1992;
Matesanz & Souza, 2009; Pandeya & Dimmock, 1993;
Wnuk & Robins, 2006; Yu et al., 2009), the inter-
mediate MAHCD was rarely studied for its metal
complexation behaviour and the complexes for their
biological activity (Ali et al., 2002; Kanwar et al.,
Many N-substituted thiosemicarbazones were pre-
pared by the condensation of Schiff’s bases of methyl-
2-arylidene hydrazinecarbodithioate (MAHCD) with
amines (Casero et al., 1980; Collins et al., 1982; Klay-
man et al., 1979, 1991; Scovill et al., 1982; Ship-
man et al., 1981). While thiosemicarbazones and their
*Corresponding author, e-mail: venkatesanj@bitmesra.ac.in

M. Mahapatra et al./Chemical Papers 67 (6) 650–656 (2013)
651
Fig. 1. Similarity of title compounds with Schiff’s base of N-hydroxy semicarbazides (SNHS) and N-hydroxy aminoguanidines
(SNHAG).
2008; Neelam et al., 2000; Saxena & Tandon, 1983;
Singh et al., 1997). Very few investigators have re-
ported biological activity of compounds with a dithio-
carbamate side chain (Cao et al., 2005; Huang et al.,
2009; Kumar et al., 2010). It is interesting to note
that MAHCD shares structural similarity with Schiff’s
bases of N-hydroxy semicarbazides (SNHS) and N-
hydroxy aminoguanidines (SNHAG) (Fig. 1). Both
SNHS and SNHAG were rigorously documented for
their anticancer activity and antiviral properties. It
was proposed that these compounds act by inhibiting
ribonucleotide reductase (RR) through metal chela-
tion (Das et al., 1999; Ren et al., 2002; T’ang et al.,
1985). With this background, twelve MAHCD deriva-
tives were synthesised and evaluated for anticancer
activity against HL60 human promyelocytic leukemia
cells and antiviral activity against a panel of viral cell
lines.
m.p. = 82◦C. (82◦C, Audrieth et al. (1954); 81–83◦C,
Klayman et al. (1979)).
Methyl hydrazinecarbodithioate (20.0 mmol) was
dissolved in 20 mL of methanol and then, equimo-
lar amount of aromatic/heteroaromatic aldehyde was
added. The mixture was refluxed for 6–12 h and the
reaction was monitored by TLC. The hot solution was
poured onto crushed ice and the precipitate obtained
was filtered (Klayman et al., 1979; Scovill et al., 1982):
yield of 60–80 %.
Anticancer activity assay procedure
The HL-60 human promyelocytic leukemia cell line
was purchased from ATCC (American Type Culture
Collection, Manassas, VA, USA). Cells were grown in
a RPMI 1640 medium supplemented with a 10 % heat
inactivated fetal calf serum (FCS), 1 % L-glutamine
and 1 % penicillin–streptomycin in a humidified atmo-
sphere containing 5 % of CO2. All media and supple-
ments were obtained from Life Technologies (Paisley,
Scotland, UK). Cell counts were determined using a
micro cell counter CC-108 (SYSMEX, Kobe, Japan).
Cells growing in the logarithmic phase of growth
were used in all experiments described below. HL-60
cells (105 per mL) were seeded in 25 cm2 Nunc tissue
culture flasks and incubated with increasing concen-
trations of drugs (IIa–IIl) at 37◦C under cell culture
conditions. Cell counts and IC50 values were deter-
mined after 24 h, 48 h, and 72 h using the micro cell
counter CC-108. Viability of the cells was determined
by trypan blue exclusion. Results were calculated as
the number of viable cells.
Experimental
Synthesis of methyl hydrazinecarbodithioate
(I) and substituted benzaldehyde hydrazones of
methyl hydrazine carbodithioate (II)
To an ice cooled solution (< 10◦C) of 19.8 g (0.300
mol) of potassium hydroxide in 24 mL of water and
20 mL of propan-2-ol, 17.1 mL of 80 % pure hy-
drazine hydrate were added and constantly stirred.
The amount of 18.2 mL (0.300 mol) of ice cooled car-
bon disulfide was added drop wise to the stirred so-
lution, maintained at < 10◦C for over about 1–1.5 h.
The bright yellow mixture formed was stirred for an
additional 1 h after which ice cooled iodomethane
(18.7 mL, 0.300 mol) was added drop wise over a 2 h
period. Stirring was continued for an additional 1 h,
and the white precipitate obtained was filtered and
washed with ice-cold water. The crude product was
recrystallised from dichloromethane: yield of 43 %;
Antiviral activity assay procedure
Antiviral assays (except anti-human immunode-
ficiency virus (HIV) assays) were based on the in-
hibition of virus-induced cytopathic effect in HEL

652
M. Mahapatra et al./Chemical Papers 67 (6) 650–656 (2013)
Fig. 2. Reaction sequence of the IIa–IIl synthesis.
(herpes simplex virus type 1 (HSV-1), HSV-2 (G),
vaccinia virus, and vesicular stomatitis virus), Vero
(parainfluenza-3, reovirus-1, Coxsackie B4, and Punta
Toro virus), HeLa (vesicular stomatitis virus, Cox-
sackie virus B4, and respiratory syncytial virus),
Madin-Darby canine kidney (MDCK) (influenza A
(H1N1; H3N2) and B virus), and CrFK (feline corona
virus (FIPV) and feline herpes virus) cell cultures.
Confluent cell cultures in microtiter 96-well plates
were inoculated with 100-cell culture inhibitory dose-
50 (CCID50) of the virus (1 CCID50 being the virus
dose to infect 50 % of the cells) in the presence of vary-
ing concentrations (100 mM, 20 mM, 5 mM, 1 mM,
200 nM) of the test compounds. Viral cytopathic ef-
fect was recorded as soon as it reached completion in
the control virus-infected cell cultures that were not
treated with the test compounds.
For the HCMV assays, confluent HEL fibroblasts
were grown in 96-well microtiter plates and infected
with the human cytomegalovirus strains Davis and
AD-169 at 100 PFU per well. After a 2 h incuba-
tion period, the residual virus was removed and the
infected cells were further incubated with a medium
containing different concentrations of the test com-
pounds (in duplicate). After incubation for 7-days at
37◦C, the virus-induced cytopathic effect was moni-
tored microscopically after ethanol fixation and stain-
ing with Giemsa dye. Antiviral activity was expressed
as the EC50 or compound concentration required for
the reduction of virus-induced cytopathogenicity by
50 %.
The varicella zoster virus (VZV) drug susceptibil-
ity tests were performed on confluent HEL cells in 96-
well microtiter plates by the plaque reduction assay.
Monolayers were infected with 20 plaque forming units
(PFU) of the cell-associated virus per well. For each
assay, virus controls (infected-untreated cells) were in-
cluded. After a 2 h incubation period, the virus inocu-
lum was removed and the media were replaced by dif-
ferent dilutions (in duplicate) of the tested molecules.
Serial dilutions of test compounds were incubated with
the infected monolayers for five days. After a five day
incubation period, the cells were fixed and stained
with Giemsa, and the level of the virus-induced cyto-
pathic effect was determined by counting the number
of plaques for each dilution. Activity was expressed as
EC50 (effective compound concentration required to
reduce virus plaque formation by 50 %) compared to
the untreated control.
The anti-HIV activity of the compounds was eval-
uated against the wild type HIV-1 strain IIIB in
MT-4 cell cultures using the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide (MTT) method.
Briefly, virus stocks were titrated in MT-4 cells and
expressed as the 50 % cell culture infective dose
(CCID50). MT-4 cells were suspended in culture
medium at 105 cells per mL and infected with HIV
at the multiplicity of infection of 0.02. Immediately
after viral infection, 100 µL of the cell suspension
were placed in each well of a flat-bottomed microtiter
tray containing various concentrations of the test com-
pounds. The test compounds were dissolved in DMSO
at 50 mM or more as stock solutions. Then, serial di-
lutions of the test compounds were made. The highest
concentration tested was 100 µM of the test compound
containing 0.2 % of DMSO, which is by itself not toxic
to cell proliferation. After four days of incubation at
37◦C, the number of viable cells was determined using
the MTT method.
Results and discussion
Compounds IIa–IIl were synthesised following the
reaction sequence outlined in Fig. 2. Methyl hy-
drazinecarbodithioate (I ) was prepared by the reac-
tion of hydrazine hydrate (85 mass %) with carbon
disulfide in the presence of potassium hydroxide at
a temperature below 10◦C; followed by the addition
of methyl iodide (Audrieth et al., 1954). Condensa-
tion of I with aromatic aldehydes/ketones in methanol
provided compounds IIa–IIl (Klayman et al., 1991;
Scovill etal., 1982). All compounds were characterised
by their 1H-NMR and FAB-MS data. Physicochem-
ical characterisation data are presented Table 1 and
spectral data of compounds IIa–IIl are presented in
Table 2.
All compounds were tested for their anticancer
activity against the HL-60 human promyelocytic
leukemia cell line and the results are presented in Ta-
ble 3. The compounds were also tested for their antivi-
ral activity against herpes simplex virus-1 (KOS), her-
pes simplex virus-2 (G), herpes simplex virus-1 TK−
(KOS ACVr), varicella-zoster virus (OKA and 07/1),
cytomegalovirus (Davis and AD169), vaccinia virus,
vesicular stomatitis virus, feline corona virus, feline
herpes virus, human immunodeficiency virus (HIV)
type 1 (IIIB) and type 2 (ROD), coxsackie virus B4,
respiratory syncytial virus, parainfluenza 3 virus, re-

M. Mahapatra et al./Chemical Papers 67 (6) 650–656 (2013)
Table 1. Characterisation data of newly prepared compounds IIa–IIl
653
Yield
%
M.p.
◦C
Compound
R
R1
Formula
Mr
IIa
IIb
IIc
IId
IIe
IIf
H
H
C9H9ClN2S2
C9H9ClN2S2
C9H10N2OS2
C9H10N2OS2
C10H12N2OS2
C10H12N2OS2
C10H12N2S2
C10H12N2S2
C10H12N2OS2
244
244
226
226
240
240
224
224
240
67
72
61
60
62
75
80
69
63
187
165
178
139
143
141
118
153
162
H
H
H
H
IIg
IIh
IIi
H
H
CH3
IIj
H
C17H16N2S2
312
61
189
IIk
IIl
–
C10H9N3OS2
C8H9N3S2
251
211
69
63
181
143
H
ovirus, sindbis virus and punta tora virus. Only re-
sults for compounds showing activity against any of
the viruses are presented in Table 4.
maximum concentration studied (100 µM, after 72 h).
All the compounds exhibited a cytotoxic concentra-
tion (CC50) of ≥ 100 µM in the HeLa cell cultures
except for IIl (36 µM), (Table 3). Compounds IIi and
IIl showed the best selectivity towards the HL60 cells
and therefore, further investigations are required.
Compounds IIc and IIi resemble the iron chelator
311 (Nꢀ-[(2-hydroxynaphthalen-1-yl)-methylidene]-
pyridine-4-carbohydrazide) and IIl resembles triapine
(3-aminopyridine-2-carbaldehyde thiosemicarbazone).
Compound IIi having a ketonic methyl group showed
activity comparable to that of iron chelator 311 at
48 h. Compound IIl also exhibited an anti-proliferative
activity comparable to that of Triapine. The analogue
of IIl with a ketonic methyl group has to be considered
for further improvement of its activity.
Compound IIl, IIi, and IIc showed IC50 values
against HL60 cells at the concentration of 0.8 µM,
≈ 1 µM, and 6.5 µM, respectively, after 72 h. It
is interesting to note that preferably compounds
with tridentate ligand characteristics (IIl, IIi, and
IIc) showed potent anti-proliferative activity against
the HL60 cells (Table 3). The activity of compound
IIi (2ꢀ-hydroxy acetophenone derivative) was higher
than that of IIc (2-hydroxy benzaldehyde deriva-
tive) and almost equally potent to IIl (pyridine 2-
carboxaldehyde derivative). All the other compounds
(IIa, IIb, IId–IIh, and IIk) were inhibitory at con-
centrations between 55 µM and 63 µM after 72 h,
except for IIj, irrespective of the nature and posi-
tion of the substitution. Compound IIj did not ex-
ert any inhibitory activity on the HL60 cells at the
It is interesting to observe that only compounds
with tridentate ligand characteristics (IIc, IIi, and IIl)
have shown antiviral activity against a few viruses and

654
M. Mahapatra et al./Chemical Papers 67 (6) 650–656 (2013)
Table 2. Spectral data of newly prepared compounds IIa–IIl
Compound
Spectral data
H NMR (DMSO-d6), δ: 2.68 (s, 3H, —SCH3); 7.41–7.87 (m, 4H, ArH); 8.41 (s, 1H, —N CH—); 12.63 (s, 1H,
1
—
—
IIa
NH)
MS, m/z (Ir/%): 244 (21.60) (M)+, 245 (63.42) (M + 1)+, 246 (16.98) (M + 2)+
1
—
IIb
IIc
H NMR (DMSO-d6), δ: 2.75 (s, 3H, —SCH3); 7.26–7.68 (m, 4H, ArH); 7.83 (s, 1H, —N CH—); 10.3 (s, 1H, NH)
—
MS, m/z (Ir/%): 244 (22.04) (M)+, 245 (61.04) (M + 1)+, 246 (16.92) (M + 2)+
1
—
—
H NMR (DMSO-d6), δ: 2.66 (s, 3H, —SCH3); 6.92–7.42 (m, 4H, ArH); 8.33 (s, 1H, —N CH—); 10.44 (s, 1H,
NH); 13.04 (s, 1H, ArOH)
MS, m/z (Ir/%): 226 (20.30) (M)+, 227 (68.61) (M + 1)+, 228 (11.09) (M + 2)+
1
—
IId
IIe
IIf
H NMR (DMSO-d6), δ: 2.73 (s, 3H, —SCH3); 6.82–7.95 (m, 4H, ArH); 8.14 (s, 1H, —N CH—); 10.06 (s, 1H,
—
NH); 13.13 (s, 1H, ArOH)
MS, m/z (Ir/%): 226 (44.77) (M)+, 227 (42.71) (M + 1)+, 228 (12.52) (M + 2)+
1H NMR (DMSO-d6), δ: 2.67 (s, 3H, —SCH3); 3.88 (s, 3H, —OCH3); 6.90–7.99 (m, 4H, ArH); 8.29 (s, 1H,
—
—N CH—); 10.17 (s, 1H, NH)
—
MS, m/z (Ir/%): 240 (24.83) (M)+, 241 (58.85) (M + 1)+, 242 (16.32) (M + 2)+
1H NMR (DMSO-d6), δ: 2.67 (s, 3H, —SCH3); 3.86 (s, 3H, —OCH3); 6.72–7.69 (m, 4H, ArH); 7.79 (s, 1H,
—
—N CH—); 10.06 (s, 1H, NH)
—
MS, m/z (Ir/%): 240 (37.65) (M)+, 241 (43.62) (M + 1)+, 242 (18.73) (M + 2)+
1
—
IIg
IIh
IIi
H NMR (DMSO-d6), δ: 2.53 (s, 3H, CH3); 2.67 (s, 3H, —SCH3); 7.26–7.80 (m, 4H, ArH); 8.12 (s, 1H, —N CH—);
—
10.36 (s, 1H, NH)
MS, m/z (Ir/%): 224 (23.63) (M)+, 225 (57.06) (M + 1)+, 226 (19.30) (M + 2)+
1
—
H NMR (DMSO-d6), δ: 2.39 (s, 3H, CH3); 2.67 (s, 3H, —SCH3); 7.21–7.63 (m, 4H, ArH); 7.84 (s, 1H, —N CH—);
—
10.27 (s, 1H, NH)
MS, m/z (Ir/%): 224 (25.05) (M)+, 225 (60.48) (M + 1)+, 226 (14.47) (M + 2)+
1H NMR (DMSO-d6), δ: 2.42 (s, 3H, CH3); 2.73 (s, 3H, —SCH3); 6.94–7.53 (m, 4H, ArH); 9.93 (NH); 11.37 (s, 1H,
ArOH)
MS, m/z (Ir/%): 240 (22.82) (M)+, 241 (54.35) (M + 1)+, 242 (22.82) (M + 2)+
1
—
IIj
IIk
IIl
H NMR (DMSO-d6), δ: 2.50 (s, 3H, —SCH3); 7.56–8.38 (m, 9H, ArH); 8.66 (s, 1H, —N CH—); 11.32 (NH)
—
MS, m/z (Ir/%): 95 (26.20), 107 (27.99), 204 (19.91), 221 (25.86)
1H NMR (DMSO-d6), δ: 2.67 (s, 3H, —SCH3); 7.2–7.9 (m, 4H, ArH); 8.2 (s, 1H, NH); 8.9 (s, 1H, —CONH—)
MS, m/z (Ir/%): 251 (23.29) (M)+, 252 (44.98) (M + 1)+, 253 (31.73) (M + 2)+
1H NMR (DMSO-d6), δ: 2.63 (s, 3H, —SCH3); 6.5–7.4 (m, 4H, ArH); 8.3 (s, 1H, NH)
MS, m/z (Ir/%): 211 (20.80) (M)+, 212 (48.32) (M + 1)+, 213 (30.87) (M + 2)+
Table 3. Cytotoxic/cytostatic activity of compounds IIa–IIl against HeLa and HL60 cells
HeLa cells
CCa50
HL60 cells
Code
IC50 (24 h)
IC50 (48 h)
IC50 (72 h)
IC50 (96 h)
µM
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
100
> 100
> 100
> 100
100
>100
> 100
100
≈ 90
> 100
> 100
97
> 100
≈ 85
96
≈ 60
70
6.5
65
≈ 60
62.5
6.5
63
–
–
–
–
–
–
–
–
59
55
≈ 60
≈ 60
59
59
96
69
57
IIi
IIj
IIk
IIl
100
100
> 100
35.8
–
≈ 85
> 100
93
1
0.6
≈ 1
> 100
64
0.8
0.4
–
≈ 1
> 100
57
0.8
–
–
–
–
–
–
0.27
Iron chelator 311b
TRPc
–
–
–
a) 50 % cytotoxic concentration as determined by measuring the cell viability with the colorimetric formazan-based MTS assay; b)
values are taken from Richardson and Milnes (1997), iron chelator 311 = (Nꢀ-[(2-hydroxynaphthalen-1-yl)-methylidene]-pyridine-
4-carbohydrazide); c) values are taken from Kowol et al. (2009); TRP = triapine (triapine = 3-aminopyridine-2-carbaldehyde
thiosemicarbazone).
are presented in Table 4. Compound IIl displayed pro-
nounced antiviral activity against HSV-1 (8–42 µM),
HSV-2 (9–11 µM ), VZV (6.5–42 µM), and vaccinia
virus (15–45 µM). It should be noted that IIl inhibits

M. Mahapatra et al./Chemical Papers 67 (6) 650–656 (2013)
655
Table 4. Antiviral activity of compounds IIc, IIi, and IIl in HEL cell cultures
ECa50
VZV
CMV
Code
HSV-1 HSV-2 Vaccinia
(KOS) (G) virus
Vesicular
HSV-1 TK−
MCCb CCc50
stomatitis virus (KOS ACVr) OKA 07-1
Davis AD169
µM
IIc
IIi
IIl
10
45
8
2
0
1
11
1
12
45
15
29
250
100
0
0
6
> 100
> 100
> 20
> 250
> 250
> 100
≥ 20
≥ 100
≥ 20
250
146
20
24
42
6.5
0.01
0.8
–
42
42
11
28
89
–
20
> 20
> 4
–
–
6.3
> 4
> 20
> 4
–
–
3.1
> 100
100
5.3
17
2.6
≥ 100
9
0
≥ 20
Brivudin
Acyclovir
Ganciclovir
0.1
183
0.4
0.03
> 200 > 200
> 200 > 200
> 200 > 200
1
0.03
a) Compound concentration required to reduce virus-induced cytopathogenicity by 50 %; b) compound concentration required to
cause a microscopically detectable alteration of normal cell morphology; c) compound concentration required to inhibit HEL cell
proliferation by 50 %.
the wild-type as well as the acyclovir-resistant HSV at
comparable compound concentrations (8–20 µM, Ta-
ble 4). Compound IIc with a 2-hydroxy substitution
and compound IIi, an acetophenone analogue of IIc,
show antiviral activity at somewhat higher concentra-
tions than IIl. Compound IId that differs from IIc by
a hydroxy functional group at the para position did
not show any appreciable antiviral activity. Additional
analogues of IIc and IIl are currently under further in-
vestigation. It should, however, be noted that IIc, IIi,
and IIl are poorly cytotoxic but they show pronounced
cytostatic activity in proliferating HEL (and HL60)
cell cultures. Therefore, the observed antiviral activ-
ity might not be due to direct antiviral activity but
rather due to indirect inhibitory action caused by the
underlying cytostatic potential of these compounds.
Lies Van den Heurck, Mr. Steven Carmans, Mrs. Anita Camps,
Mrs. Kristien Erven and Mr. Kris Uyttersprot for excellent
technical assistance.
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Conclusions
The present investigation revealed that: i) com-
pounds with a metal chelating functional group (IIc,
IIi, and IIl) at their aryl end were found to be ac-
tive and ii) the methyl dithioate (—CSSCH3) group
is not an bioisosteric equivalent of hydroxamate
(—CONHOH) or amidoxime (—CNHNHOH) (Fig 1.).
The compounds investigated are known as intermedi-
ates in the synthesis of many thiosemicarbazones but
their usefulness as medicinally active agents has not
yet been studied. The study suggests a possibility of
intermediates with specific pharmacophoric features
for the intended activities that can provide a new scaf-
fold for these activities.
Acknowledgements. The author acknowledges the Univer-
sity Grants Commission (UGC) & All-India Council for Tech-
nical Education (AICTE), India, for financial support (JRF)
to the first author and the GOA (no. 10/014) of the KU Leu-
ven; Sophisticated Instrumentation Facility (SAIF) of the Cen-
tral Drug Research Institute (CDRI), Lucknow, for enabling the
use of the facility for spectral characterisation of compounds.
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