Stereoselective synthesis and antiviral activity of (1E,2Z,3E)-1- (piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono] -4-(aryl1)but-3-enes

Article abstract of DOI:10.1002/ardp.200900195

The reaction of benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide 1b with 2-oxo-N-arylpropanehydrazonoyl chlorides 2a-dyielded (1Z,2E)-2-[(benzoyl/ benzothiazol-2-oyl)hydrazono]-N-(aryl)-propanehydrazonoyl chlorides 3a-e. The reaction of 3a-c with sodium benzenesulphinate furnished sulphones 5a-c while the reaction of 5d, e with hydroxylamine afforded hydroxomoyl derivatives 6a, b. The one-pot sterioselective reaction of N-(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of(1E,2Z,3E)-1-(piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/ benzothiazol-2-oyl)hydrazono]-4-(aryl¹)-but-3-enes 7a-g. Xray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a-g possessed a significant antiviral activity against herpes simplex viruses (HSV-1). Compound 7d reduced the number of viral plaques of herpes simplex type-1 (HSV-1) by 67%, with respect to the effect of reference drug Aphidicolin.

Full text of DOI:10.1002/ardp.200900195

152
Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
Full Paper
Stereoselective Synthesis and Antiviral Activity of (1E,2Z,3E)-1-
(Piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-
2-oyl)hydrazono]-4-(aryl1)but-3-enes
Hatem A. Abdel-Aziza1,2, Bakr F. Abdel-Wahab2, and Farid A. Badria3
1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
2 Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt
3 Department of Pharmacognosy, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
The reaction of benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide 1b with 2-oxo-N-arylpro-
panehydrazonoylchlorides2a–dyielded(1Z,2E)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-N-(aryl)-
propanehydrazonoyl chlorides 3a–e. The reaction of 3a–c with sodium benzenesulphinate fur-
nishedsulphones5a–cwhilethereactionof5d,ewithhydroxylamineaffordedhydroxomoylderiv-
atives 6a, b. Theone-pot sterioselective reactionofN-(aryl)propanehydrazonoylchlorides 3withcer-
tainaromaticaldehydesinthepresenceofpiperidineresultedintheformationof(1E,2Z,3E)-1-(piper-
idin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-4-(aryl1)-but-3-enes 7a–g. X-
ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with
respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperi-
dinyl amidrazones 7a–g possessed a significant antiviral activity against herpes simplex viruses
(HSV-1). Compound 7d reduced the number of viral plaques of herpes simplex type-1 (HSV-1) by 67%,
withrespecttotheeffectofreferencedrugAphidicolin.
Keywords: Antiviral activity / Benzothiazole / HSV-1 / Hydrazones / X-ray crystallography /
Received: August 15, 2009; Accepted: November 20, 2009
DOI 10.1002/ardp.200900195
appeared to be particularly damaging to the nervous sys-
tem, and it increases the risk of developing Alzheimer's
disease [6–8].
Introduction
Viral infections are considered one of the principle
threats to human life and health worldwide. The viral dis-
eases caused by herpes simplex viruses, HSV-1 and HSV-2,
were categorized into several distinct disorders based on
the site of infection. HSV infection may affect the face
(orofacial herpes), genitalia (genital herpes), hand (herpes
whitlow), eye (herpes keratitis), or the brain (herpes ence-
phalitis) [1–4]. The common opportunistic ocular infec-
tions, corneal epithelial and stromal keratitis, are caused
by herpes simplex virus, HSV-1; they are a leading cause
of blindness [5]. Moreover, AIDS patients are prone to
severe complications from HSV infections. HSV-1
Hydrazones have been reported as useful antiviral
agents. Some acetylhydrazones revealed a remarkable
antiviral activity against HSV-1 [9], whereas arylhydra-
zones inhibited the replication of HIV-1 [10]. Further-
more, an excellent antiviral activity has been demon-
strated by several heteroarylhydrazones versus influenza
A2, A3, and semliki forest viruses [11]. Additionally, 2-sub-
stituted benzothiazoles were intensively studied as anti-
viral agents. For example, the in-vivo antiviral activity of
2-aminobenzothiazole has a potency quite comparable to
that of the antiviral drug Amantadine against influenza
A2 strains [12]. A series of 2-substituted benzothiazoles
have been reported for treating HIV infection and AIDS
[13], also some amidino benzothiazoles have been
described as potent anti-HIV agents [14]. Moreover, fused
benzothiazoles exerted antiviral activity versus herpes
simplex virus HSV-1 [15].
Correspondence: Hatem A. Abdel-Aziz, Department of Pharmaceutical
Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabia.
E-mail: hatem_741@yahoo.com
Fax: +966 146 76220
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Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
(1E)-1-(Piperidin-1-yl)-N2-arylamidrazones
153
exchangeable signals of two NH groups in the regions d:
9.56–10.04 and d: 10.87–11.16 ppm in addition to the sin-
glet signal of the methyl group in the region d: 2.31–2.34
ppm. The analyses of the latter products confirmed the
assigned structure 3 (Scheme 1). Recently, we reported
the X-ray diffraction for the benzofuran analogue of
structure 3. It confirmed that the stereochemistry of
such a class of bi-hydrazones is the (1Z,2E)-configuration
[21].
Arylsulphones are a promising class of antiviral agents.
Arylsulphones of indole [28], thiophene [29], and pyrrole
[30] have been shown to display interesting antiviral
activity. Some derivatives of 3 have been selected for the
synthesis of new bi-hydrazones bearing a phenylsul-
phone moiety. Thus, reaction of 3a–c with sodium ben-
zenesulphinate afforded the corresponding sulphones
5a–c, respectively (Scheme 1). The structure of the latter
sulphones was assigned by their IR, 1H-NMR, and MS spec-
tra.
Moreover, the reaction of 3d or 3e with hydroxylamine
hydrochloride, in the presence of potassium carbonate,
yielded the corresponding N-hydroxy-2-(2-(benzothiazol-
2-carbonyl)hydrazono)-N9-(4-aryl)propanehydrazonamide
6a, b, respectively (Scheme 1). The structure of 6a, b was
confirmed on the basis of their spectroscopic data. For
example, the IR spectrum of 6a showed absorption bands
in the region 3410–3120 cm–1 of three NH groups and an
OH function, and the band of the carbonyl group at 1680
Reagents and conditions: (a) EtOH, reflux 9 h, 70–79%; (b) PhSO2Na N 2 H2O, reflux
18 h, 52–58%; (c) NH2OH N HCl, K2CO3, EtOH, reflux 45 min, 50–56%.
Scheme 1. Synthesis of compounds 3a–e, 5a–c and 6a–b.
Considering the above-mentioned facts and in the
light of our ongoing research of developing new mole-
cules with potent antiviral activity against herpes sim-
plex virus HSV-1 [16–20], particularly, with respect to its
risk in AIDS and Alzheimer patients, we synthesized a ser-
ies of benzoyl/benzothiazoloyl hydrazones bearing a sul-
fone or piperidine moiety for their antiviral activity
against herpes simplex viruses HSV-1. The cytotoxicity of
the newly synthesized compounds was estimated.
1
cm–1. Its H-NMR spectrum revealed four D2O exchange-
able singlet signals (three NH + OH), whereas its mass
spectrum showed a peak corresponding to its molecular
ion at m/z: 402 [M+].
The piperidine motif has been reported as a key struc-
tural component of several successful antiviral drug can-
didates [31–40] where piperidine-based phenoxy [34], pyr-
azole [35], alkylamine [36], carboxamide [37], sulphone
[38], alkene [39], or diketone [40] derivatives possessed a
unique antiviral activity. From the above mentioned
facts and in continuation of our interest in the synthesis
of poly-functionally piperidines of expected biological
importance [21, 24], we report here the utility of bi-hydra-
zones 3a–e in a one-pot stereoselective synthesis of the
title compounds. Thus, condensation of 3a–e with cer-
tain aromatic aldehydes in refluxing ethanol in the pres-
ence of four molar ratios of piperidine afforded the reac-
tion product which precipitated during reflux. The IR
spectra of the latter products exhibited, in each case, a
band in the region 1686–1639 cm–1 due to the carbonyl
absorption; also, the absorption bands of two NH func-
Results and discussion
Chemistry
Our previous work on the chemistry of bi-hydrazones [21]
as part of a program, directed us towards the synthesis of
biologically active heterocycles [21–27]. In the present
study, we aim to report the synthesis of (1Z,2E)-2-[(ben-
zoyl/benzothiazol-2-oyl)hydrazono]-N-(aryl)propanehydra-
zonoyl chloride 3a–e (Scheme 1). Thus, the reaction of
benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide
1b with 2-oxo-N-arylpropanehydrazonoyl chlorides 2a–d
in refluxing ethanol afforded, in each case, a single prod-
uct. IR spectra of the latter products exhibited a carbonyl
absorption band in the region 1683–1652 cm–1 in addi-
tion to the absorption bands of two NH functions in the
region m 3455–3182 cm–1. Their 1H-NMR showed two D2O
1
tions appeared in the region 4012–3118 cm–1. The H-
NMR spectra of the latter products showed two signals in
the regions d: 8.89–9.52 and 10.47–10.88 ppm assigned to
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H. A. Abdel-Aziza et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
Figure 1a. X-ray structure of (1E,2Z,3E)-7g.
Reagents and conditions: (a) Appropriate aldehyde, EtOH, piperidine (4 eq.), reflux
8 h, 64–75%.
Scheme 2. Synthesis of compounds 7a–g.
Hydrogen atoms are omitted for clarity.
Figure 1b. View of (1E,2Z,3E)-7g.
1
the two NH groups. The H-NMR spectra of the reaction
products revealed that the olefinic protons were consid-
erably shifted downfield appearing in the aromatic
region. The spectroscopic data of the latter provide sup-
port for the suggested structure 7 (Scheme 2) and ruled
out both of the expected cyclized products 8 and 9
(Scheme 2). However, X-ray analysis of amidrazone 7g not
only excluded the other possible products but also
showed the structural geometry of 7g as (1E,2Z,3E)-config-
uration (Figs. 1a and 1b). X-ray analysis of amidrazone 7g
showed a conversion of the configuration with respect to
the geometry of 3 and it confirmed both the stereoselec-
tivity of the latter reaction and the E configuration of the
amidrazone skeleton (1E = 170.18). The selected bond dis-
tances of 7g and torsion angles of three essential double
bonds 1E, 2Z, and 3E of (1E,2Z,3E)-7g are illustrated in
Table 1.
Table 1. Characteristic bond lengths (ꢀ) and torsion angles (8) of
(1E,2Z,3E)-7g.
bond length (ꢀ)
N8–C18
N7–N8
1.375 (4)§
1.389 (4)&
1.304 (4)#
1.358 (4){
1.468 (4)
1.466 (5)
1.503 (5){
1.293 (4)
1.362 (3)
N3–C6
O2–C6
C6–C20
S1–C20
N4–C20
C5–C14
C5–C9
1.349 (4)
1.218 (4)
1.505 (5)
1.727 (4)
1.298 (4)
1.460 (4)
1.306 (4)
1.464 (5)
N7–C16
N12–C16
N12–C19
N12–C28
C14–C16
N10–C14
N3–N10
C9–C21
In-vitro anti-herpes simplex-1 virus (HSV-1) and
cytotoxicity assays
torsion angles (8)
Compounds 5a–c, 6a, b, and 7a–g were tested for their
possible antiviral and cytotoxicity activity. The com-
pounds were tested for antiviral activity against herpes
simplex type 1 (HSV-1) grown on Vero African green mon-
key kidney cells. An improved plaque-reduction assay for
antiviral activity was used to test our compounds. Plaque-
reduction assays typically use a monolayer of cultured
host cells which are allowed to bind virus, then, they are
overlayed with a layer of medium thickened with agar or
(1E) N12–C16–N7–N8
(2Z) C16–C14–N10–N3
(3E) C21–C5–C9–C21
170.1 (8)**
0.8 (5)*
–179.7 (11)**
The bond lengths of (1E,2Z,3E)-7g are well within the range that
typically occurred in other amidrazone derivatives: § 1.391(2)–
1.396(3) ꢀ; & 1.342(4)–1.351(2) ꢀ; # 1.286(3)–1.294(2) ꢀ; {
1.373(3)–1.405(4) ꢀ, and { 1.491(4)–1.511(3) ꢀ [21]. The torsion
angles of (1E,2Z,3E)-7g are also well within the range that is typ-
ically reported: * Z = 08 fi € 308 and ** E = € 1508 fi 1808.
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Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
(1E)-1-(Piperidin-1-yl)-N2-arylamidrazones
155
Table 2. Results of in vitro anti-herpes simplex-1 virus (HSV-1)
and cytotoxicity.
the antiviral activity. Similarly, the derivative 7b that
contained the 4-methoxybenzylidine group, showed
slightly higher inhibition of HSV-1 (29%) than that of the
parent amidrazone 7a with the benzylidine group (23%).
On the other hand, compound 7f with a 4-chlorophenyl-
hydrazone group showed 62% reduction of the HSV-1
plaques, and, replacing this group by 4-nitrophenylhy-
drazone as in 7g, lowered the antiviral activity to 33%.
Taken together, the results of 7a–g provide evidence that
the structural features of the arylidine moieties and
changes in the aryl group of the amidrazone skeleton sig-
nificantly affects their anti-herpes simplex-1 virus (HSV-1)
activity.
In conclusion, we described a facile synthesis of poly-
functionally (1Z,2E)-2-[(benzoyl/benzothiazol-2-oyl)hydra-
zono]-N-(aryl)propanehydrazonoyl chloride bearing two
activated centers which were used as electrophilic substi-
tution substrates or C-nucleophiles. Some of the new
piperidinyl amidrazones showed a significant antiviral
activity against herpes simplex type-1 (HSV-1).
#
Compound
% Reduction§ MAC&
CD50
5a
5b
5c
6a
6b
7a
7b
7c
7d
7e
7f
None
None
None
None
None
22
29
16
67
28
–
–
–
–
0.02
0.02
0.04
0.01
0.02
0.02
0.03
0.01
0.02
0.01
0.02
0.01
0.2
–
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.005
62
33
7g
Aphidicolin{ 100
§ Percent (%) reduction in the number of viral plaques; & mini-
mum antiviral concentration (in mg/mL); # cytotoxicity (com-
pound concentration caused 50% loss of the monolayer present
around the viral plaques) (in mg/mL); { positive antiviral con-
trol; –: Not detected.
another thickener which makes plaque formation possi-
ble by preventing mixing due to currents in the medium.
Samples to be tested for antiviral activity are either incor-
porated into the thickened layer or absorbed in a paper
disc placed on the thickened layer. The thickened layer
can cause several types of technical problems. In his
assay, Shier reduced the assay size to fit the wells of 96-
well microliter trays. Also he used serial dilutions of sam-
ples in parallel wells in a tray allowing an estimation of
end-point concentrations for antiviral agents. Shier's
modifications reduced the sample size, the cost, and
eliminated the potential for interference by thickening
agents. At the same time, this assay retains the ability to
estimate the cytotoxicity which is reflected as loss of the
cell monolayer in which the plaques are normally
formed [41–43].
Experimental
Chemistry
Melting points were measured with a Gallenkamp apparatus
(Weiss-Gallenkamp, London, UK). IR spectra were recorded on
Shimadzu FT-IR 8101 PC infrared spectrophotometer (Shi-
madzu, Tokyo, Japan). The NMR spectra were recorded on a Var-
ian Mercury VX-300 NMR spectrometer (Varian, Palo Alto, CA,
USA). 1H-NMR spectra were run at 300 MHz in deuterated dime-
thylsulphoxide (DMSO-d6). Chemical shifts (dH) are reported rela-
tive to TMS as internal standard. All coupling constant (J) values
are given in Hertz. Chemical shifts (dC) are reported relative to
DMSO-d6 as internal standards. The abbreviations used are as fol-
lows: s, singlet; d, doublet; m, multiplet; D2O exch., exchanged
with D2O; all the NH exchanged with D2O. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at 70 eV. Elemen-
tal analyses were carried out at the Microanalytical Center of
Cairo University and are within € 0.4% of the theoretical value.
X-ray crystallography was carried out on a Kappa CCD Enraf Non-
ius FR 590 diffractometer, National Research Center, Dokki,
Cairo, Egypt. Benzothiazole-2-carbohydrazide 1b [44] and 2-oxo-
N-arylpropanehydrazonoyl chlorides 2a–d [45] were prepared
according to the literature procedures. Benzoyl hydrazine 1a
was used as obtained commercially. The reactions were moni-
tored and the purity of the products was checked by TLC plates
(0.25 mm silica gel, aluminum sheets 60 F254, Merck, Germany).
The spots were visualized using 254 nm UV lamp.
The modified assay was used to examine compounds
5a–c, 6a, b, and 7a–g. Aphidicolin was used as a positive
control. All compounds exhibit cytotoxicity and no selec-
tive antiviral activity.
Sulphones 5a–c and hydroxomoyles 6a, b showed no
antiviral activity but piperidinyl amidrazones 7a–g
showed a weak to moderate activity in reducing the num-
ber of plaques at the same concentration (0.1 mg/mL).
These results imply that the piperidine moiety attached
to the bi-hydrazone backbone is an essential pharmaco-
phoric site. Compound 7d was the best among the tested
compounds; it reduced the number of viral plaques of
herpes simplex type-1 (HSV-1) by 67%, with respect to the
reference drug aphidicolin. Replacing the thienylidine
moiety in 7d by a benzylidine group as in 7c decreased
General procedure for the synthesis of (1Z,2E)-2-
(benzoyl/benzothiazol-2-oyl)-N-arylpropanehydrazonoyl
chlorides 3a–e
A mixture of benzoyl hydrazine 1a or benzothiazole-2-carbohy-
drazide 1b (10 mmol) and 2-oxo-N-arylpropanehydrazonoyl
chloride 2a–d (10 mmol) in absolute ethanol (50 mL) was
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H. A. Abdel-Aziza et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
refluxed for 9 h. Then left to cool, the formed solid was filtered
off, washed with ethanol, and recrystallized from EtOH/DMF to
afford the corresponding hydrazonoyl chlorides 3a–e, respec-
tively.
Synthesis of 1-phenylsulfonyl-1-arylhydrazono-2-
(benzoyl/benzothiazol-2-oyl)propane 5a–c
To a solution of the appropriate propanehydrazonoyl chloride
3a–c (1 mmol) in absolute ethanol (50 mL), sodium benzenesul-
phinate dihydrate (0.4 g, 2 mmol) was added. The mixture was
refluxed for 18 h, then left to cool. The reaction mixture was
poured into cold water and the solid product filtered off, washed
with water, dried, and finally recrystallized from EtOH/DMF to
afford the corresponding sulphones 5a–c.
(1Z,2E)-2-(Benzoylhydrazono)-N-
phenylpropanehydrazonoyl chloride 3a
Pale yellow powder, yield (78%); m. p.: 198–2008C; IR (KBr) mmax
cm–1: 3455, 3303 (2 NH), 1683 (C=O), 1593 (C=N); 1H-NMR (DMSO-
d6) d: 2.31 (s, 3H, CH3), 7.05–7.98 (m, 10H, ArH), 9.74 (s, D2O exch.,
1H, NH), 10.94 (s, D2O exch., 1H, NH); MS m/z (%): 316 [M+ + 2] (3.1),
315 [M+ + 1] (2.2), 314 [M+] (8.9), 77 (100). Anal. calcd. for
C16H15ClN4O: C, 61.05; H, 4.80; N, 17.80. Found: C, 60.82; H, 4.88;
N, 17.93.
1-Phenylsulfonyl-1-phenylhydrazono-2-
(benzoylhydrazono)propane 5a
Yellow powder, yield (58%); m. p.: 215–2178C; IR (KBr) mmax cm–1:
3300–3180 (2 NH), 1669 (C=O), 1599 (C=N), 1292, 1135 (SO2); 1H-
NMR (DMSO-d6) d: 2.48 (s, 3H, CH3), 6.91–7.97 (m, 15H, ArH),
11.66 (s, D2O exch., 1H, NH), 14.52 (s, D2O exch., 1H, NH); MS m/z
(%): 420 [M+] (4.1), 77 (100). Anal. calcd. for C22H20N4O3S: C, 62.84;
H, 4.79; N, 13.32; S, 7.63. Found: C, 63.02; H, 4.75; N, 13.32; S,
7.51.
(1Z,2E)-2-(Benzoylhydrazono)-N-(4-
tolyl)propanehydrazonoyl chloride 3b
Yellow powder, yield (74%); m. p.: 203–2058C; IR (KBr) mmax cm–1:
3390, 3272 (2 NH), 1668 (C=O), 1590 (C=N); 1H-NMR (DMSO-d6) d:
2.34 (s, 3H, CH3), 2.37 (s, 3H, CH3), 7.10 (d, J = 7.5 Hz, 2H, ArH),
7.23 (d, J = 7.5 Hz, 2H, ArH), 7.35–7.93 (m, 5H, ArH), 10.04 (s, D2O
exch., 1H, NH), 10.87 (s, D2O exch., 1H, NH); MS m/z (%): 330 [M+ +
2] (4.3), 329 [M+ + 1] (3.0), 328 [M+] (14.1), 77 (100). Anal. calcd. for
C17H17ClN4O: C, 62.10; H, 5.21; N, 17.04. Found: C, 61.88; H, 5.35;
N, 16.90.
1-Phenylsulfonyl-1-(4-tolylhydrazono)-2-
(benzoylhydrazono)propane 5b
Yellow powder, yield (55%); m. p.: 245–2478C; IR (KBr) mmax cm–1:
3300–3175 (2 NH), 1641 (C=O), 1582 (C=N), 1293, 1138 (SO2); 1H-
NMR (DMSO-d6) d: 2.25 (s, 3H, CH3), 2.48 (s, 3H, CH3), 6.84 (d, J =
7.5 Hz, 2H, ArH), 7.10 (d, J = 7.5 Hz, 2H, ArH), 7.55–7.95 (m, 10H,
ArH), 11.63 (s, D2O exch., 1H, NH), 14.52 (s, D2O exch., 1H, NH);
MS m/z (%): 434 [M+] (11.5), 77 (100). Anal. calcd. for C23H22N4O3S:
C, 63.58; H, 5.10; N, 12.89; S, 7.38. Found: C, 63.44; H, 4.97; N,
12.96; S, 7.35.
(1Z,2E)-2-{[(Benzothiazol-2-yl)carbonyl]hydrazono}-N-
phenylpropanehydrazonoyl chloride 3c
Yellow powder, yield (75%); m. p.: 216–2188C; IR (KBr) mmax cm–1:
3409, 3294 (2 NH), 1680 (C=O), 1595 (C=N); 1H-NMR (DMSO-d6) d:
2.31 (s, 3H, CH3), 7.09–7.89 (m, 9H, ArH), 9.84 (s, D2O exch., 1H,
NH), 10.93 (s, D2O exch., 1H, NH); MS m/z (%): 373 [M+ + 2] (2.1), 372
[M+ + 1] (1.5), 371 [M+] (6.5), 135 (100). Anal. calcd. for
C17H14ClN5OS: C, 54.91; H, 3.79; N, 18.83; S, 8.62. Found: C, 55.07;
H, 3.67; N, 18.87; S, 8.55.
1-Phenylsulfonyl-1-phenylhydrazono-2-{[(benzothiazol-2-
yl)carbonyl]hydrazono}propane 5c
Yellow powder, yield (52%); m.p.: 247–2498C; IR (KBr) mmax cm–1:
3350–3180 (2 NH), 1655 (C=O), 1598 (C=N), 1292, 1135 (SO2); 1H-
NMR (DMSO-d6) d: 2.49 (s, 3H, CH3), 6.67–8.18 (m, 14H, ArH),
11.65 (s, D2O exch., 1H, NH), 14.50 (s, D2O exch., 1H, NH); MS m/z
(%): 477 [M+] (6.2), 77 (100). Anal. calcd. for C23H19N5O3S2: C, 57.85;
H, 4.01; N, 14.66; S, 13.43. Found: C, 57.66; H, 4.13; N, 14.65; S,
13.28.
(1Z,2E)-2-{[(Benzothiazol-2-yl)carbonyl]hydrazono}-N-(4-
chlorophenyl)propanehydrazonoyl chloride 3d
Synthesis of N-hydroxy-2-(2-(benzothiazol-2-oyl)
Yellow powder, yield (79%); m. p.: 237–2398C; IR (KBr) mmax cm–1:
3316, 3182 (2 NH), 1652 (C=O), 1588 (C=N); 1H-NMR (DMSO-d6) d:
2.32 (s, 3H, CH3), 7.12–7.98 (m, 8H, ArH), 10.03 (s, D2O exch., 1H,
NH), 11.16 (s, D2O exch., 1H, NH); MS m/z (%): 409 [M+ + 3] (6.7), 408
[M+ + 2] (17.4), 407 [M+ + 1] (56.8), 406 [M+] (16.1), 135 (100). Anal.
calcd. for C17H13Cl2N5OS: C, 50.26; H, 3.23; N, 17.24; S, 7.89.
Found: C, 50.35; H, 3.17; N, 17.19; S, 7.83.
hydrazono)-N9-(4-aryl)propanehydrazonamide 6a, b
A mixture of 3d or 3e (1 mmol) of hydroxylamine hydrochloride
(0.11 g, 1.5 mmol) and anhydrous potassium carbonate (0.21 g,
1.5 mmol) in ethanol (50 mL) was refluxed for 45 min, then left
to cool. The reaction mixture was poured into cold water and
the solid product was filtered off, washed with water, dried, and
finally recrystallized from EtOH/DMF to afford 6a and 6b, respec-
tively.
(1Z,2E)-2-{[(Benzothiazol-2-yl)carbonyl]hydrazono}-N-(4-
N-Hydroxy-2-(2-(benzothiazol-2-oyl)hydrazono)-N9-(4-
nitrophenyl)propanehydrazonoyl chloride 3e
Yellow powder, yield (70%); m. p.: 276–2788C; IR (KBr) mmax cm–1:
3350, 3208 (2 NH), 1664 (C=O), 1592 (C=N); 1H-NMR (DMSO-d6) d:
2.32 (s, 3H, CH3), 7.11–8.02 (m, 8H, ArH), 9.56 (s, D2O exch., 1H,
NH), 10.83 (s, D2O exch., 1H, NH); MS m/z (%): 418 [M+ + 2] (4.8),
417 [M+ + 1] (2.5), 416 [M+] (12.8), 135 (100). Anal. calcd. for
C17H13ClN6O3S: C, 48.98; H, 3.14; N, 20.16; S, 7.69. Found: C,
49.13; H, 3.18; N, 20.11; S, 7.74.
chlorophenyl)propanehydrazonamide 6a
Yellow powder, yield (50%); m. p.: >3008C; IR (KBr) mmax cm–1:
1
3410–3120 (3 NH + OH), 1680 (C=O), 1589 (C=N) cm–1; H-NMR
(DMSO-d6) d: 2.37 (s, 3H, CH3), 4.55 (s, D2O exch., 1H, -OH), 7.00–
7.96 (m, 9H, ArH and -NH-OH), 8.87 (s, D2O exch., 1H, =NNH-),
10.24 (s, D2O exch., 1H, -CONH-); MS m/z (%): 404 [M+ + 1] (16.9),
403 [M+ + 1] (11.0), 402 [M+] (48.8), 135 (100). Anal. calcd. for
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Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
(1E)-1-(Piperidin-1-yl)-N2-arylamidrazones
157
C17H15ClN6O2S: C, 50.68; H, 3.75; N, 20.86; S, 7.96. Found: C,
50.47; H, 3.83; N, 20.72; S, 8.11.
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(4-tolylhydrazono)-2-
[(benzoyl)hydrazono]-4-(thein-2-yl)but-3-ene 7d
Yellow crystals, yield (73%); m.p.: 218–2208C; IR (KBr) mmax cm–1:
3287–3170 (2NH), 1668 (C=O), 1585 (C=N); 1H-NMR (DMSO-d6) d:
1.60 (m, 6H, 3 CH2 of piperidine), 2.33 (s, 3H, CH3), 3.32 (m, 4H, 2
CH2 of piperidine), 6.96–8.02 (m, 14H, ArH and olefinic proto-
nes), 8.89 (s, D2O exch., 1H, =NNH-), 10.88 (s, D2O exch., 1H,
-CONH-); MS m/z (%): 471 [M+] (17.3), 84 (100). Anal. calcd. for
C27H29N5OS: C, 68.76; H, 6.20; N, 14.85; S, 6.80. Found: C, 68.58;
H, 6.04; N, 14.94; S, 6.63.
N-Hydroxy-2-(2-(benzothiazol-2-oyl)hydrazono)-N9-(4-
nitrophenyl)propanehydrazonamide 6b
Orange fibers, yield (56%); m.p.: >3008C; IR (KBr) mmax cm–1: 3395–
3130 (3 NH + OH), 1682 (C=O), 1586 (C=N) cm–1; 1H-NMR (DMSO-
d6) d: 2.36 (s, 3H, CH3), 5.04 (s, D2O exch., 1H, -OH), 6.97–8.08 (m,
9H, ArH and -NH-OH), 9.11 (s, D2O exch., 1H, =NNH-), 10.65 (s, D2O
exch., 1H, -CONH-); MS m/z (%): 413 [M+] (26.8), 135 (100). Anal.
calcd. for C17H15N7O4S: C, 49.39; H, 3.66; N, 23.72; S, 7.76. Found:
C, 49.50; H, 3.59; N, 23.73; S, 7.64.
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(phenylhydrazono)-2-
[(benzothiazol-2-oyl)hydrazono]-4-(phenyl) but-3-ene 7e
Yellow crystals, yield (75%); m. p.: 221–2238C; IR (KBr) mmax cm–1:
4012–3193 (2 NH), 1686 (C=O), 1598 (C=N); 1H-NMR (DMSO-d6) d:
1.63 (m, 6H, 3 CH2 of piperidine), 3.30 (m, 4H, 2 CH2 of piperi-
dine), 6.92–7.99 (m, 14H, ArH and olefinic protones), 8.97 (s, D2O
exch., 1H, =NNH-), 10.86 (s, D2O exch., 1H, -CONH-); MS m/z (%):
509 [M+ + 1] (4.2), 508 [M+] (4.6), 84 (100). Anal. calcd. for
C29H28N6OS: C, 68.48; H, 5.55; N, 16.52; S, 6.30. Found: C, 68.25;
H, 5.39; N, 16.70; S, 6.09.
General procedure for synthesis of (1E,2Z,3E)-1-
(piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/
benzothiazol-2-oyl)hydrazono]-4-(aryl1)but-3-enes 7a–g
To a solution of propanehydrazonoyl chloride 3a–e (1 mmol) in
ethanol (20 mL), piperidine (0.34 g, 4 mmol) and the appropriate
aldehyde (1 mmol) were added. The reaction mixture was
refluxed for 8 h. The precipitated product was filtered off.
Recrystallization from EtOH/DMF afforded compounds 7a–g,
respectively.
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(4-chlorophenyl-
hydrazono)-2-[(benzothiazol-2-oyl)hydrazono]-4-
(phenyl)but-3-ene 7f
Yellow crystals, yield (67%); m. p.: 239–2418C; IR (KBr) mmax cm–1:
3384, 3235 (2 NH), 1683 (C=O), 1601 (C=N); 1H-NMR (DMSO-d6) d:
1.52 (m, 6H, 3 CH2 of piperidine), 3.29 (s, 3H, OCH3), 3.30 (m, 4H,
2 CH2 of piperidine), 6.87–8.08 (m, 15H, ArH and olefinic proto-
nes), 8.96 (s, D2O exch., 1H, =NNH-), 10.47 (s, D2O exch., 1H,
-CONH-); MS m/z (%): 545 [M+ + 2] (5.8), 544 [M+ + 1] (4.5), 543 [M+]
(13.9), 84 (100). Anal. calcd. for C29H27ClN6OS: C, 64.14; H, 5.01; N,
15.47; S, 5.90. Found: C, 63.96; H, 4.94; N, 15.34; S, 5.97.
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(phenylhydrazono)-2-
[(benzoyl)hydrazono]-4-(phenyl)but-3-ene 7a
Yellow crystals, yield (64%); m. p.: 240–2428C; IR (KBr) mmax cm–1:
3384, 3235 (2 NH), 1683 (C=O), 1601 (C=N); 1H-NMR (DMSO-d6) d:
1.51 (m, 6H, 3 CH2 of piperidine), 3.45 (m, 4H, 2 CH2 of piperi-
dine), 6.69–7.98 (m, 17H, ArH and olefinic protones), 9.02 (s, D2O
exch., 1H, =NNH-), 10.81 (s, D2O exch., 1H, -CONH-); MS m/z (%):
452 [M+ + 1] (2.9), 451 [M+] (7.4), 84 (100). Anal. calcd. for
C28H29N5O: C, 74.47; H, 6.47; N, 15.51. Found: C, 74.33; H, 6.54; N,
15.60.
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(4-nitrophenyl-
hydrazono)-2-[(benzothiazol-2-oyl)hydrazono]-4-
(phenyl)but-3-ene 7g
Yellow crystals, yield (69%); m.p.: 272–2748C; IR (KBr) mmax cm–1:
3370–3118 (2 NH), 1680 (C=O), 1589 (C=N); 1H-NMR (DMSO-d6) d:
1.60 (m, 6H, 3 CH2 of piperidine), 3.25 (m, 4H, 2 CH2 of piperi-
dine), 6.87–8.11 (m, 13H, ArH and olefinic protones), 9.14 (s, D2O
exch., 1H, =NNH-), 11.70 (s, D2O exch., 1H, -CONH-); MS m/z (%):
555 [M+ + 2] (1.5), 554 [M+ + 1] (2.9), 553 [M+] (6.0), 84 (100). Anal.
calcd. for C29H27N7O3S: C, 62.91; H, 4.92; N, 17.71; S, 5.79. Found:
C, 62.75; H, 5.04; N, 17.70; S, 5.84.
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(phenylhydrazono)-2-
[(benzoyl)hydrazono]-4-(4-methoxyphenyl) but-3-ene 7b
Yellow crystals, yield (66%); m. p.: 236–2388C; IR (KBr) mmax cm–1:
3393, 3219 (2 NH), 1682 (C=O), 1603 (C=N); 1H-NMR (DMSO-d6) d:
1.52 (m, 6H, 3 CH2 of piperidine), 3.64 (m, 4H, 2 CH2 of piperi-
dine), 3.77 (s, 3H, OCH3), 6.71–7.92 (m, 16H, ArH and olefinic pro-
tones), 9.52 (s, D2O exch., 1H, =NNH-), 10.65 (s, D2O exch., 1H,
-CONH-); MS m/z (%): 481 [M+] (9.8), 77 (100). Anal. calcd. for
C29H31N5O2: C, 72.33; H, 6.49; N, 14.54. Found: C, 72.50; H, 6.45;
N, 14.67.
X-ray crystallography
A single crystal of compound 7g was obtained by slow evapora-
tion at room temperature, from a mixture of ethanol/DMF (v/v =
5:1). The crystal structure was solved and refined using maxus
(nonius, Deflt and MacScience, Japan) [46] Mo-Ka radiation (k =
0.71073 ꢀ) and a graphite monochromator were used for data
collection. The chemical formula and ring labeling system is
shown in Fig. 1. Crystal data for compound 7g: C28H27N7O3S, Mr,
553.645; system, monoclinic; Space group, P21/c; unit cell dimen-
sions, a 12.8288 (4) ꢀ, b 11.2318 (4) ꢀ, c 20.4612 (9) ꢀ, a 90.008, b
92.4035 (12)8; V, 2945.7 (2) ꢀ3; Z, 4; Dx, 1.248 mg m–3; h range for
data collection, 2.910–27.4858; l(Mo-Ka), 0.15 mm–1; T, 298 K;
measured reflections, 11328; independent reflections, 8615;
(1E,2Z,3E)-1-(Piperidin-1-yl)-1-(4-tolylhydrazono)-2-
[(benzoyl)hydrazono]-4-(phenyl)but-3-ene 7c
Yellow crystals, yield (68%); m. p.: 249–2518C; IR (KBr) mmax cm–1:
3266–3187 (2 NH), 1639 (C=O), 1571 (C=N); 1H-NMR (DMSO-d6) d:
1.61 (m, 6H, 3 CH2 of piperidine), 2.34 (s, 3H, CH3), 3.30 (m, 4H, 2
CH2 of piperidine), 6.0–8.0 (m, 16H, ArH and olefinic protones),
9.43 (s, D2O exch., 1H, =NNH-), 10.75 (s, D2O exch., 1H, -CONH-);
MS m/z (%): 465 [M+] (4.4), 84 (100). Anal. calcd. for C29H31N5O: C,
74.81; H, 6.71; N, 15.04. Found: C, 74.57; H, 6.59; N, 14.86.
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158
H. A. Abdel-Aziza et al.
Arch. Pharm. Chem. Life Sci. 2010, 343, 152–159
observed reflections, 1609; Rint, 0.038; R(all), 0.313; wR(ref), 0.083;
wR(all), 0.187; S(ref), 1.827; S(all), 1.976; D/rmax, 0.045; Dqmax, 0.89
eꢀ3, Dqmin, – 1.03 eꢀ3. Crystallographic data for the structures 7g
have been deposited with the Cambridge Crystallographic Data
Center (CCDC) under the number 742663. Copies of the data can
be obtained, free of charge, on application to CCDC 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or at www.ccdc.cam.ac.uk].
with medium, and fixed with 3.7% (v/v) formaldehyde in saline
for at least 20 min. The fixed cells were rinsed with water, and
examined visually. Antiviral activity is identified as confluent,
relatively unaltered monolayers of stained Vero cells treated
with HSV-1. Cytotoxicity was estimated as the concentration
that caused approximately 50% loss of the monolayer present
around the plaques caused by HSV-1.
The authors have declared no conflict of interest.
Antiviral and cytotoxicity assays
Sample preparation
Samples were prepared for assay by dissolving in 50 mL of DMSO
and diluting aliquots into sterile culture medium at 0.4 mg/mL.
These solutions were subdiluted to 0.02 mg/mL in sterile
medium and the two solutions used as stocks to test samples at
100, 50, 20, 10, 5, 2, and 1 mg/mL in triplicate in the wells of
microtiter plates.
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www.archpharm.com