A convenient preparation of 2-(2-arylidene)- and 2-(2-polyhydroxyalkylidene)hydrazono-4-imidazolidinones with various heterocyclic side chain substituents at position 5 as potential antiviral and antitumor agents

Article abstract of DOI:10.1080/10426500211714

A variety of novel 5-[(Z)-arylidene]-2-[(2-(E)-arylidene)hydrazono]4-imidazolidinones 1a-c to 4a,b and 5-[(Z)-arylidene]-2-[(2-(E)-polyhydroxyalkylidene)hydrazono]-4- imidazolidinones 5a-c to 7a-c were prepared from the reaction of 5-[(Z)-arylidene]-2-methylmercaptohydantoins 8a-c with 2-(E)-arylidene hydrazones 13a-d and/or 2-(E)-monosaccharides hydrazones 16a-c. The linear structure, and not that of the angular isomer, has been selected for the products. This structure has been confirmed from a model study of the condensation of 5-[(Z)-2-thienylidene]-2-hydrazono-4-imidazolidinone 9a with benzaldehyde and D-galactose, respectively. The acetylation and benzoylation reactions of compounds 1-7 have been studied. All the new compounds were tested for their potential antiviral and antitumor activities.

Full text of DOI:10.1080/10426500211714

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A Convenient Preparation of 2-(2-Arylidene)-
and 2-(2-Polyhydroxyalkylidene)hydrazono-4-
imidazolidinones with Various Heterocyclic Side
Chain Substituents at Position 5 as Potential
Antiviral and Antitumor Agents
Ahmed I. Khodair
To cite this article: Ahmed I. Khodair (2002) A Convenient Preparation of 2-(2-Arylidene)- and
2-(2-Polyhydroxyalkylidene)hydrazono-4-imidazolidinones with Various Heterocyclic Side Chain
Substituents at Position 5 as Potential Antiviral and Antitumor Agents, Phosphorus, Sulfur, and
Silicon and the Related Elements, 177:5, 1157-1173, DOI: 10.1080/10426500211714
To link to this article: http://dx.doi.org/10.1080/10426500211714
Published online: 27 Oct 2010.
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Date: 30 May 2016, At: 01:43

Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1157–1173
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092442
A CONVENIENT PREPARATION OF
2-(2-ARYLIDENE)- AND
2-(2-POLYHYDROXYALKYLIDENE)HYDRAZONO-4-
IMIDAZOLIDINONES WITH VARIOUS
HETEROCYCLIC SIDE CHAIN SUBSTITUENTS AT
POSITION 5 AS POTENTIAL ANTIVIRAL AND
ANTITUMOR AGENTS
Ahmed I. Khodair
Chemistry Department, Faculty of Education, Tanta University,
Kafr El-Sheikh Branch, Kafr El-Sheikh, Egypt
(Received September 24, 2001; accepted November 30, 2001)
A variety of novel 5-[(Z)-arylidene]-2-[(2-(E)-arylidene)hydrazono]-
4-imidazolidinones 1a–c to 4a,b and 5-[(Z)-arylidene]-2-[(2-(E)-
polyhydroxyalkylidene)hydrazono]-4-imidazolidinones 5a–c to 7a–c
were prepared from the reaction of 5-[(Z)-arylidene]-2-
methylmercaptohydantoins 8a–c with 2-(E)-arylidene hydrazones
13a–d and/or 2-(E)-monosaccharides hydrazones 16a–c. The linear
structure, and not that of the angular isomer, has been selected for the
products. This structure has been confirmed from a model study of the
condensation of 5-[(Z)-2-thienylidene]-2-hydrazono-4-imidazolidinone
9a with benzaldehyde and D-galactose, respectively. The acetylation
and benzoylation reactions of compounds 1–7 have been studied.
All the new compounds were tested for their potential antiviral and
antitumor activities.
Keywords: Antitumor agents; antiviral; 2-(E)-Monosaccharides
hydrazones; 5-[(Z)-arylidene]-2-methylmercaptohydantoins; 5-[(Z)-
(arylidene]-2-[(2-(E)-polyhydroxyalkylidene)hydrazono]-4-imidazoli-
dinones
Present address Fakulta¨t fu¨r Chemie, Universita¨t Konstanz, Fach M 725, D-78457
Konstanz, Germany.
The author expresses gratitude and thanks to Professor John P. Bader, Antiviral
Evaluation Branch and Professor V. L. Narayanan, Drug Synthesis and Chemistry
Branch, National Cancer Institute, USA for carrying out the antiviral and antitumor
screening.
Address correspondence to A. I. Khodair, Department of Chemistry, Faculty of
Education, Tanta University, Kafr El-Sheikh, Egypt. E-mail: khodair 62@yahoo.com
1157

1158
A. I. Khodair
INTRODUCTION
In continuation of the study on the synthesis of 2-hydrazono-4-
imidazolidinones1,2 the convenient syntheses of new hydrazonoimi-
dazolidinones with various heterocyclic side chains substituents at
position 5 as potential antiviral and antitumor activities are reported.
Substituted 4-imidazolidinones at C-5 are associated with a wide
7
range of biological properties, including anticonvulsant,3 antiviral,5
antitumor,8 and platelet inhibitory activities.9 Furthermore, intro-
duction of a furan-2-yl or thien-2-yl groups on to the position 5 of
20-deoxyuridine afforded compounds with marked activity against
HSV-1.10,11 In this respect, it seemed worthwhile to link the imida-
zolidinone to an hydrophilic moiety such as a glycoside. It was thus
anticipated that these heterocycles would posses better water solubil-
ity and an improved selectivity toward cancer cells which are known to
be specifically enriched in carbohydrate receptors such as lectins.12
Structures such as 5a–c to 7a–c were selected and their synthesis
planned via the anticipated coupling of these two moieties by an azine
unit. Indeed the preparation of simpler analogs such as 1a–c to 4a,b was
first studied in order to test two synthetic pathways (vide infra) and the
possible tautomeric equilibrium of such structures (notwithstanding
the two azine isomers). Moreover, a number of 2-(alkylidenehydrazono)-
4-imidazolidinone derivatives have been found to be useful inhibitors of
the Maillard reaction in vitro and, as such, are potentially useful in the
treatment of diseases caused by this reaction such as disorders asso-
ciated with diabetes and aging. They also have hypoglycemic activity,

Potential Antiviral and Antitumor Agents
1159
and are characterized by a long-lasting activity, excellent adsorption
properties, low toxicity, and high stability.13,14
Retrosynthetic analysis shows that arylazinoimidazolidinones 1–7
could be prepared using two different strategies (Scheme 1). Path A
relies on the condensation of an aldehyde hydrazone with methylthio
derivative 8. These steps are inverted in path B which is based on the
condensation of an aldehyde with an imidazolohydrazine 9, which may
be prepared from the reaction of the already mentioned methylthio
derivative 8 with hydrazine hydrate.
SCHEME 1
RESULTS AND DISCUSSION
The present work describes the synthesis, conformational anal-
ysis, and biological testing of a new series of 5-[(Z)-arylidene]-
2-[(2-(E)-arylidene]hydrazono)-4-imidazolidinones 1a–c to 4a,b
and
5-[(Z)-arylidene]-2-[(2-(E)-polyhydroxyalkylidene]hydrazono)-
4-imidazolidinones 5a–c to 7a–c via two different routes. The
condensation of aromatic aldehydes with 2-thiohydantoin 10 by
stirring in a solution of piperidine and anhydrous ethanol afforded
5-[(Z)-arylidene]-2-thiohydantoins 11a–c, which on methylation gave
the corresponding 5-[(Z)-arylidene]-2-methylmercaptohydantoins
8a–c (Scheme 2). In our hands these compounds could be conveniently
prepared in one pot by the reaction of compound 10 with aromatic

1160
A. I. Khodair
SCHEME 2 Reagents and conditions: (i) ArCHO, piperidine, EtOH, r.t.;
(ii) NaOH, MeOH, MeI, r.t.; (iii) ArCHO, KOH, MeOH, stirring 12 h, r.t., MeI,
stirring 6 h; (iv) NH2NH2.H2O, EtOH, reflux; (v) NH2NH2.H2O, AcOH, reflux.
aldehydes in presence of potassium hydroxide, followed by the addition
of iodomethane at room temperature. When compounds 8a–c were
heated with hydrazine hydrate in boiling anhydrous ethanol until the
evolution of methanethiol could not be detected, the corresponding
5-[(Z)-arylidene]-2-hydrazono-4-imidazolidinones 9a–c were obtained
in low yields. On the other hand, when compounds 8a–c were heated
with hydrazine hydrate in boiling acetic acid until the evolution of
methanethiol could not be detected, the N,N-bis-(5-(Z)-arylidene-4-oxo-
2-imidazolidinylidene)hydrazines 12a–c were obtained in quantitative

Potential Antiviral and Antitumor Agents
1161
yields. The structures of 9a–c and 12a–c were assigned on the basis of
elemental analysis and spectral data (IR, 1H NMR, 13C NMR and MS).
The IR absorption spectrum of compound 9a was characterized by the
1
presence of signals for the NH2 and NH groups at 3312 and 3157 cm
respectively, in addition to the carbonyl group at 1722 cm 1. While the
IR absorption spectrum of compound 12a was characterized by the
absence of a signal for the NH2 group at 3312 cm 1, the presence of a
1
signal at 1718 cm due to the carbonyl group was found, in addition
to the NH group at 3198 cm 1. The H NMR spectra of compounds
1
9a and 12a showed a signals at 6.74, 6.75 assigned to the vinylic
protons, indicating the presence of a Z-configurations for the exocyclic
double bond, in agreement with the 1H NMR spectra of 5-(E)- and
5-(Z)-arylidenehydantoin derivatives whose vinyl protons appear at
17
6.10–6.35 and 6.40–6.7515
respectively (Scheme 2).
As path B gives compounds 9a–c in low yields, we turned atten-
tion to the use of the aldehyde hydrazones according to path A. Thus,
2-(E)-arylidene hydrazones 13a–d were prepared following the method
of Lock18 via the reaction of hydrazine hydrate and aromatic aldehy-
des in ethanol at room temperature. Compounds 13a–d were condensed
with 5-[(Z)-arylidene]-2-methylmercaptohydantoins 8a–c to give 5-[(Z)-
arylidene]-2-[(2-(E)-arylidene]hydrazono)-4-imidazolidinones 1a–c to
4a,b respectively. Compound 1a was also independently synthesized
through another pathway via the condensation of 9a with the ben-
zaldehyde in refluxing ethanol for 12 h (54%). The structures of
1a–c to 4a,b were established on the basis of their elemental analy-
1
ses and spectral data (IR, H NMR, 13C NMR, and MS). The IR ab-
sorption spectrum of compound 1a was characterised by the presence
of a signal for the NH group at 3142 cm 1, in addition to the carbonyl
group at 1728 cm 1. The singlet observed at 6.75 for the correspond-
ing vinylic proton is in agreement with a Z-configuration of the double
bond and this is confirmed by the 13C NMR spectrum which showed a
singlet at 106.09 ppm. The corresponding carbon [(CD3)2SO] for 5-(Z)-
and 5-(E)-arylidenehydantoin derivatives give signals at 105–113 ppm
17
and 113–120 ppm,15
respectively (Scheme 3). Treatment of com-
pounds 1a–c and 4a with acetic anhydride in pyridine at room tem-
perature gave 5-[(Z)-arylidene]-2-(1-acetyl-2-(E)-arylidenehydrazono)-
4-imidazolidinones 14a–d. The structures of 14a–d were established on
1
the basis of their elemental analyses and spectral data (IR, H NMR,
13C NMR, and MS). The IR absorption spectrum of compound 14a was
characterized by the presence of a signal for the acetoxy carbonyl group
at 1752 cm 1, in addition to the carbonyl group at 1727 cm 1. The
1H NMR spectrum of compound 14a showed a singlet at 6.82 as-
signed to the vinyl proton, indicating the presence of a Z-configuration

1162
A. I. Khodair
SCHEME 3 Reagents and conditions: (i) ArCH NNH2 (13a–d), EtOH, reflux;
(ii) ArCHO, EtOH, reflux; (iii) Ac2O, pyridene, r.t.; (iv) Ac2O, reflux.
1
for the exocyclic double bond, in agreement with the H NMR spec-
tra of 5-(E)- and 5-(Z)-arylidenehydantoin derivatives whose vinyl pro-
17
tons respectively appear at 6.10–6.35 and 6.40–6.75.15
On the
other hand, when compounds 1c, 2b and 3c were treated with reflux-
ing acetic anhydride the corresponding 5-[(Z)-arylidene]-3-acetyl-2-(1-
acetyl-2-(E)-arylidenehydrazono)-4-imidazolidinones 15a–c were pro-
duced. The structures of 15a–c were established on the basis of their
elemental analyses and spectral data (IR, 1H NMR, 13C NMR and MS).
The structure of 15a was supported by its mass spectra, which showed
1
a molecular ion peak at m/z 455 and its H NMR (CDCl3) spectrum
showed the anomeric proton as a singlet at 7.78, indicating the pres-
ence of only the Z-configuration of the exocyclic double bond. This is

Potential Antiviral and Antitumor Agents
1163
confirmed by its 13C NMR NMR (CDCl3) spectrum which shows a sin-
glet at 114.54 ppm assigned to the vinylic carbon. The corresponding
carbon [CDCl3] for 5-(Z)- and 5-(E)-arylidenehydantoin derivatives give
signals at 105–115 ppm and 115–125 ppm15 17 respectively (Scheme 3).
The synthesis of compounds 5–7 was then carried out. Thus,
2-(E)-monosaccharides hydrazones 16a–c were prepared according to
the published methods1 via the condensation of hydrazine hydrate and
monosaccharides including D-galactose, D-mannose and L-arabinose
in anhydrous methanol at room temperature. Compounds 16a–c
were condensed with 5-[(Z)-arylidene]-2-mercaptohydantoins 8a–c
in refluxing methanol to afford the corresponding 5-[(Z)-arylidene]-
2-((2-(E)-polyhydroxyalkylidene)hydrazono)-4-imidazolidinones 5a–c
to 7a–c. The structures of 5a–c to 7a–c were established on the
basis of their elemental analyses and spectral data (IR, 1H NMR,
13C NMR, and MS). Analytical data for compound 5a revealed a
1
molecular formula C14H18N4O6S (m/z 370). The H NMR spectrum of
compound 5a showed the presence of a singlet at 6.73 assigned to
the vinylic proton, proving a Z-configuration of the exocyclic double
bond. The doublet at 7.46 with J = 7.52 Hz was due to H-10, and the
doublet at 4.52 with J = 6.97 Hz were assigned to H-20, indicating
the presence of E-configuration of the other exocyclic double bond,
in accordance with the reported results for D-ribose E-hydrazone
and D-ribose Z-hydrazone which showed signals for H-1, H-2 at
6.70–7.40, 4.10–4.70 and
6.50–6.80, 4.80–5.30 respectively.19
Compound 5a was also independently synthesized through another
pathway via condensation of 9a with D-galactose in refluxing methanol
for 24 h (47%). Treatment of compounds 5b,c and/or 6a–c with acetic
anhydride in pyridine at room temperature gave the corresponding
5-[(E)-2-arylidene]-2-(1-acetyl-2-(E)-(polyacetylalkylidenehydrazono)-
4-imidazolidinones 17a–e. On the other hand, treatment of com-
pounds 5b with benzoyl chloride in pyridine at room temperature gave
the corresponding 5-[(Z)-2-arylidene]-2-(1-benzoyl-2-(E)-(2,3,4,5,6-
penta-O-benzoylhexylidenehydrazono)-4-imidazolidinone (18). The
structures of 17a–e and 18 were established on the basis of their
elemental analyses and spectral data (IR, 1H NMR, 13C NMR and
MS). Analytical data for compound 17b revealed a molecular formula
C32H36N5O13 (m/z 697). The IR spectrum of compound 17b was
characterized by the absence of an hydroxy groups of the galactose
1
moiety and the presence of an acetoxy carbonyl at 1754 cm 1. The H
NMR spectrum of compound 17b showed a singlet at 6.70 assigned to
a vinylic proton. This proves a Z-configuration of the exocyclic double
bond. The doublet at 6.62 with a spin-spin coupling constant equal
to 9.52 Hz, corresponding to the orientation of H-10 and H-20 protons.

1164
A. I. Khodair
TABLE I IR and 1H NMR Data for 1–18
1
Compound
IR (KBr) (cm
)
1H NMR (D3C)2SO/
1a
3142 (NH), 1728 (CO)
3144 (NH), 1730 (CO)
3141 (NH), 1729 (CO)
3147 (NH), 1728 (CO)
3145 (NH), 1726 (CO)
3146 (NH), 1724 (CO)
3146 (NH), 1733 (CO)
3142 (NH), 1726 (CO)
3140 (NH), 1727 (CO)
3143 (NH), 1732 (CO)
3146 (NH), 1728 (CO)
11.57 (s, 1H, NH), 10.65 (br. s, 1H, NH),
8.20 (s, 1H, HC N), 7.90–7.12 (m, 8 H, Ar H),
6.75 (s, 1H, HC C)
11.86 (s, 1H, NH), 10.81 (s, 1H, NH),
8.32 (s, 1H, HC N), 7.95–6.62 (m, 8 H, Ar H),
6.30 (s, 1H, HC C)
11.71 (s, 1H, NH), 11.62 (s, 1H, NH),
10.57 (br. s, 1H, NH), 8.26 (s, 1H, HC N),
8.21–7.10 (m, 10 H, Ar H), 6.73 (s, 1H, HC C)
11.75 (s, 1H, NH), 10.55 (br. s, 1H, NH),
8.23 (s, 1H, HC N), 7.80–7.15 (m, 6 H, Ar H),
6.72 (s, 1H, HC C)
11.74 (s, 1H, NH), 10.53 (br. s, 1H, NH),
8.58 (s, 1H, HC N), 8.50–6.62 (m, 6 H, Ar H),
6.27 (s, 1H, HC C)
11.85 (s, 1H, NH), 11.76 (s, 1H, NH),
10.46 (br. s, 1H, NH), 8.32 (s, 1H, HC N),
8.40–7.13 (m, 8 H, Ar H), 6.70 (s, 1H, HC C)
11.78 (s, 1H, NH), 11.67 (s, 1H, NH),
10.50 (br. s, 1H, NH), 8.85 (s, 1H, HC N),
8.39–7.08 (m, 8 H, Ar H), 6.70 (s, 1H, HC C)
11.73 (s, 1H, NH), 11.52 (s, 1H, NH),
10.48 (br. s, 1H, NH), 8.90 (s, 1H, HC N),
8.40–6.65 (m, 8 H, Ar H), 6.28 (s, 1H, HC C)
11.68 (s, 2 H, 2 NH), 11.51 (s, 2 H, N1-H, NH),
8.98 (s, 1H, HC N), 8.37–7.08 (m, 8 H, Ar H),
6.66 (s, 1H, HC C)
11.73 (s, 1H, NH), 10.65 (br. s, 1H, NH),
8.26 (s, 1H, HC N), 8.10–6.72 (m, 6 H, Ar H),
6.70 (s, 1H, HC C)
11.70 (s, 1H, NH), 10.60 (br. s, 1H, NH),
8.17 (s, 1H, HC N), 8.00–6.63 (m, 6 H, Ar H),
6.25 (s, 1H, HC C)
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
5a
3436 (OH), 3192 (NH),
1718 (CO)
11.51 (s, 1H, NH), 10.45 (br. s, 1H, NH),
7.61 (d, 1H, H-3), 7.55 (d, 1H, H-5),
0
0
7.46 (d, J1
= 7.52 Hz, 1H, H-10),
2
7.09 (t, 1H, H-4), 6.73 (s, 1H, HC C),
4.90 (d, 1H, 20-OH), 4.52 (m, 3 H, H-20, H-30,
30-OH), 4.18 (m, 2 H, 50-OH, 40-OH),
3.68 (t, 1H, 60-OH), 3.55 (m, 2 H, H-50, H-40),
3.45–3.28 (m, 2 H, H-60, H-600)
5b
3438 (OH), 3190 (NH),
1720 (CO)
11.60 (s, 1H, NH), 10.70 (br. s, 1H, NH),
7.70 (d, 1H, H-5), 7.66 (d, 1H, H-3),
0
0
6.92 (d, J1
= 7.55 Hz, 1H, H-10),
2
6.59 (dd, 1H, H-4), 6.20 (s, 1H, HC C),
4.65 (d, 1H, 20-OH), 4.47 (m, 3 H, H-20, H-30,
30-OH), 4.15 (m, 2 H, 50-OH, 40-OH),
3.70 (t, 1H, 60-OH),00), 3.56 (m, 2 H, H-50, H-40),
3.47–3.27 (m, 2 H, H-60, H-600)

Potential Antiviral and Antitumor Agents
1165
TABLE I IR and 1H NMR Data for 1–18 (Continued)
1
Compound
IR (KBr) (cm
)
1H NMR (D3C)2SO/
5c
3436 (OH), 3200 (NH),
1724 (CO)
11.56 (s, 1H, NH), 10.50 (br. s, 1H, NH),
8.37 (d, 1H, H-2), 8.14 (d, 1H, H-7),
7.46 (d, J1
= 7.68 Hz, 1H, H-10),
0
0
2
7.11–7.23 (m, 3 H, H-4, H-5, H-6),
6.70 (s, 1H, HC C), 4.70 (d, 1H, 20-OH),
4.50 (m, 3 H, H-20, H-30, 30-OH), 4.20 (m, 2 H,
50-OH, 40-OH), 3.76 (t, 1H, 60-OH),
3.60 (m, 2 H, H-50, H-40), 3.50–3.30 (m, 2 H,
H-60, H-600)
6a
6b
6c
7a
7b
3435 (OH), 3196 (NH),
1725 (CO)
11.72 (s, 1H, NH), 10.60 (br. s, 1H, NH),
7.62 (d, 1H, H-3), 7.54 (d, 1H, H-5),
7.48 (d, J1
= 6.38 Hz, 1H, H-10),
0
0
2
7.11 (t, 1H, H-4), 6.70 (s, 1H, HC C),
4.92 (d, 1H, 20-OH), 4.45 (m, 3 H, H-20, H-30,
30-OH), 4.20 (m, 2 H, 50-OH, 40-OH),
3.65 (t, 1H, 60-OH), 3.52–3.30 (m, 4 H, H-60,
H-600, H-50, H-40)
3433 (OH), 3202 (NH),
1723 (CO)
11.70 (s, 1H, NH), 10.65 (br. s, 1H, NH),
7.72 (d, 1H, H-5), 7.68 (d, 1H, H-3),
0
0
7.08 (d, J1
= 6.35 Hz, 1H, H-10),
2
6.60 (dd, 1H, H-4), 6.25 (s, 1H, HC C),
4.68 (d, 1H, 20-OH), 4.50 (m, 3 H, H-20, H-30,
30-OH), 4.20 (m, 2 H, 50-OH, 40-OH),
3.75 (t, 1H, 60-OH), 00), 3.56 (m, 2 H, H-50,
H-40), 3.46–3.25 (m, 2 H, H-60, H-600)
11.72 (s, 1H, NH), 11.56 (s, 1H, N3-H),
10.50 (br. s, 1H, N1-H), 8.38 (d, 1H, H-2),
3430 (OH), 3197 (NH),
1718 (CO)
0
0
8.18 (d, 1H, H-7), 7.80 (d, J1
= 6.25 Hz,
2
1H, H-10), 7.45 (t, 1H, H-6), 7.15 (m, 2 H, H-4,
H-5), 6.70 (s, 1H, HC C), 4.92 (d, 1H, 20-OH),
4.42 (m, 3 H, H-20, H-30, 30-OH), 4.18 (m, 2 H,
50-OH, 40-OH), 3.60 (t, 1H, 60-OH), 3.56–3.30
(m, 4 H, H-60, H-600, H-50, H-40)
3430 (OH), 3192 (NH),
1722 (CO)
11.51 (s, 1H, NH), 10.45 (br. s, 1H, NH),
7.61 (d, 1H, H-3), 7.55 (d, 1H, H-5),
0
0
7.46 (d, J1
= 6.56 Hz, 1H, H-10),
2
7.08 (t, 1H, H-4), 6.70 (s, 1H, HC C),
4.82 (d, 1H, 20-OH), 4.61 (m, 2 H, 30-OH,
40-OH), 4.42 (m, 2 H, H-20, H-30), ), 3.80
(t, 1H, 50-OH), 3.65–3.20 (m, 4 H, H-50,
H-500, H-40)
3435 (OH), 3210 (NH),
1728 (CO)
11.30 (s, 1H, NH), 10.80 (br. s, 1H, NH),
7.71 (d, 1H, H-5), 7.66 (d, 1H, H-3),
0
0
6.92 (d, J1
= 6.34 Hz, 1H, H-10),
2
6.61 (d, 1H, H-4 furyl), 6.22 (s, 1H, HC C),
4.78 (d, 1H, 20-OH), 4.67 (m, 2 H, 30-OH,
40-OH), 4.50 (m, 2 H, H-20, H-30), 3.72 (t, 1H,
50-OH), 3.60–3.20 (m, 3 H, H-50, H-500, H-40)
(Continued on next page)

1166
A. I. Khodair
TABLE I IR and 1H NMR Data for 1–18 (Continued)
1
Compound
IR (KBr) (cm
)
1H NMR (D3C)2SO/
7c
3433 (OH), 3196 (NH),
1720 (CO)
11.75 (s, 1H, NH), 11.62 (s, 1H, NH),
10.56 (br. s, 1H, NH), 8.40 (d, 1H, H-2),
0
0
8.20 (d, 1H, H-7), 7.75 (d, J1
= 6.30 Hz,
2
1H, H-10), 7.50 (t, 1H, H-6), 7.20 (m, 2 H, H-4,
H-5), 6.72 (s, 1H, HC C), 4.85 (d, 1H, 20-OH),
4.60 (m, 2 H, 30-OH, 40-OH), 4.35 (m, 2 H,
H-20, H-30), 3.75 (t, 1H, 50-OH),
3.60–3.30 (m, 3 H, H-50, H-500, H-40)
11.80 (s, 1H, NH), 7.86 (d, 1H, H-3),
7.68 (d, 1H, H-5), 7.22 (s, 1H, CH),
7.18 (dd, 1H, H-4), 2.64 (s, 3 H, SMe)
11.78 (s, 1H, NH), 7.88 (d, 1H, H-5),
7.36 (d, 1H, H-3), 6.71 (dd, 1H, H-4),
6.32 (s, 1H, CH), 2.66 (s, 3 H, SMe)
12.02 (d, 1H, NH), 11.56 (s, 1H, NH),
7.15–8.60 (m, 6 H, CH, Ar H),
8a
8b
8c
9a
9b
3192 (NH), 1718 (CO)
3198 (NH), 1719 (CO)
3194 (NH), 1720 (CO)
2.63 (s, 3 H, SMe)
3312 (NH2), 3157
(NH), 1722 (CO)
11.80 (br. s, 2 H, 2NH), 7.90 (d, 1H, H-3),
7.82 (d, 1H, H-5), 7.20 (t, 1H, H-4),
6.74 (s, 1H, CH), 5.20 (br. s, 2 H, NH2)
11.78 (br. s, 1H, 2NH), 7.86 (d, 1H, H-5),
7.21 (d, 1H, H-3), 6.70 (dd, 1H, H-4),
6.35 (s, 1H, CH), 5.18 (br. s, 2 H, NH2)
11.56 (br. s, 3 H, 3NH), 8.17–7.06 (m, 5 H, Ar H),
6.64 (s, 1H, CH), 5.10 (br. s, 2 H, NH2)
11.82 (br. s, 2 H, 2NH), 7.90 (d, 1H, H-3),
7.64 (d, 1H, H-5), 7.12 (t, 1H, H-4),
6.75 (s, 1H, CH)
3320 (NH2), 3152
(NH), 1719 (CO)
9c
3314 (NH2), 3149
(NH), 1725 (CO)
3143 (NH), 1727 (CO)
12a
12b
12c
14a
14b
14c
14d
15a
3145 (NH), 1725 (CO)
3148 (NH), 1728 (CO)
11.67 (br. s, 2 H, 2NH), 7.70 (d, 1H, H-5),
7.60 (d, 1H, H-3), 6.60 (dd, 1H, H-4),
6.30 (s, 1H, CH)
12.02 (d, J = 2.30 Hz, 1H, 1NH),
11.50 (br. s, 2 H, 2NH), 8.14–7.11 (m, 5 H,
Ar H), 6.70 (s, 1H, CH)
3204 (NH), 1752 (Ac),
1727 (CO)
11.70 (s, 1H, NH), 8.25 (s, 1H, HC N),
7.60–7.10 (m, 8 H, Ar H), 6.82 (s, 1H, HC C),
2.60 (s, 3 H, Ac)
11.68 (s, 1H, NH), 8.45 (s, 1H, HC N),
8.35–6.68 (m, 8 H, Ar H), 6.35 (s, 1H, HC C),
2.58 (s, 3 H, Ac)
11.68 (s, 1H, N3 H), 8.86 (s, 1H, HC N),
8.40–7.15 (m, 10 H, Ar H), 6.70 (s, 1H,
HC C), 2.98, 2.58 (2s, 6 H, s, 2 Ac)
11.75 (s, 1H, NH), 8.78 (s, 1H, HC N),
8.42–7.12 (m, 10 H, Ar H), 6.75 (s, 1H,
HC C), 3.15, 2.56 (2s, 6 H, s, 2 Ac)
8.57 (s, 1H, HC N), 8.48–7.41 (m, 11H, Ar H,
HC C), 2.68, 2.64, 2.54 (3s, 9 H, 2 Ac)
3200 (NH), 1755 (Ac),
1730 (CO)
3211 (NH), 1757 (Ac),
1728 (CO)
3208 (NH), 1758 (Ac),
1725 (CO)
1752 (Ac), 1727 (CO)

Potential Antiviral and Antitumor Agents
1167
TABLE I IR and 1H NMR Data for 1–18 (Continued)
1
Compound
IR (KBr) (cm
)
1H NMR (D3C)2SO/
15b
1750 (Ac), 1728 (CO)
1756 (Ac), 1729 (CO)
8.45 (s, 1H, HC N), 8.10–6.70 (m, 6 H, Ar H),
6.38 (s, 1H, HC C), 2.82, 2.56 (2s, 6 H, 2 Ac)
8.85 (s, 1H, HC N), 8.38–7.10 (m, 10 H, Ar H),
6.72 (s, 1H, HC C), 3.08, 3.18, 2.78, 2.58 (2s,
12 H, 4 Ac)
15c
17a
3196 (NH), 1758 (Ac),
1717 (CO)
11.76 (s, 1H, NH), 7.76 (d, 1H, H-5),
7.68 (d, 1H, H-3), 6.60 (dd, 1H, H-4),
0
0
6.55 (d, J1
= 9.50 Hz, 1H, H-10),
2
6.25 (s, 1H, HC C), 5.56 (dd, 1H, H-20),
5.42 (m, 1H, H-30), 5.40 (m, 1H, H-40),
5.30 (m, 1H, H-50), 4.22 (dd, 1H, H-600),
3.85 (dd, 1H, H-60), 2.50, 2.12, 2.06, 2.00 (4 s,
18 H, 5 Ac)
17b
3202 (NH), 1754 (Ac),
1719 (CO)
11.74 (s, 1H, NH), 8.34 (s, 1H, H-2),
8.15 (d, 1H, H-7), 7.25 (d, 1H, H-6),
7.12 (m, 2 H, H-4, H-5), 6.70 (s, 1H, HC C),
6.62 (d, J1
= 9.52 Hz, 1, H, H-10),
0
0
2
5.60 (dd, 1H, H-20), 5.45 (m, 1H, H-30),
5.40 (m, 1H, H-40), 5.32 (m, 1H, H-50),
4.25 (dd, 1H, H-600), 3.78 (dd, 1H, H-60), 3.05,
2.58, 2.08, 2.02, 1.98 (5s, 15 H, 5 Ac)
11.56 (s, 1H, N3 H), 7.60 (d, 1H, H-3),
7.50 (d, 1H, H-5), 7.08 (t, 1H, H-4),
17c
17d
17e
18
3192 (NH), 1755 (Ac),
1720 (CO)
0
0
6.75 (s, 1H, HC C), 6.60 (d, J1
= 9.25 Hz,
2
1H, H-10), 5.75 (t, 1H, H-20), 5.48 (m, 1H,
H-30), 5.22 (m, 1H, H-40), 4.30 (dd, 1H, H-500),
4.15 (dd, 1H, H-50), 2.54, 2.13, 2.10, 2.06, 2.03
(5s, 15 H, 5 Ac)
3194 (NH), 1757 (Ac),
1728 (CO)
11.75 (s, 1H, N3 H), 7.80 (d, 1H, H-5),
7.68 (d, 1H, H-3), 6.61 (dd, 1H, H-4),
0
0
6.52 (d, J1
= 9.20 Hz, 1H, H-10), 6.30
2
(s, 1H, HC C), 5.76 (dd, 1H, H-20), 5.50
(m, 1H, H-30), 5.25 (m, 1H, H-40), 4.32
(m, 1H, H-500), 4.16 (dd, 1H, H-50), 2.60, 2.11,
2.08, 2.02, 2.00 (5s, 15 H, 5 Ac)
3204 (NH), 1750 (Ac),
1718 (CO)
11.70 (s, 1H, N3 H), 8.35 (s, 1H, H-2), 8.20
(d, 1H, H-7), 7.25 (d, 1H, H-6), 7.15
(m, 2 H, H-4, H-5), 6.74 (s, 1H, HC C), 6.60
(d, J1
= 9.26 Hz, 1H, H-10), 5.70 (dd, 1H,
0
0
2
H-20), 5.50 (dd, 1H, H-30), 5.24 (m, 1H, H-40),
4.30 (dd, 1H, H-500), 4.12 (dd, 1H, H-50), 3.12,
2.60, 2.12, 2.08, 2.03, 1.98 (5 s, 15 H, 5 Ac)
11.56 (s, 1H, NH), ), 8.50–6.60 (m, 33 H, Ar H),
3204 (NH), 1750 (Ac),
1718 (CO)
6.59 (d, J1
= 9.55 Hz, 1H, H-10), 6.35
0
0
2
(s, 1H, HC C), 5.60 (dd, 1H, H-20), 5.54
(m, 1H, H-30), 5.48 (m, 1H, H-40), 5.40
(m, 1H, H-50), 4.30 (dd, 1H, H-600), 4.08
(dd, 1H, H-60)

1168
A. I. Khodair
SCHEME 4 Reagents and conditions: (i) 2-(E)-monosaccarides hydrazones
(16a–c), MeOH, reflux; (ii) monosaccarides, NH2NH2 H2O, MeOH, reflux;
(iii) Ac2O, pyridene, r.t.; (iv) H5C6COCl, pyridene, r.t.
This indicates the presence of the E-configuration of the other exocyclic
double bond (Scheme 4).
Biological Evaluation
Compounds 1a–c to 7a–c were tested against HIV-1 (HTLV IIIB) in
MT-4 cells and were found to be inactive.20 For antitumor activities, the
compounds 1a–c to 7a–c were screened against leukaemia, non-small
cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer,

Potential Antiviral and Antitumor Agents
1169
TABLE II 13C NMR Data for Some Selected Compounds Listed in Table I
Compound
13C NMR (D3C)2SO/
1a
168.70 (C-10), 161.75 (C-4), 157.00 (C-2), 127.67, 127.99, 128.80, 129.16,
129.31, 129.33, 129.97, 129.99, 130.02, 134.04, 138.28 (C Ar, C-5),
106.09 ( HC)
1b
169.68 (C-10), 163.16 (C-4), 152.44 (C-2), 93.86, 111.01, 123.82, 126.00,
126.95, 128.02, 142.12, 148.25, 150.54 (C Ar, C-5), 110.09 ( CH)
169.96 (C-2), 164.27 (C-4), 150.50 (C-2), 145.33 (C-5), 136.94 (C-5),
116.51 (C-3), 113.26 ( CH), 108.24 (C-4), 12.12 (Me)
10b
renal cancer, prostate cancer, and breast cancer and were found to be
inactive.21,22
EXPERIMENTAL
NMR spectra were measured on a Bruker Advance DPX 300 MHz spec-
trometers for solutions in DMSO-d6 using TMS as internal standard.
The chemical shifts are given as values, and the J values are given
in Hz. Mass spectra were recorded on a Varian MAT 112 spectrometer.
Melting points ( C, uncorrected) were recorded on a Gallenkamp melt-
ing point apparatus. Aluminium sheets coated with silica gel 60 F254
(Merck) were used for TLC. Detection was effected by viewing under a
short wavelength UV lamp. IR spectra (KBr disc) were obtained on a
Pye Unicam Spectra 1000. Analytical data were performed on C, H, N,
Elemental analyzer Carls Erba 1106.
5-(Z)-Arylidene-2-thiohydantoins (11a–c). To
a
mixture of
2-thiohydantoin (10, 1.16 g, 10 mmol), piperidine (3 drops), and abso-
lute ethanol (30 ml) was added the appropriate aromatic aldehydes
(10 mmol). The reaction mixture was stirred 12 h at room tempera-
ture until the starting material was consumed (TLC). The reaction
mixture was diluted with cold water, followed by neutralization with
diluted hydrochloric acid. The separated yellow solid was collected
by filtration and recrystallized from ethanol to give the products
11a–c.7
5-[Z)-Arylidene]2-methylmercaptohydantoins (8a–c). Compounds
11a–c (10 mmol) were suspended in aq. sodium hydroxide (12.60 %,
3.50 ml) at room temperature To this suspension was added 25 ml of
methanol, and the mixture become clear after stirring 5 min. Methyl
iodide (1.56 g, 11 mmol) was added, and the mixture was stirred
12 h at room temperature. The separated yellow solid was collected
by filtration and recrystallized from methanol to afford the products
8a–c.

1170
A. I. Khodair
TABLE III Melting Points, Yields, and Analytical Data for 1–18
Found/Calculated (%)
Melting
Compound point ( C) (g, %)
Yield Molecular formula
(MW)
M+
(m/z )
C
H
N
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
5a
5b
5c
6a
6b
6c
7a
7b
7c
8a
8b
8c
9a
9b
238
270
294
245
252
297
350
249
287
205
210
215
220
240
192
180
198
190
198
177
214
168
242
276
212
273
312
298
318
202
190
217
244
224
160
230
197
222
170
168
156
155
2.3, 78 C15H12N4OS (296) 60.6/60.8 4.4/4.1 19.0/18.9 296
1.82, 68 C15H12N4O2 (280)
2.00, 61 C19H15N5O (329)
64.4/64.3 4.6/4.3 19.7/20.0 280
69.0/69.3 4.8/4.6 21.1/21.3 329
2.11, 70 C13H10N4OS2 (302) 51.3/51.6 3.5/3.3 18.4/18.5 302
1.52, 53 C13H10N4O2S (286) 54.2/54.5 3.8/3.5 19.7/19.6 286
2.01, 60 C17H13N5OS (335) 60.5/60.9 4.2/3.9 20.7/20.9 335
2.91, 87 C17H13N5OS (335) 60.7/60.9 4.1/3.9 20.6/20.9 335
2.52, 79 C17H13N5O2 (319)
3.42, 93 C21H16N6O (368)
63.7/63.9 4.4/4.1 21.5/21.9 319
68.2/68.5 4.5/4.4 22.6/22.8 368
1.97, 69 C13H10N4O2S (286) 54.4/54.5 3.8/3.5 19.3/19.6 286
1.94, 72 C13H10N4O3 (270) 57.7/57.8 3.9/3.7 20.4/20.7 270
2.81, 76 C14H18N4O6S (370) 45.1/45.4 5.2/4.9 14.8/15.1 370
2.55, 72 C14H18N4O7 (354)
3.06, 76 C18H21N5O6 (403)
47.3/47.5 5.2/5.1 15.5/15.8 354
53.3/53.6 5.3/5.2 17.6/17.4 403
2.59, 70 C14H18N4O6S (370) 45.2/45.4 5.1/4.9 14.9/15.1 370
2.58, 73 C14H18N4O7 (354)
2.74, 68 C18H21N5O6 (403)
47.2/47.5 5.4/5.1 15.5/15.8 354
53.5/53.6 5.5/5.2 17.1/17.4 403
2.79, 82 C13H16N4O5S (340) 45.7/45.9 5.0/4.7 16.4/16.5 340
1.68, 52 C13H16N4O6 (324)
2.98, 80 C17H19N5O5 (373)
2.06, 92 C9H8N2OS2 (224)
1.81, 87 C9H8N2O2S (208)
47.8/48.1 5.4/5.0 17.1/17.3 324
54.6/54.5 5.5/5.2 18.7/18.5 373
47.9/48.2 3.4/3.6 12.3/12.5 224
51.6/51.9 3.7/3.9 13.3/13.5 208
2.48, 96 C13H11N3OS (257) 60.5/60.7 4.4/4.3 15.9/16.3 257
0.58, 28 C8H8N4OS (208)
0.48, 25 C8H8N4O2 (192)
1.15, 48 C12H11N5O (241)
45.9/46.1 3.8/3.9 26.5/26.9 208
49.6/50.0 3.9/4.2 28.9/29.2 192
59.5/59.7 4.9/4.6 28.6/29.0 241
9c
12a
12b
12c
14a
14b
14c
14d
15a
15b
15c
17a
17b
17c
17d
17e
18
2.72, 96 C16H12N6O2S2 (284) 49.8/50.0 3.4/3.1 21.7/21.9 284
2.88, 82 C16H12N6O4 (352)
4.05, 90 C24H18N8O2 (450)
54.4/54.5 3.7/3.4 23.6/23.9 352
63.7/64.0 4.2/4.0 24.8/24.9 450
2.97, 88 C17H14N4O2S (338) 60.0/60.3 4.4/4.2 16.5/16.6 338
2.64, 88 C17H14N4O3 (322)
3.76, 91 C23H19N5O3 (413)
63.2/63.3 4.7/4.4 17.2/17.4 322
66.4/66.8 4.9/4.6 16.6/16.9 413
3.56, 85 C21H17N5O3S (419) 59.9/60.1 4.5/4.1 16.5/16.7 419
3.96, 87 C25H21N5O4 (455) 65.7/65.9 4.9/4.6 15.3/15.4 455
3.03, 82 C17H14N4O4S (370) 55.0/55.1 4.0/3.8 14.8/15.1 370
4.66, 87 C29H24N6O5 (536) 64.8/64.9 4.8/4.5 15.3/15.7 536
4.60, 76 C26H30N4O13 (606) 51.1/51.5 5.3/5.0 8.8/9.2 606
5.26, 77 C32H36N5O13 (697) 54.8/55.1 5.4/5.1 9.7/10.0 697
4.62, 84 C23H26N4O10S (550) 49.8/50.2 5.1/4.8 10.0/10.2 550
3.20, 60 C23H26N4O11 (534) 51.4/51.7 5.3/4.9 10.3/10.5 534
5.25, 84 C29H31N5O11 (625) 55.3/55.7 5.1/5.0 11.0/11.2 625
8.02, 82 C56H42N4O13 (978) 68.3/68.7 4.0/4.3 5.6/5.7 978

Potential Antiviral and Antitumor Agents
1171
General Procedures for the Reaction of Hydrazine
Hydrate with 8a–c
Method A. A suspension of 8a–c (10 mmol) in absolute ethanol (20 ml)
and hydrazine hydrate (2 ml) was heated under reflux for 12 h until the
starting material was consumed (TLC), and the odor of methanethiol
could not be detected. It was left to cool, and the separated yellow
product was collected by filtration and recrystallized (ethanol) to afford
5-[(Z)-arylidene]-2-hydrazono-4-imidazolidinones (9a–c).
Method B. A mixture of each 8a–c (10 mmol) and a slight excess of
hydrazine hydrate (0.55 g, 11 mmol) in glacial acetic (2 ml) was refluxed
for 4 h until the starting material was consumed (TLC), and the odor of
methanethiol could not be detected. After cooling, the separated yellow
solid was washed with ethanol and recrystallized (DMF) to yield N,N-
bis-(5-(Z)-arylidene-4-oxo-2-imidazolidinylidene)hydrazines (12a–c).
General Procedures for the Preparation of
5-[(Z)-Arylidene]-2-[(2-(E)-arylidene]hydrazono)-
4-imidazolidinones 1a–c to 4a,b
Method A. A mixture of 5-[(Z)-arylidene]-2-methylmercaptohydantoins
8a–c (10 mmol) and 2-(E)-arylidene hydrazone 13a–c (10 mmol) in
ethanol (30 ml) was heated under reflux for 48 h until the starting ma-
terial was consumed (TLC) and the evolution of methanethiol ceased.
After cooling, the separated yellow solid was collected by filtration and
recrystallized (EtOH) to give the products 1a–c to 4a,b.
Method B. A mixture of 5-[(Z)-2-thienylidene]-2-hydrazono-4-
imidazolidinone 9a (1.04 g, 5 mmol) and benzaldehyde (5.03 g, 5 mmol)
in absolute ethanol (25 ml) was heated under reflux for 24 h until the
starting material was consumed (TLC). The separated yellow solid was
collected and recrystallized (EtOH) to give 0.80 g (54 %) of 5-[(Z)-2-
thienylidene]-2-((2-(E)-benzylidene)hydrazono)-4-imidazolidinone 1a.
General Procedures for the Reaction of Acetic
Anhydride with 1–4
Method A. A cold solution of 1a–c and 4a (0.5 g) in anhydrous pyridine
(5ml)wastreatedwithaceticanhydride(5ml). Thereactionmixturewas
kept overnight at room temperature with occasional stirring and then
poured on to crushed ice. The separated yellow solid was collected by fil-
tration and recrystallized (EtOH) to give the products 5-[(Z)-arylidene]-
2-(1-acetyl-2-(E)-arylidene)hydrazono)-4-imidazolidinones 14a–d.
Method B. A solution of 1c, 2b and 3c (0.5 g) in acetic anhy-
dride (4 ml) was heated under reflux on a boiling water bath for 2 h.

1172
A. I. Khodair
The reaction mixture was cooled and poured on to crushed ice. The
separated yellow solid was collected by filtration and recrystallized
(EtOH) to give the products 5-[(Z)-arylidene]-3-acetyl-2-(1-acetyl-2-(E)-
arylidene)hydrazono)-4-imidzolidinones 15a–c.
General Procedures for the Preparation of
5-[(Z)-Arylidene]-2-((2-(E)-polyhydroxyalkylidene)-
hydrazono)-4-imidazolidinones 5a–c to 7a–c
Method A—General Procedure. A mixture of 8a–c (0.01 mmol) and
monosaccharide E-hydrazones (16a–c) (0.01 mmol) in methyl alcohol
(50 ml) was heated under reflux for 48 h until the starting material
was consumed (TLC) and the evolution of methanethiol ceased. The
yellow solid, which separated, was collected and recrystallized (DMF)
to afford the products 5a–c to 7a–c.
Method B. A mixture of 5-((Z)-2-thienylidene)-2-hydrazono-4-
imidazolidinone 9a (1.04 g, 5 mmol) and D-galactose (0.90 g, 5 mmol)
in methanol (25 ml) was heated under reflux for 24 h until the start-
ing material was consumed (TLC). The yellow solid, which separated,
was collected by filtration and recrystallized (DMF) to give 5-[(Z)-
2-thienylidene]-2-[(2-(E)-D-galactose]hydrazono)-4-imidazolidinone 5a
in 47% yield.
5-[(Z)-Arylidene]-2-(1-acetyl-2-(E)-2,3,4,5,6-penta-O-acetyl-D-
galactose)hydrazono)-4-imidazolidinones (17a–e).
A cold solution
of 5b,c and 7a–c (0.5 g) in anhydrous pyridine (5 ml) was treated
with acetic anhydride (5 ml). The reaction mixture was kept overnight
at room temperature with occasional stirring and then poured on to
crushed ice. The separated yellow solid was collected by filtration and
recrystallized (ethanol) to give the products 17a–e.
5-[(Z)-2-Furylidene]-2-(1-benzoyl-2-[(E)-20,30,40,50,60-penta-O-
benzoyl-D-galactose]hydrazono)-4-imidazolidinone (18). A cold solution
of 5b (0.5 g) in anhydrous pyridine (5 ml) was treated with benzoyl
chloride (1 ml). The mixture was kept for overnight at room temper-
ature with occasional shaking. It was poured on to crushed ice and
the product was collected by filtration, washed repeatedly with water,
dried and recrystallized from ethanol to give the product 18.
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[1] A. I. Khodair and P. Bertrand, Tetrahedron, 54, 4859 (1998).
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Potential Antiviral and Antitumor Agents
1173
[4] F. L. Wessels, T. J. Schwan, and S. F. Pong, J. Pharm. Sci., 69, 1102 (1980).
[5] K. R. Bharucha, V. Pavilinis, D. Ajdukovic, and H. M. Shrenk, Ger. Fat. 2, 329, 745
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[7] A. A. El-Barbary, A. I. Khodair, E. B. Pedersen, and C. Nielsen, J. Med. Chem., 37,
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