Synthesis and antimicrobial activity of new phenytoin derivatives and their acyclic nucleoside analogs

Article abstract of DOI:10.1007/s10593-012-1097-9

New phenytoin derivatives and their N-substituted acyclic nucleoside analogs were prepared. The synthesized compounds were tested for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Streptomyces Sp. Most of the tested compounds exhibited moderate to high antimicrobial activity while a few compounds were found to exhibit little or no activity against the tested microorganisms.

Full text of DOI:10.1007/s10593-012-1097-9

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF NEW
PHENYTOIN DERIVATIVES AND THEIR ACYCLIC
NUCLEOSIDE ANALOGS
O. M. Ali1, H. H. Amer1, A. A. Mosaad2, and A. A.-H. Abdel-Rahman1*
New phenytoin derivatives and their N-substituted acyclic nucleoside analogs were prepared. The
synthesized compounds were tested for their antimicrobial activity against Escherichia coli,
Staphylococcus aureus, and Streptomyces Sp. Most of the tested compounds exhibited moderate to high
antimicrobial activity while a few compounds were found to exhibit little or no activity against the
tested microorganisms.
Keywords: acyclic nucleosides, phenytoin derivatives, sugar hydrazones, antimicrobial activity.
Phenytoin (5,5-diphenylhydantoin) (1) is one of the most widely used drugs in the therapy of epilepsy. The
risks associated with the use of this formulation are obvious, taking into account its high acidity, as well as the
precipitation of the free acid [1]. The classical prodrug approach to improve membrane permeability of drug
molecules employs lipophilic derivatives to increase passive membrane penetration. In recent years, different
nutrient transporters (i.e., oligopeptide, amino acid, and glucose transporters) have been identified and cloned. The
active nutrient transport systems have become a target for prodrug design [2]. Hydrazones have been
demonstrated to possess antimicrobial, antibacterial, anticonvulsant, analgesic, anti-inflammatory, antiplatelet,
antitubercular, and antitumor activities [3-5], among others. In addition, some of the new hydrazide-hydrazones
[6] that have been recently synthesized were active against the same strain of Mycobacterium tuberculosis H37Rv
between the concentrations of 0.78–6.25 g/ml. These compounds were reported to have inhibitory activity in mice
infected with various strains of M. tuberculosis [7] and showed less toxicity [8]. Some hydrazide-hydrazones were
reported to have lower toxicity than hydrazides because of blockage of the NH2 group. A number of studies were
devoted to the in vitro and in vivo metabolism of hydrazide-hydrazones. In in vitro metabolism studies, it has been
found that hydrazide-hydrazones undergo hydrolytic reactions, the aromatic rings undergoing aromatic
hydroxylation reactions [9, 10]. Furthermore, nucleoside analogs are structurally, metabolically, and
pharmacodynamically related agents that have diverse biological actions and therapeutic effects, including antiviral
[11, 12] and antitumor activities [13-15]. The above facts and our interest [16-20] in the attachment of carbohydrate
moieties to newly synthesized heterocycles in order to find new biologically active lead compounds promoted us to
synthesize new substituted phenytoins and their acyclic nucleoside analogs and evaluate their antimicrobial activity.
_______
*To whom correspondence should be addressed, e-mail: adelnassar63@yahoo.com.
1Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt.
2Department of Bacteriology, Faculty of Veterinary Medicine, Menoufia University, Sadat City, Egypt; e-mail:
aamosaad@yahoo.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1124-1131, July, 2012. Original
article submitted October 10, 2010.
0009-3122/12/4807-1043©2012 Springer Science+Business Media New York
1043

In this investigation, phenytoin (1) was allowed to react with ethyl bromoacetate in dry acetone and in
the presence of anhydrous potassium carbonate to afford 1-ethoxycarbonylmethylphenytoin (2) [21]. Treatment
of compound 2 with hydrazine hydrate in ethanol at reflux temperature gave the corresponding hydrazide 3 in
90% yield. The structures of products 2 and 3 were confirmed by 1H NMR and mass spectra, which agreed with
the assigned structures. 1-Phenitoinylacetic acid hydrazide (3) was allowed to react with D-xylose, L-arabinose,
O
O
H
H
N
N
O
BrCH2CO2Et
K2CO3
Ph
Ph
Ph
Ph
H
N
.
N2H4 H2O
O
O
H
N
Ph
Ph
N
N
MeCN, 
EtOH, 
O
N
H
OEt
NH2
1
O
O
N
2
3
O
O
H
H
N
N
Ph
Ph
Ph
O
H
N
R1CHO
Ac2O–Py
rt
O
N
Ph
N
H
EtOH
AcOH

R2
N
N
R1
O
5a-d
O
4a-d
Ac2O
O
H
N

Ph
Ph
O
N
N
N
Ac
O
R2
6a-d
OH
HO
HO
OH
OH
HO
HO
OH
R1
HO
HO
OH
HO
=
OH
OH
OH
OH
OH
OH
c
a
b
d
OAc
AcO
AcO
OAc
OAc
OAc
AcO
AcO
R2
=
OAc
OAc
OAc
AcO
AcO
AcO
OAc
OAc
OAc
OAc
a
c
d
b
D-galactose, and D-mannose in an aq. ethanolic solution with a catalytic amount of acetic acid, and the
corresponding sugar N-acylhydrazones 4a-d were obtained in 85–87% yields. The structures of these
compounds were confirmed by analytical and spectral data. The IR spectra of compounds 4a-–d showed the
presence of characteristic absorption bands corresponding to the hydroxy groups in the region 3340–3415 cm-1.
1
The H NMR spectra showed signals of the sugar chain protons at 3.24-4.19 ppm and the H-1' methine proton
as a doublet in the range 7.10-7.18 ppm. Treatment of the sugar hydrazones 4a-d with acetic anhydride in
pyridine at room temperature gave the corresponding per-O-acetyl derivatives 5a-d in 95–97% yields. The
1H NMR spectra of compounds 5a-d showed the signals of the O-acetyl group protons at 1.94-2.16 ppm. The
1044

rest of the sugar protons appeared in the range 4.10-5.80 ppm. The reaction of sugar arylhydrazones with
boiling acetic anhydride is well known to give either the corresponding per-O,N-acetyl derivatives or the
respective per-O,N-acetyl-1,3,4-oxadiazoline derivatives [11, 22-24]. In our case, reaction of the sugar
hydrazones 4a-d with acetic anhydride at 100°C gave the sugar-substituted 1,3,4-oxadiazoline derivatives 6a-d
1
in 80–85% yields. The H NMR spectra of compounds 6a-d showed signals of the O- and N-acetyl group
methyl protons. The rest of the sugar chain protons appeared in the range 4.00-5.47 ppm. Phenytoin hydrazide 3
was refluxed with various aromatic aldehydes in ethanol and in the presence of a catalytic amount of acetic acid
to afford the corresponding Schiff bases 7a-f in 90-95% yields.
O
H
N
Ph
R3CHO
O
H
N
N
Ph
3
EtOH
AcOH

N
R3
O
7a-f
7 a R3 = 2-BrC6H4, b R3 = 4-ClC6H4, c R3 = 4-FC6H4,
d R3 = 4-Me2NC6H4, e R3 = 5-methylfuran-2-yl, f R3 = pyren-1-yl
The synthesized compounds were evaluated for their antimicrobial activity against Escherichia coli
(gram-negative bacteria), Staphylococcus aureus (gram-positive bacteria), and Streptomyces Sp. The values of
minimal inhibitory concentrations (MIC) of the tested compounds are presented in Table 1.
The MIC values of the most active compounds were in accord with the results obtained in the primary
screening. The results revealed that the compounds showed varying degrees of inhibition against the tested
microorganisms. In general, compounds 5d, 6d, and 7c,e displayed the highest activity against Staphylococcus
TABLE 1. Minimal Inhibitory Concentrations of the Title Compounds,* µg/ml
Compound
Escherichia coli
Staphylococcus aureus
Streptomyces Sp.
500
500
100
250
125
100
125
100
250
500
250
100
125
500
100
125
75
250
225
125
500
225
125
225
100
125
500
250
100
125
500
100
225
75
500
475
100
225
125
125
125
75
4a
4b
4c
4d
5a
5b
5c
5d
6a
75
100
100
250
100
75
6b
6c
6d
7a
7b
7c
225
250
75
7d
7e
125
45
225
34
250
31
7f
Penicillin
_______
* Negative control DMSO, no activity.
1045

Aureus, followed by compounds 4c, 5b, 6a, and 7a. Compounds 4c, 5b,d, 6d, 7c, and 7e displayed the highest
inhibition activity against Escherichia coli with an MIC value of 75–100 µg/ml, followed by derivatives 5a,c,
7a,d, and 7f. Compounds 4c, 5d, 6a-c, 7a,b,e revealed the highest activity against Streptomyces Sp.
In conclusion, new phenytoin N-substituted acyclic nucleoside analogs were prepared and studied for
their antimicrobial activity. Substitution at the free N-1 in the phenytoin moiety afforded compounds with
increased inhibitory activities with respect to the three microorganisms.
EXPERIMENTAL
1
The IR spectra were recorded on a Perkin Elmer model 1720 FTIR spectrometer in KBr pellets. H
NMR spectra were recorded on a Varian Gemini 200 NMR spectrometer at 300 MHz in DMSO-d6 with TMS as
internal standard. Elemental analyses were performed on a 2400 CHN Perkin Elmer Elemental Analyzer at the
Microanalytical Data Center at the Faculty of Science, Cairo University, Egypt. Melting points were determined
with a Kofler block apparatus and are uncorrected. The progress of the reactions was monitored by TLC using
silica gel plates 60 F 245 (5% MeOH in CH2Cl2).
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)acetohydrazide (3). A solution of the ester 2 [21] (3.38 g,
10 mmol) in EtOH (20 ml) and hydrazine hydrate (10 ml) was refluxed for 4 h. The solvent was removed under
reduced pressure, and the remaining precipitate was collected, dried, and recrystallized from EtOH. Yield 2.91 g
1
(90%). White powder, mp 172-174°C. IR spectrum, ν, cm-1: 1695 (C=O), 3427 (NH). H NMR spectrum, δ,
ppm: 4.57 (2H, s, NCH2); 5.80 (2H, br. s, NH2); 7.23-7.43 (10H, m, H Ph); 8.22 (1H, br. s, NH); 9.92 (1H, br. s,
NH). Mass spectrum, m/z (Irel, %): 324 [M]+ (25). Found, %: C 62.88; H 4.68; N 17.09. C17H16N4O3. Calculated,
%: C 62.95; H 4.97; N 17.27.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(alditolylmethylidene)acetohydrazides 4a-d (General
Method). Hydrazide 3 (3.24 g, 10 mmol) in EtOH (10 ml) was added to a vigorously stirred solution of the
corresponding monosaccharide (10 mmol) in H2O (2 ml) and AcOH (1 ml). The mixture was heated to reflux,
and the resulting solution was concentrated under reduced pressure and left to cool. The formed precipitate was
collected by filtration, washed with water and cold EtOH, dried, and recrystallized from EtOH to afford the
corresponding sugar hydrazones 4a–d.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(D-xylotetritolylmethylidene)acetohydrazide (4a).
1
Yield 3.96 g (87%). White powder, mp 164-166°C. IR spectrum, ν, cm-1: 3300 (NH), 3415 (OH). H NMR
spectrum, δ, ppm (J, Hz): 3.26-3.55 (5H, m, 2',3',4'-CH, 5'-CH2), 4.48 (2H, br. s, 2OH); 4.60 (2H, s, NCH2); 5.21
(2H, br. s, 2OH); 7.13 (1H, d, J = 2.5, 1'-CH); 7.23-7.37 (10H, m, H Ph); 9.62 (1H, br. s, NH); 11.08 (1H, br. s,
NH). Mass spectrum, m/z (Irel, %): 456 [M]+ (11). Found, %: C 57.50; H 5.11; N 12.19. C22H24N4O7. Calculated,
%: C 57.89; H 5.30; N 12.27.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(L-arabinotetritolylmethylidene)acetohydrazide
(4b). Yield 3.87 g (85%). White powder, mp 172-174°C. IR spectrum, ν, cm-1: 3432 (NH), 3345 (OH). 1H NMR
spectrum, δ, ppm (J, Hz): 3.24-3.45 (5H, m, 2',3',4'-CH, 5'-CH2); 4.40 (2H, br. s, 2OH); 4.58 (2H, s, NCH2);
5.18 (2H, br. s, 2OH); 7.18 (1H, d, J = 2.5, 1'-CH); 7.23-7.42 (10H, m, H Ph); 9.63 (1H, br. s, NH); 11.12 (1H,
br. s, NH). Mass spectrum, m/z (Irel, %): 456 [M]+ (11). Found, %: C 57.61; H 5.07; N 12.03. C22H24N4O7.
Calculated, %: C 57.89; H 5.30; N 12.27.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(D-galactopentitolylmethylidene)acetohydrazide
(4c). Yield 4.18 g (86%). White powder, mp 200-202°C. IR spectrum, ν, cm-1: 3270 (NH), 3340 (OH). 1H NMR
spectrum, δ, ppm: 3.24-3.85 (5H, m, 3',4',5'-CH, 6'-CH2); 4.19-4.21 (1H, m, H-2'); 4.42 (1H, br. s, OH); 4.61
(2H, br. s, 2OH); 4.60 (2H, s, NCH2); 5.03 (2H, br. s, 2OH); 7.18-7.40 (11H, m, H Ph, 1'-CH); 9.30 (1H, br. s,
NH); 11.04 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 486 [M]+ (32). Found, %: C 56.60; H 5.21; N 11.30.
C23H26N4O8. Calculated, %: C 56.79; H 5.39; N 11.52.
1046

2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(D-mannopentitolylmethylidene)acetohydrazide (4d).
1
Yield 4.22 g (87%). White powder, mp 192-194°C. IR spectrum, ν, cm-1: 3425 (NH), 3340 (OH). H NMR
spectrum, δ, ppm (J, Hz): 3.27-4.15 (6H, m, 2',3',4',5'-CH, 6'-CH2); 4.53 (3H, br. s, 3OH); 4.61 (2H, s, NCH2);
4.75 (2H, br. s, 2OH); 7.10 (1H, d, J = 2.5, 1'-CH); 7.28-7.38 (10H, m, H Ph); 9.60 (1H, br. s, NH); 11.11 (1H,
br. s, NH). Mass spectrum, m/z (Irel, %): 486 [M]+ (27). Found, %: C 56.55; H 5.13; N 11.25. C23H26N4O8.
Calculated, %: C 56.79; H 5.39; N 11.52.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(tetra- and penta-O-acetylalditolylmethylidene)ace-
tohydrazides 5a-d (General Method). Acetic anhydride (1.02 g, 10 mmol) was added to a solution of sugar
hydrazones 4a-d (1 mmol) in pyridine (7 ml) with stirring at room temperature overnight. The resulting solution
was poured onto crushed ice, and the product that separated was collected by filtration, washed with a saturated
solution of NaHCO3 followed by water, and then dried. The products were recrystallized from EtOH to afford
O-acetyl derivatives 5a-d.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(2,3,4,5-tetra-O-acetyl-D-xylotetritolylmethylide-
ne)-acetohydrazide (5a). Yield 5.99 g (96%). White powder, mp 140-142°C. 1H NMR spectrum, δ, ppm (J, Hz):
1.96 (3H, s), 2.04 (3H, s), 2.10 (3H, s), and 2.12 (3H, s, 4CH3CO); 4.15-4.17 (2H, m, 5'-CH2); 4.23-4.28 (1H,
m, H-4'); 4.58 (2H, s, NCH2); 5.60-5.64 (1H, m, H-3'); 5.76-5.80 (1H, m, H-2'); 7.26 (1H, d, J = 2.5, H-1');
7.35-7.45 (10H, m, H Ph); 9.14 (2H, br. s, 2NH). Mass spectrum, m/z (Irel, %): 624 [M]+ (5). Found, %: C 57.45;
H 5.10; N 8.65. C30H32N4O11. Calculated, %: C 57.69; H 5.16; N 8.97.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(2,3,4,5-tetra-O-acetyl-L-arabinotetritolylmethylidene)-
1
acetohydrazide (5b). Yield 5.92 g (95%). White powder, mp 137-139°C. H NMR spectrum, δ, ppm (J, Hz):
1.95 (3H, s), 2.04 (3H, s), 2.10 (3H, s), and 2.13 (3H, s, 4CH3CO); 4.17-4.19 (2H, m, 5'-CH2); 4.25-4.27 (1H,
m, 4'-CH); 4.55 (2H, s, NCH2); 5.60-5.63 (1H, m, 3'-CH); 5.74-5.77 (1H, m, 2'-CH); 7.27 (1H, d, J = 2.5,
1'-CH); 7.34-7.61 (10H, m, H Ph); 9.11 (2H, br. s, 2NH). Mass spectrum, m/z (Irel, %): 624 [M]+ (9). Found, %: C
57.53; H 5.06; N 8.54. C30H32N4O11. Calculated, %: C 57.69; H 5.16; N 8.97.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(2,3,4,5,6-penta-O-acetyl-D-galactopentitolylmethyl-
1
idene)acetohydrazide (5c). Yield 6.75 g (97%). White powder, mp 120-122°C. H NMR spectrum, δ, ppm: 1.95
(3H, s), 2.02 (3H, s), 2.10 (3H, s), 2.13 (3H, s), and 2.16 (3H, s, 5CH3CO); 4.11-4.15 (2H, m, 6'-CH2); 4.54-4.57
(1H, m, 5'-CH); 4.63 (2H, s, NCH2); 4.74-4.78 (1H, m, H-4'); 5.19-5.21 (1H, m, H-3'); 5.49-5.53 (1H, m, 2'-CH);
7.25-7.38 (11H, m, H Ph, 1'-CH); 9.16 (2H, br. s, 2NH). Mass spectrum, m/z (Irel, %): 696 [M]+ (13). Found, %: C
56.67; H 5.03; N 7.87. C33H36N4O13. Calculated, %: C 56.89; H 5.21; N 8.04.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(2,3,4,5,6-penta-O-acetyl-D-mannopentitolylmethyl-
1
idene)acetohydrazide (5d). Yield 6.61 g (95%). White powder, mp 102-103°C. H NMR spectrum, δ, ppm:
1.94 (3H, s), 2.03 (3H, s), 2.10 (3H, s), 2.12 (3H, s), and 2.15 (3H, s, 5CH3CO); 4.10-4.13 (2H, m, 6'-CH2);
4.54-4.58 (1H, m, 5'-CH); 4.60 (2H, s, NCH2); 4.72-4.76 (1H, m, 4'-CH); 5.18-5.22 (1H, m, 3'-CH); 5.52-5.55
(1H, m, 2'-CH); 7.28-7.41 (11H, m, H Ph, 1'-CH); 9.16 (2H, br. s, 2NH). Mass spectrum, m/z (Irel, %): 697
[M+H]+ (10). Found, %: C 56.60; H 5.00; N 7.83. C33H36N4O13. Calculated, %: C 56.89; H 5.21; N 8.04.
1-[4-Acetyl-5-(tetra- and penta-O-acetylalditolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-5,5-di-
phenylimidazolidine-2,4-diones 6a-d (General Method). A solution of sugar hydrazones 4a-d (1 mmol) in
acetic anhydride (5 ml) was heated at 100°C for 3 h. The resulting solution was poured onto crushed ice, and the
product that separated was collected by filtration, washed with a saturated solution of NaHCO3 followed by
water, and then dried. The products were recrystallized from EtOH to give oxadiazolines 6a-d.
1-[4-Acetyl-5-(1,2,3,4-tetra-O-acetyl-D-xylotetritolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-5,5-di-
phenylimidazolidine-2,4-dione (6a). Yield 0.53 g (80%). Pale-yellow resin. 1H NMR spectrum, δ, ppm (J, Hz):
1.95 (3H, s), 1.98 (3H, s), 2.01 (3H, s), 2.10 (3H, s), and 2.29 (3H, s, 5CH3CO); 3.85 (2H, s, NCH2); 4.01-4.04
(1H, m) and 4.09-4.13 (1H, m, 4''-CH2); 4.98-5.01 (1H, m, 3''-CH); 5.18-5.22 (1H, m, 2''-CH); 5.40 (1H, dd, J = 3.2,
J = 6.2, 1''-CH); 5.95 (1H, d, J = 6.2, H-5'); 7.25-7.39 (10H, m, H Ph); 11.15 (1H, br. s, NH). Mass spectrum, m/z
(Irel, %): 667 [M+H]+ (9). Found, %: C 57.44; H 5.05; N 8.33. C32H34N4O12. Calculated, %: C 57.66; H 5.14; N
8.40.
1047

1-[4-Acetyl-5-(1,2,3,4-tetra-O-acetyl-L-arabinotetritolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-
5,5-diphenylimidazolidine-2,4-dione (6b). Yield 0.55 g (82%). Pale-yellow resin. 1H NMR spectrum, δ, ppm (J,
Hz): 1.95 (3H, s), 1.97 (3H, s), 2.04 (3H, s), 2.13 (3H, s), and 2.23 (3H, s, 5CH3CO); 3.88 (2H, s, NCH2); 4.00-
4.04 (1H, m) and 4.12-4.15 (1H, m, 4''-CH2); 5.07–5.10 (1H, m, 3''-CH); 5.22-5.25 (1H, m, 2''-CH); 5.47 (1H,
dd, J = 3.2, J = 6.2, 1''-CH); 5.98 (1H, d, J = 6.2, H-5'); 7.25-7.43 (10H, m, H Ph); 11.12 (1H, br. s, NH). Mass
spectrum, m/z (Irel, %): 667 [M+H]+ (7). Found, %: C 57.40; H 5.00; N 8.23. C32H34N4O12. Calculated, %:
C 57.66; H 5.14; N 8.40.
1-[4-Acetyl-5-(1,2,3,4,5-penta-O-acetyl-D-galactopentitolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-
1
5,5-diphenylimidazolidine-2,4-dione (6c). Yield 0.59 g (80%). Pale-yellow resin. H NMR spectrum, δ, ppm (J,
Hz): 1.95 (3H, s), 1.96 (3H, s), 2.01 (3H, s), 2.10 (3H, s), 2.19 (3H, s), and 2.28 (3H, s, 6CH3CO); 3.93 (2H, s,
NCH2); 4.05-4.08 (1H, m) and 4.12-4.15 (1H, m, 5''-CH2); 4.94-4.99 (1H, m, 4''-CH); 5.23-5.26 (1H, m, 3''-CH);
5.33-5.36 (1H, m, 2''-CH); 5.43 (1H, dd, J = 3.2, J = 6.2, 1''-CH); 5.94 (1H, d, J = 6.2, H-5'); 7.25-7.35 (10H, m, H
Ph); 10.90 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 738 [M]+ (9). Found, %: C 56.76; H 5.02; N 7.39.
C35H38N4O14. Calculated, %: C 56.91; H 5.19; N 7.58.
1-[4-Acetyl-5-(1,2,3,4,5-penta-O-acetyl-D-mannopentitolyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-
1
5,5-diphenylimidazolidine-2,4-dione (6d). Yield 0.62 g (85%). Pale-yellow resin. H NMR spectrum, δ, ppm
(J, Hz): 1.95 (3H, s), 1.99 (3H, s), 2.03 (3H, s), 2.10 (3H, s), 2.13 (3H, s), and 2.29 (3H, s) (6CH3CO); 3.95
(2H, s, NCH2); 4.11-4.14 (1H, m) and 4.17-4.20 (1H, m, 5''-CH2); 4.99-5.02 (1H, m, 4''-CH); 5.19-5.23 (1H,
m, 3''-CH); 5.31-5.34 (1H, m, 2''-CH); 5.43 (1H, dd, J = 3.2, J = 6.2, 1''-CH); 5.99 (1H, d, J = 6.2, H-5'); 7.25-7.38
(10H, m, H Ph); 9.20 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 738 [M]+ (13). Found, %: C 56.68; H 5.07; N
7.33. C35H38N4O14. Calculated, %: C 56.91; H 5.19; N 7.58.
Schiff Bases 7a-f (General Method). A solution of compound 3 (3.24 g, 10 mmol) and an aromatic
aldehyde (10 mmol) in abs. EtOH (50 ml) and AcOH (1 ml) was refluxed for 6–8 h (TLC). The solvent was
evaporated under reduced pressure and the residue was collected by filtration and recrystallized from EtOH.
N'-(2-Bromobenzylidene)-2-(2,4-dioxo-5,5-diphenylimidazolidin-1-yl)acetohydrazide (7a). Yield
4.51 g (92%). White powder, mp 290-292°C. 1H NMR spectrum, δ, ppm: 4.51 (2H, s, NCH2); 7.25-7.59 (14H, m,
H Ph, H Ar); 8.40 (2H, br. s, CH=N, NH); 9.93 (1H, br. s, NH). Mass spectrum (for 79Br isotope), m/z (Irel, %): 490
[M]+ (10). Found, %: C 58.50; H 3.73; N 11.29. C24H19BrN4O3. Calculated, %: C 58.67; H 3.90; N 11.40.
N'-(4-Chlorobenzylidene)-2-(2,4-dioxo-5,5-diphenylimidazolidin-1-yl)acetohydrazide (7b). Yield 4.10
1
g (92%). White powder, mp 310-312°C. H NMR spectrum, δ, ppm: 4.59 (2H, s, NCH2); 7.29-7.79 (14H, m,
H Ph, H Ar); 8.48 (2H, br. s, CH=N, NH); 9.99 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 446 [M]+ (13).
Found, %: C 64.33; H 4.13; N 12.29. C24H19ClN4O3. Calculated, %: C 64.50; H 4.29; N 12.54.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(4-fluorobenzylidene)acetohydrazide (7c). Yield 4.00 g
1
(93%). White powder, mp 320-322°C. H NMR spectrum, δ, ppm: 4.62 (2H, s, NCH2); 7.32-7.75 (14H, m,
H Ph, H Ar); 8.50 (2H, br. s, CH=N, NH); 10.02 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 430 [M]+ (22).
Found, %: C 66.88; H 4.32; N 12.93. C24H19FN4O3. Calculated, %: C 66.97; H 4.45; N 13.02.
N'-[4-(Dimethylamino)benzylidene]-2-(2,4-dioxo-5,5-diphenylimidazolidin-1-yl)acetohydrazide
1
(7d). Yield 4.32 g (95%). White powder, mp 334-336°C. H NMR spectrum, δ, ppm: 2.95 (6H, s, 2CH3); 4.55
(2H, s, NCH2); 7.22-7.55 (14H, m, H Ph, H Ar); 8.30 (2H, br. s, CH=N, NH); 9.92 (1H, br. s, NH). Mass
spectrum, m/z (Irel, %): 455 [M]+ (17). Found, %: C 68.33; H 5.44; N 15.17. C26H25N5O3. Calculated, %:
C 68.56; H 5.53; N 15.37.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-[5-(methylfuran-2-yl)methylidene]acetohydrazide
(7e). Yield 3.95 g (95%). White powder, mp 265-267°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s, CH3);
4.53 (2H, s, NCH2); 6.24 (1H, d, J = 3.4, H-4 Fur); 6.79 (1H, d, J = 3.4, H-3 Fur); 7.22-7.55 (10H, m, H Ph);
8.22 (2H, br. s, CH=N, NH); 9.99 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 416 [M]+ (25). Found, %:
C 66.19; H 4.73; N 13.22. C23H20N4O4. Calculated, %: C 66.34; H 4.84; N 13.45.
2-(2,4-Dioxo-5,5-diphenylimidazolidin-1-yl)-N'-(pyren-1-ylmethylidene)acetohydrazide (7f). Yield
4.82 g (90%). White powder, mp 284-286°C. 1H NMR spectrum, δ, ppm: 4.55 (2H, s, NCH2); 7.22-7.55 (10H,
1048

m, H Ph); 7.70-7.85 (9H, m, H Pyrene); 8.52 (2H, br. s, CH=N, NH); 10.02 (1H, br. s, NH). Mass spectrum, m/z
(Irel, %): 536 [M]+ (23). Found, %: C 76.00; H 4.43; N 10.31. C34H24N4O3. Calculated, %: C 76.11; H 4.51;
N 10.44.
Antimicrobial Testing. The hole plate method was the most suitable technique for investigating the
antibacterial activities of the different compounds. Nutritive agar plates seeded with the test organisms (three
plates for each organism) were allowed to solidify, and then 5 mm diameter holes were formed in the plates
using a cork borer. Each hole was filled with one drop of the ethanolic solution of the tested compound, while
the hole in the center of the plate was filled with one drop of ethanol. Plates were separately incubated at the
optimum temperature for each test organism for 24 h. Inhibition zones (zones with no growth) around the holes
were measured as an indicator of the antibacterial action [25, 26].
REFERENCES
1.
2.
3.
4.
5.
6.
J. Bosch, T. Roca, J. Domènech, and M. Suriol, Bioorg. Med. Chem. Lett., 9, 1859 (1999).
C. Yang and A. K. Mitra, J. Pharm. Sci., 90, 340 (2001).
S. Rollas, N. Gülerman, and H. Erdeniz, Farmaco, 57, 171 (2002).
S. G. Kücükgüzel, S. Rollas, I. Kücükgüzel, and M. Kiraz, Eur. J. Med. Chem., 34, 1093 (1999).
S. G. Kücükgüzel, E. E. Oruc, S. Rollas, F. Sahin, and A. Ozbek, Eur. J. Med. Chem., 37, 197 (2002).
K. B. Kaymakcioglu, E. E. Oruc, S. Unsalan, F. Kandemirli, N. Shvets, S. Rollas, and D. Anatholy, Eur.
J. Med. Chem., 41, 1253 (2006).
7.
8.
9.
P. P. T. Sah and S. A. Peoples, J. Am. Pharm. Assoc., 43, 513 (1954).
E. M. Bavin, D. J. Drain, M. Seiler, and D. E. Seymour, J. Pharm. Pharmacol., 4, 844 (1954).
S. G. Komurcu, S. Rollas, M. Ulgen, J. W. Gorrod, and A. Cevikbas, Boll. Chim. Farm., 134, 375
(1995).
10.
11.
M. Ulgen, B. B. Durgun, S. Rollas, and J. W. Gorrod, Drug Metab. Drug Interact., 13, 285 (1997).
M. T. Abdel-Aal, W. A. El-Sayed, and E. S. H. El-Ashry, Arch. Pharm. Chem. Life Sci., 339, 356
(2006).
12.
13.
W. A. El-Sayed, A. A.-H. Abdel-Rahman, and M. M. M. Ramiz, Z. Naturforsch., 64c, 323 (2009).
M. Y. W. Chu, F. N. M. Naguib, M. H. Iltzsch, M. H. el Kouni, S. H. Chu, S. Cha, and P. Calabresi,
Cancer Res., 44, 1852 (1984).
14.
K. S. Park, M. H. el Kouni, T. A. Krenitsky, S. H. Chu, and S. Cha, Biochem. Pharmacol., 35, 3853
(1986).
15.
16.
17.
18.
19.
T.-S. Lin and M.-C. Liu, J. Med. Chem., 28, 971 (1985).
W. A. El-Sayed, M. M. M. Ramiz, and A. A.-H. Abdel-Rahman, Monatsh. Chem., 139, 1499 (2008).
W. A. El-Sayed, N. M. Fathi, W. A. Gad, and E. S. H. El-Ashry, J. Carbohydr. Chem., 27, 357 (2008).
W. A. El-Sayed, I. F. Nassar, and A. A.-H. Abdel-Rahman, Monatsh. Chem., 140, 365 (2009).
W. A. El-Sayed, A. E. Rashad, S. M. Awad, and M. M. Ali, Nucleosides, Nucleotides Nucleic Acids, 28,
261 (2009).
20.
W. A. El-Sayed, F. A. El-Essawy, O. M. Ali, A. M. Barsis, and A. A.-H. Abdel-Rahman, Monatsh.
Chem., 141, 1021 (2010).
21.
22.
K. Kiec-Kononowicz and A. Zejc, Pol. J. Chem., 58, 761 (1984).
M. T. Abdel-Aal, W. A. El-Sayed, S. M. El-Kosy, and E. S. H. El-Ashry, Arch. Pharm. Chem. Life Sci.,
341, 307 (2008).
23.
24.
25.
26.
L. Somogyi, Carbohydr. Res., 54, C14 (1977).
L. Somogyi, Carbohydr. Res., 64, 289 (1978).
A. M. Janssen, J. J. Scheffer, and A. B. Svendsen, Planta Med., 395 (1986).
M. T. Shaaban and M. E. El-Sharif, Afr. J. Mycol. Biotechnol., 9, 15 (2001).
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