Structure-activity relationships of 3-substituted-5,5-diphenylhydantoins as potential antiproliferative and antimicrobial agents

Article abstract of DOI:10.2298/JSC110314143T

A series of twelve 3-substituted-5,5-diphenylhydantoins was synthesized, including some whose anticonvulsant activities have already been reported in the literature. Their antiproliferative activities against HCT-116 human colon carcinoma cells were evalu

Full text of DOI:10.2298/JSC110314143T

J. Serb. Chem. Soc. 76 (12) 1597–1606 (2011)
UDC 547.783:547.6:544.022:615.28–188
JSCS–4232
Original scientific paper
Structure–activity relationships of 3-substituted-5,5-
-diphenylhydantoins as potential antiproliferative
and antimicrobial agents
NEMANJA TRIŠOVIĆ1#, BOJAN BOŽIĆ1#, ANA OBRADOVIĆ2,
OLGICA STEFANOVIĆ2, SNEŽANA MARKOVIĆ2, LJILJANA ČOMIĆ2,
3
1 #
*
BILJANA BOŽIĆ and GORDANA UŠĆUMLIĆ
1Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4,
11000 Belgrade, 2Faculty of Science, University of Kragujevac, Radoja
Domanovića 12, 34000 Kragujevac and 3Faculty of Biology, University of
Belgrade, Studentski trg 3, 11000 Belgrade, Serbia
(Received 14 March, revised 2 May 2011)
Abstract: A series of twelve 3-substituted-5,5-diphenylhydantoins was synthe-
sized, including some whose anticonvulsant activities have already been re-
ported in the literature. Their antiproliferative activities against HCT-116 hu-
man colon carcinoma cells were evaluated to determine structure–activity
relationships. Almost all of the compounds exhibited statistically significant
antiproliferative effects at a concentration of 100 μM, while the derivative
bearing a benzyl group was active even at lower concentrations. Moreover,
their in vitro antibacterial activities against Escherichia coli ATCC 25922, Sta-
phylococcus aureus ATCC 25923 and clinical isolates of Escherichia coli, Pro-
teus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylo-
coccus aureus were evaluated. Only the 3-isopropyl and 3-benzyl derivatives
showed weak antibacterial activities against the Gram-positive bacterium E.
faecalis and the Gram-negative bacteria E. coli ATCC 25922 and E. coli.
Keywords: phenytoin derivatives; antiproliferative activity; antimicrobial
activity; structure–activity relationship.
INTRODUCTION
The derivatives of hydantoin (imidazolidine-2,4-dione) are well known and
clinically widely used in the therapy of epilepsy and cardiac arrhythmias.
®
Phenytoin (5,5-diphenylhydantoin, Dilantin ), one of the oldest anticonvulsants,
is very effective in controlling a variety of seizure disorders, while impairing
1
neurological function only slightly, if at all. These effects are due to a selective
*Corresponding author. E-mail: goca@tmf.bg.ac.rs
# Serbian Chemical Society member.
doi: 10.2298/JSC110314143T
1597
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1598
TRIŠOVIĆ et al.
block of high frequency neuronal activity. The drug targets the neuronal voltage-
sensitive sodium channels (NVSC) to reproduce the normal ion potential and is
known to block the release of neurotransmitters, such as serotonin and nore-
pinephrine. At an appropriate level, it inhibits monoamine oxidase activity and
2
tends to alter the membrane potential as well.
After 70 years of phenytoin application, the precise physiological effects of
the drug have not been completely determined and it still remains an important
subject for new investigations. The drug and its metabolite 5-(4-hydroxyphenyl)-
5-phenylhydantoin were reported to possess significant hypolipidemic activity,
which is reflected in the reduction of both serum cholesterol and triglyceride
3
levels. Phenytoin did not show inhibitory effect on the growth of a spectrum of
microorganisms (Mycobacterium smegmatis, Candida albicans, Staphylococcus
4
aureus, Pseudomonas aeruginosa and Escherichia coli). Furthermore, a slight
increased occurrence of E. coli agglutinins was found in patients on long-term
5
phenytoin therapy. In dermatology, the drug has been investigated for the treat-
6
ment of ulcers, epidermolysis bullosa and different inflammatory conditions.
Hydantoin derivatives are found in many area of medicinal chemistry (sero-
7
tonin and fibrinogen receptor antagonists, inhibitors of the glycine binding site
8
of the NMDA receptor, antagonists of leukocyte cell adhesion, acting as allo-
9
steric inhibitors of the protein–protein interaction ). In particular, several reports
10,11
present interest in cancer research.
Cancer is one of the most devastating
diseases of today. It is manifested as uncontrolled growth of cells and invasion or
intrusion into and the destruction of adjacent tissues. Although the progress is
evident in diagnosis, surgical techniques, patient care and adjuvant therapies,
12
most of the deaths from cancer are due to metastases. Spiromustin, a hydan-
toin-containing nitrogen mustard, rapidly penetrates the blood-brain barrier and
13
14,15
directs drug delivery to brain tumors. Carmi et al.
demonstrated that 5-
-benzylidenehydantoins could function as bioisosters of 4-anilinoquinazolines,
which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
approved for the treatment of lung cancer. They suggested that the presence of an
aromatic unit at position C5 is an important structural feature for interactions with
molecular targets. Recently, Ananda Kumar and co-workers investigated the anti-
proliferative effect of certain diazaspiro bicyclo hydantoin derivatives against hu-
16,17
man leukemia K562 and CEM cells.
They reported that the cytotoxic acti-
vities of compounds bearing a substituent at the N3 position increase in the order
alkene > ester > ether. A similar conclusion was reached in a comparative study
of the cytostatic activities of L- and D-amino acid derivatives of hydroxyurea and
hydantoins. The best antitumor activities were achieved with lipophilic com-
18
pounds having cycloalkyl, phenyl and benzhydryl substituents.
A deeper understanding of the SARs and modeling of new derivatives with
potential antitumor activity can be facilitated by accumulation of detailed struc-
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

ANTIPROLIFERATIVE AND ANTIMICROBIAL ACTIVITIES OF HYDANTOINS
1599
tural and pharmacological data. In this context, a set of twelve phenytoin de-
rivatives bearing different alkyl (methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-
butyl and benzyl), alkenyl (allyl), ether (ethoxymethyl, benzyloxymethyl), ester
(acetoxymethyl) and alkanoyl (benzoyl) substituents at the N3 position was syn-
thesized (Table I). The antiproliferative activity was evaluated against the HCT-
-116 human colon carcinoma cell line. These structural modifications of the phe-
nytoin molecule led to several derivatives exhibiting different degrees of anti-
20
convulsant activity (Table I). Poupaert et al. observed that the anti-electroshock
activity was decreased when the hydantoin ring was N-methylated. The 3-alko-
xymethyl derivatives were reported to be active against electrically as well as
19,22
chemically induced seizures.
On the other hand, 3-(acetoxymethyl)-5,5-di-
phenylhydantoin resembled the parent compound showing good activity against
23
maximal electroshock seizures, but was inactive against pentylenetetrazole. In
24,25
previous papers,
the hypothesis that the ability to form hydrogen bonds plays
the determining role in the anticonvulsant action of these compounds was con-
firmed.
TABLE I. Structures and anticonvulsant potencies of the investigated compounds
Compound
R
ED50a / mg kg-1
1
2
H
CH3
≈7.519
39.620
3
C2H5
–
4
n-C3H7
–
5
6
i-C3H7
n-C4H9
–
–
7
8
9
10
11
12
13
i-C4H9
–
C6H5CH2
CH2=CHCH2
C2H5OCH2
C6H5CH2OCH2
CH3C(=O)OCH2
C6H5CO
>20019
30.421
–
>2522
<12.519
–
aThe effective dose required to protect mice against spasms induced by the maximum electric shock (MES)
Certain derivatives of hydantoin, which contained aromatic or heterocyclic
26
substituents at the nitrogen, were reported to exhibit antimicrobial effects.
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1600
TRIŠOVIĆ et al.
Hence, the in vitro antimicrobial activities of the investigated compounds were
additionally evaluated against E. coli ATCC 25922, S. aureus ATCC 25923 and
clinical isolates of E. coli, Proteus mirabilis, P. aeruginosa, Enterococcus
faecalis and S. aureus.
RESULTS AND DISCUSSION
Antiproliferative screening
The investigation of the antiproliferative activities of the phenytoin deri-
vatives on the HCT-116 cell line at a concentration of 100 μM showed that al-
most all of the compounds, except 2, 3 and 10, exhibited statistically significant
antiproliferative effects, as is shown in Fig. 1. Furthermore, 8 at concentrations of
0.01, 0.1, 1, 10 and 100 μM showed significant antiproliferative effects (Fig. 2),
while compound 9 demonstrated a statistically significant antiproliferative effect
at a concentration of 10 μM. Interestingly, valproate (valproic acid) manifested a
similar dose-dependent inhibition of proliferation of gastrointestinal neuroen-
27
28
docrine and carcinoid cancer cells. Valproic acid is a simple branched-chain
fatty acid, the anticonvulsant efficacy of which is comparable to that of pheny-
29
toin. The other compounds showed no significant inhibition of HCT-116 proli-
feration at lower concentrations.
Fig. 1. The antiproliferative effect of 3-substituted-5,5-diphenylhydantoins on the HCT-116
cell line. The cells were treated with a 100 μM concentration of the drugs during a 24 h
exposure. The antiproliferative effect was measured by the MTT assay. The results
are expressed as the means ± SD from cells cultured in triplicate
(*p < 0.05, **p < 0.01, ***p < 0.001, compound vs. the control).
N-Alkylation of the phenytoin molecule resulted in a diminished ability to
form hydrogen bonds and also a decreased antiproliferative activity of com-
pounds 2–7 at a concentration of 100 μM. A net stepwise increase in the size of
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

ANTIPROLIFERATIVE AND ANTIMICROBIAL ACTIVITIES OF HYDANTOINS
1601
the alkyl substituent resulted in a slight decrease in the potencies of the com-
pounds with the exception of the isopropyl group. Furthermore, compounds 11
and 12, potent anticonvulsants, manifested a cytotoxic activity to the cancer cells
similar to that of the parent compound 1. The unexpected activity of compound 8
in low concentrations implies that the relative activity of these compounds is not
determined only by the physico–chemical properties of the substituent at the N3
position. It might only be assumed that compounds bearing a benzyl unit (8 and
11) are well located in the molecular target, while the derivative with a rigid
benzoyl group (13) is not well tolerated.
Fig. 2. The antiproliferative effect of 8 on HCT-116 cell line. The cells were treated with
various concentrations of drugs during a 24 h exposure. The antiproliferative effect was
measured by the MTT assay. The results are expressed as the means ± SD from cells cultured
in triplicate. (*p < 0.05, **p < 0.01, ***p < 0.001, different concentrations vs. control).
Antibacterial screening
The investigated phenytoin derivatives were additionally screened for their
in vitro antibacterial activities against three Gram-positive and four Gram-ne-
30
gative bacteria using the well-diffusion method and the microdilution method
31
with resazurin. Overnight cultures of standard strains of E. coli ATCC 25922,
S. aureus ATCC 25923 and clinical isolates of E. coli, P. mirabilis, P. aerugi-
nosa, E. faecalis and S. aureus were used for the preparation of the bacterial
suspensions. The in vitro antibacterial activities of the new compounds against
both Gram-positive and Gram-negative bacteria are listed in Table II. Among the
tested compounds, only 5 and 8 showed significant antibacterial activity against
the Gram-positive bacterium E. faecalis and the Gram-negative bacteria E. coli
ATCC 25922 and E. coli (clinical isolate). The active compounds showed the
best effects against E. coli.
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1602
TRIŠOVIĆ et al.
TABLE II. Antibacterial activity of the tested 3-alkyl-5,5-diphenylhydantoins
E. coli ATCC 25922
E. coli
MIC MBC IZ MIC MBC IZ MIC MBC
>103 >103 >103 >103 >103 >103
P. mirabilis
P. aeruginosa
Compds.
IZa
MICb MBCc
IZ
1–4
5
6 and 7
8
/
>103 >103
–
–
–
21.25±1.50 250 >500 23.00±0.00 125 125
–
>103 >103 >103 >103
20.05±2.28 500 >500 20.50±0.71 250 250
9–13
–
>103 >103
>103 >103
S. aureus ATCC 25923
E. faecalis
S. aureus
MIC
IZa
–
MICb MBCc
IZ
MIC
MBC
IZ
–
MBC
1–4
5
6 and 7
8
>103
>103
500
–
>103
>103
>103
>103
21.00±0.00 250
>103
18.75±1.50 500
>103
–
>103
500
9–13
–
>103
aInhibition zone, mm; bminimum inhibitory concentration, μM; cminimum bactericidal concentration, μM
Compound 8 demonstrated weak antibacterial activity as an additional bio-
logical effect. Compound 5, which was shown to be an exception from the group
of 3-alkyl substituted derivatives, exhibited a similar effect. Since cytochrome
P450 enzymes are responsible for the metabolism of an ever-expanding array of
32
drugs, Suzuki and co-workers tested, among others, the inhibitor potencies of 5
and 8 against recombinant CYP2C19 and CYP2C9 to probe their interactions
with their active sites. Metabolic profiling and homology modeling studies sug-
gested that the 3-benzyl substituted derivative was preferentially bound in the
active site of CYP2C19 with its C5 phenyl group oriented towards the active
oxygen and the benzyl group bound within a lipophilic pocket of the receptor.
We are of the opinion that these structural features might be responsible for the
biological activity of compound 8. Several examples from the literature indicate
that a benzyl group attached to the nitrogen atom is a promising pharmacophore
33–35
for antiproliferative activity to be exhibited.
Since the molecular basis of the
biological activity of 8 remains to be determined, further experiments aimed at
defining the modes of actions are currently in progress.
EXPERIMENTAL
Chemistry
The methods for the preparations of the investigated compounds are presented in Scheme
1. In the synthesis of 2–9, commercially obtained 5,5-diphenylhydantoin (1, Fluka) was
alkylated at the N3 position using the corresponding alkyl halide in K2CO3/dimethylform-
amide.32 The alkoxymethyl substituent was introduced by the reaction of phenytoin sodium
salt (15) in dimethylformamide with the appropriate chloromethyl alkyl ether (10 and 11).19
The process for preparing 15 was described in the literature.36 3-Acetoxymethyl-5,5-diphenyl-
hydantoin (12) was prepared by the reaction of 3-(hydroxymethyl)-5,5-diphenylhydantoin and
acetic anhydride, and 3-(hydroxymethyl)-5,5-diphenylhydantoin (14) was initially synthesized
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

ANTIPROLIFERATIVE AND ANTIMICROBIAL ACTIVITIES OF HYDANTOINS
1603
by the addition of 1 to formaldehyde in the presence of sodium hydroxide in ethanol.23 3-Ben-
zoyl-5,5-diphenylhydantoin (13) was synthesized in the reaction of phenytoin sodium salt and
benzoyl chloride in dry benzene.37 The structures of the compounds were determined by their
1
melting points, and IR, H- and 13C-NMR spectra, which were in agreement with literature
1
data. The H- and 13C-NMR spectral measurements were performed on a Bruker AC 250
1
spectrometer at 250 MHz for the H-NMR and 62.89 MHz for the 13C-NMR spectra. FT-IR
spectra were recorded on a Bomem MB 100 spectrophotometer. The spectra were recorded at
room temperature in DMSO-d6. The chemical shifts are expressed in ppm values referenced to
TMS (δH = 0 ppm) in 1H-NMR spectra, and the residual solvent signal (δC = 39.5 ppm,) in the
13C-NMR spectra. Elemental analysis was realized using an Elemental Vario EL III micro-
analyzer. The yield and chemical characterization of the newly synthesized compound 7 are
given here.
Scheme 1. Synthesis of the investigated derivatives of phenytoin (1). Reagents and conditions:
a) alkyl halide (1.1 eq.), K2CO3, DMF, r. t., 24 h; b) formalin, NaOH, EtOH, r. t., 30 min;
c) Ac2O, r. t. 24 h; d) NaOH, benzene, reflux, 6 h; e) chlormethyl alkyl ether
(1.1 eq.), DMF, r. t., 24 h; f) benzoyl chloride, benzene, reflux, 6 h.
Characterization
3-Isobutyl-5,5-diphenylhydantoin (7). White crystalline solid; yield 72 %; mp: 119–122
°C; Anal. Calcd. for C19H20N2O2: C, 74.00; H, 9.08; N, 6.54 %. Found C 74.08, H, 9.10, N
6.57 %. IR (KBr, cm-1 ): 3293 (N–H), 1705, 1775 (C=O). 1H-NMR (200 MHz, DMSO-d6, δ /
/ ppm): 9.66 (1H, s, NH), 7.26–7.44 (10H, m, 2Ph–H), 3.25–3.29 (2H, m, CH2–N), 1.89–2.03
(1H, m, CH–CH2N), 0.78 (6H, d, J = 7.0 Hz, 2CH3). 13C-NMR (50 MHz, DMSO-d6, δ /
/ ppm): 173.60 (C4), 155.85 (C2), 140.03 (Ph–C), 128.81 (Ph–CH), 128.37 (Ph–CH), 126.82
(Ph–CH), 69.22 (C5), 45.40 (CH2–N), 27.12 (CH), 19.91 (CH3).
In vitro antiproliferative screening
The antiproliferative potential of the investigated phenytoin derivatives was determined
using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay for the
HCT-116 human colon cancer cell line. The relative antiproliferative potency is expressed as
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1604
TRIŠOVIĆ et al.
the percentage of proliferation inhibition of the control HCT cells cultured without com-
pounds in the cell cultivation medium. The HCT-116 cells were maintained in Dulbecco-mo-
dified Eagle medium (DMEM) supplemented with 10 % fetal bovine serum. The cells were
grown in 75 ml culture bottles supplied with 12 ml DMEM, and after a few passages, the cells
were seeded in a 96-well plate. The cells were cultured in a humidified atmosphere of 5 %
CO2 at 37 °C. The HCT-116 cells were treated with 0.01, 0.1, 1, 10 and 100 μM concen-
trations of the investigated compounds for 24 h. Untreated cells served as the control. After 24
h of treatment, the cell proliferation was determined by the MTT assay. This test is based on
the color reaction of mitochondrial dehydrogenase from living cells with MTT. Briefly, 10 ml
of MTT solution (5 mg ml-1) was added to each well after 24 h of culture and the cultures
were incubated for an additional 3 h at 37 °C. The produced formazan was dissolved by over-
night incubation in SDS–HCl (10 % SDS (sodium dodecyl sulfate) in 0.01 M HCl) and absor-
bance was measured at the dual wavelengths of 570/650 nm with an ELISA 96-well plate
reader. The percentage of viable cells was calculated as the ratio between the absorbance at
each dose of the compounds and the absorbance of the untreated control×100.
In vitro antibacterial screening
An overnight culture of standard strains of E. coli ATCC 25922, S. aureus ATCC 25923
and clinical isolates of E. coli, P. mirabilis, P. aeruginosa, E. faecalis and S. aureus were used
for the preparation of bacterial suspensions. The turbidity of the initial bacterial suspensions
was adjusted by comparing with a 0.5 McFarland standard and then diluted 1:100 in sterile
0.85 % saline.
Antibacterial assay was realized by the well-diffusion method30 and the microdilution
method with resazurin.31 The diffusion method is a qualitative test which allows the classi-
fication of microorganisms as susceptible or resistant to the test substance according to
diameter of the zone of inhibition. Petri plates with Mueller–Hinton agar were inoculated with
adequate bacterial suspensions. The surface of the media was allowed to dry for 3–5 min at room
temperature. Subsequently, wells (7 mm) were made in the plate with a sterile metal cylinder,
which were filled with 100 μl of solutions of the tested compounds; concentration of 1000
μM. The antibacterial activity was evaluated by measuring the diameters of the zones of
inhibition. All tests were performed in triplicate and the results are expressed as mean ± standard
deviation. A negative control was prepared with the same solvent used to dissolve the tested
substances (5 % DMSO) to ensure that the solvent had no effect on bacterial growth. Each test
also included a growth control and a sterility control. The minimum inhibitory concentration
(MIC) and the minimum bactericidal concentration (MBC) were determined using the
microdilution plate method. Two-fold, serial dilutions of the tested compounds were
performed in Mueller-Hinton broth. The obtained concentration range was from 1000 to 7.81
μM. The diluted bacterial suspensions (10 μl) were added to each well to give a final
concentration of 5×105 CFU mL-1. Finally, 10 μl resazurin indicator solution was added.
Resazurin is an oxidation–reduction indicator used for the evaluation of microbial growth. It is
a blue non-fluorescent dye that becomes pink and fluorescent when reduced to resorufin by
the oxidoreductases within viable cells. The inoculated plates were incubated at 37 °C for 24
h. The MIC is defined as the lowest concentration of a tested substance that prevented the
resazurin color change from blue to pink. Each test included a growth control and a sterility
control. All tests were performed in triplicate and the MIC values were constant. The MBC was
determined by plating 10 μl of samples from wells where no indicator color change was
recorded onto nutrient agar medium. At the end of the incubation period, the lowest
concentration with no visible growth was defined as the MBC.
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

ANTIPROLIFERATIVE AND ANTIMICROBIAL ACTIVITIES OF HYDANTOINS
1605
CONCLUSIONS
In summary, an evaluation of 3-substituted-5,5-diphenylhydantoins as poten-
tial antiproliferative and antimicrobial agents was reported. The trend of the
changes in the biological effects produced by substituents at position N3 was
studied. Compound 8 showed significant antiproliferative activity even in low
concentrations. In addition, it exhibited weak antibacterial activity. Since the
molecular basis of its biological activity remains to be determined, further experi-
ments aimed at defining the modes of its actions are currently in progress.
Acknowledgements. The authors acknowledge the financial support of the Ministry of
Education and Science of the Republic of Serbia (Project 172013).
И З В О Д
УТИЦАЈ СТРУКТУРЕ НА АНТИПРОЛИФЕРАТИВНУ И АНТИБАКТЕРИЈСКУ
АКТИВНОСТ 3-СУПСТИТУИСАНИХ-5,5-ДИФЕНИЛХИДАНТОИНА
НЕМАЊА ТРИШОВИЋ1, БОЈАН БОЖИЋ1, АНА ОБРАДОВИЋ2, ОЛГИЦА СТЕФАНОВИЋ2,
СНЕЖАНА МАРКОВИЋ2, ЉИЉАНА ЧОМИЋ2, БИЉАНА БОЖИЋ3 и ГОРДАНА УШЋУМЛИЋ1
1Tehnolo{ko–metalur{ki fakultet, Univerzitet u Beogradu, Karnegijeva 4, 11000 Beograd,
2Prirodno–matemati~ki fakultet, Univerzitet u Kragujevcu, Radoja Domanovi}a 12, 34000 Kragujevac
i 3Biolo{ki fakultet, Univerzitet u Beogradu, Studentski trg 3, 11000 Beograd
Синтетисана је серија од дванаест 3-супституисаних-5,5-дифенилхидантоина, која обу-
хвата неке од деривата чије су антиконвулзивне активности познате у литератури. Одређена
је њиховa антипролиферативнa активност према ћелијској линији хуманог карцинома коло-
на, како би се утврдио утицај структуре на активност. Скоро сва једињења испољавају анти-
пролиферативан ефекат у концентрацији од 100 μM, док је дериват са бензил групом активан
и у нижим концентрацијама. Додатно је одређена и антибактеријска активност проучаваних
једињења према Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 и клинич-
ким изолатима Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Enterococcus
faecalis и Staphylococcus aureus. 3-Изопропил и 3-бензил деривати показују слабу активност
према грам-позитивној бактерији E. faecalis и грам-негативним бактеријама E. coli ATCC
25922 и E. coli.
(Примљено 14. марта, ревидирано 2. маја 2011)
REFERENCES
1. Y. Yaari, M. E. Selzer, J. H. Pincus, Ann. Neurol. 20 (1986) 171
2. K. Kikuchi, C. I. McCormick, E. A. Neuwelt, J. Neurosurg. 61 (1984) 1085
3. J. H. Maguire, A. R. Murthy, I. H. Hall, Eur. J. Pharm. 117 (1985) 135
4. N. Esiobu, N. Hoosein, Anton. Leeuw. Int. J. G. 83 (2003) 63
5. P. Andersen, L. Mosekailde, T. Hjort Clin. Exp. Immunol. 45 (1981) 137
6. N. Scheinfeld, Dermatol. Online J. 9 (2003) 6
7. G. P. Moloney, G. R. Martin, N. Mathews, A. Milne, H. Hobbs, S. Dosworth, P. Y. Sang,
C. Knight, M. Williams, M. Maxwell, R. Glen, J. Med. Chem. 42 (1999) 2504
8. M. Jansen, H. Potschka, C. Brandt, W. Löscher, G. Dannhardt, J. Med. Chem. 46 (2003) 64
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

1606
TRIŠOVIĆ et al.
9. K. Last-Barney, W. Davidson, M. Cardozo, L. L. Frye, C. A. Grygon, J. L. Hopkins, D.
D. Jeanfavre, S. Pav, C. Qian, J. M. Stevenson, L. Tong, R. Zindell, T. A. Kelly, J. Am.
Chem. Soc. 123 (2001) 5643
10. N. R. Penthala, T. R. Yerramreddy, P. A. Crooks, Bioorg. Med. Chem. Lett. 21 (2011) 1411
11. D. Lesuisse, J. Mauger, C. Nemecek, S. Maignan, J. Boiziau, G. Harlow, A. Hittinger, S.
Ruf, H. Strobel, A. Nair, K. Ritter, J.-L. Malleron, A. Dagallier, Y. El-Ahmad, J.-P.
Guilloteau, H. Guizani, H. Bouchard, C. Venot, Bioorg. Med. Chem. Lett. 21 (2011) 2224
12. I. Fidler, J. Semin. Cancer Biol. 12 (2002) 89
13. D. D. Shoemaker, P. J. O’Dwyer, S. Marsoni, J. Plowman, J. P. Davignon, R. D. Davis,
Invest. New Drugs 1 (1983) 303
14. C. Carmi, A. Cavazzoni, V. Zuliani, A. Lodola, F. Bordi, P. V. Plazzi, M. Mor, Bioorg.
Med. Chem. Lett. 16 (2006) 4021
15. A. Cavazzoni, R. R. Alfieri, C. Carmi, V. Zuliani, M. Galetti, C. Fumarola, R. Frazzi, M.
Bonelli, F. Bordi, A. Lodola, M. Mor, P. G. Petronini, Mol. Cancer Ther. 7 (2008) 361
16. C. S. Ananda Kumar, C. V. Kavitha, K. Vinaya, S. B. Benaka Prasad, N. R. Thimme-
goweda, S. Chandrappa, S. C. Raghavan, K. S. Rangappa, Invest. New. Drugs 27 (2009) 327
17. C. V. Kavitha, N. Mridula, C. S. Ananda Kumar, C. Bibha, K. Muniyappa, K. S. Ran-
gappa, S. C. Raghavan, Biochem. Pharmacol. 77 (2009) 348
18. N. Opačić, M. Barbarić, B. Zorc, M. Cetina, A. Nagl, D. Frković, M. Kralj, K. Pavelić, J.
Balzarini, G. Andrei, R. Snoeck, E. De Clercq, S. Ralić-Malić, M. Mintas, J. Med. Chem.
48 (2005) 475
19. J. A. Vida, M. H. O’Dea, C. M. Samour, J. Med. Chem. 18 (1975) 383
20. J. H. Poupaert, D. Vandervorst, P. Guiot, M. M. M. Moustafa, P. Dumont, J. Med. Chem.
27 (1984) 76
21. F. Sandberg, Acta Physiol. Scand. 24 (1951) 149
22. C. M. Samour, J. Reinhard, J. A, Vida, J. Med. Chem. 14 (1971) 187
23. J. A. Vida, W. R. Wilber, J. Med. Chem. 14 (1971) 190
24. N. Banjac, G. Ušćumlić, N. Valentić, D. Mijin, J. Solution Chem. 36 (2007) 869
25. N. Divjak, N. Banjac, N. Valentić, G. Ušćumlić, J. Serb. Chem. Soc. 74 (2009) 1195
26. E. Szymańska, K. Kieć-Kononowicz, A. Białecka, A. Kasprowicz, Farmaco 57 (2002) 39
27. V. Baradari, A. Huether, M. Höpfner, D. Schuppan, H. Scherübl, Endocr.-Relat. Cancer
13 (2006) 1237
28. D. Y. Greenblatt, A. M. Vaccaro, R. Jaskula-Sztul, L. Ning, M. Haymart, M. Kunnima-
laiyaan, H. Chen, Oncologist 12 (2007) 942
29. E. Perucca, CNS Drugs 16 (2002) 695
30. C. Perez, M. Paul, P. Bazerque, Acta Bio. Med. Exp. 15 (1990) 113
31. S. D. Sarker, L. Nahar, Y. Kumarasamy, Methods 42 (2007) 321
32. H. Suzuki, M. B. Kneller, D. A. Rock, J. P. Jones, W. F. Trager, A. E. Rettie, Arch.
Biochem. Biophys. 429 (2004) 1
33. L. J. Marton, A. E. Pegg, Annu. Rev. Pharmacol. 35 (1995) 55
34. C. Gao, Y. Jiang, C. Tan, X. Zu, H. Liu, D. Cao, Bioorg. Med. Chem. 16 (2008) 8670
35. G. T. Elliott, W. A. Nagle, K. F. Kelly, D. McCollough, R. L. Bona, E. R. Burns, J. Med.
Chem. 32 (1989) 1039
36. R. Gulaboski, A. Galland, G. Bouchard, K. Caban, A. Kretschmer, P.-A. Carrupt, Z.
Stojek, H. H. Girault, F. Scholz, J. Phys. Chem., B 108 (2004) 4565
37. L. P. Kulev, A. A. Shesterova, Zhch. Obszh. Khim. 31 (1961) 1378.
Available online at www.shd.org.rs/JSCS
_______________________________________________________________________________________________________________________________________
2011 Copyright (CC) SCS

Copyright of Journal of the Serbian Chemical Society is the property of National Library of Serbia and its
content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for individual use.