Synthesis and QSAR modeling of 2-acetyl-2-ethoxycarbonyl-1-[4(4′-arylazo)-phenyl]-N,N-dimethylaminophenyl aziridines as potential antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2008.02.016

The present communication deals with the synthesis of a series of 2-acetyl-2-ethoxycarbonyl-1-[4(4′-arylazo)-phenyl]-N,N-dimethylaminophenyl aziridines. The compounds were synthesized in excellent yields (70-80%) and the structures were established on the

Full text of DOI:10.1016/j.ejmech.2008.02.016

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European Journal of Medicinal Chemistry 44 (2009) 251e259
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and QSAR modeling of 2-acetyl-2-ethoxycarbonyl-1-[4(40-
arylazo)-phenyl]-N,N-dimethylaminophenyl aziridines as potential
antibacterial agents
*
Pratibha Sharma , Ashok Kumar, Siya Upadhyay, Vinita Sahu, Jitendra Singh
School of Chemical Sciences, Devi Ahilya University, Takshashila Campus, Indore 452 001, MP, India
Received 6 September 2007; received in revised form 14 January 2008; accepted 8 February 2008
Available online 29 February 2008
Abstract
The present communication deals with the synthesis of a series of 2-acetyl-2-ethoxycarbonyl-1-[4(40-arylazo)-phenyl]-N,N-dimethylamino-
phenyl aziridines. The compounds were synthesized in excellent yields (70e80%) and the structures were established on the basis of consistent
IR, 1H NMR and elemental analysis data. The purity has been ascertained by chromatographic resolution using acetic acidetoluene (6:4 v/v) as
binary eluent. All the compounds have been tested for their antimicrobial activity against a representative panel of bacteria i.e. Bacillus subtilis,
Escherichia coli, Pseudomonas diminuta and Staphylococcus aureus using azinomycin as reference drug. All the synthesized compounds were
found to exhibit profound antimicrobial activity.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Quantitative structureeactivity relationship (QSAR); 2-Acetyl-2-ethoxycarbonyl-1-[4(40-arylazo)-phenyl]-N,N-dimethylaminophenyl aziridines; Anti-
bacterial; Molar refractivity
1. Introduction
purine bases in the duplex DNA sequence 50-d (PuNPy)-30,
via the electrophilic C10 and C21 carbons, which make these
compounds to act as antitumour agents. Also, antibiotic and
antitumour activities [12e17] exhibited by Mitomycin C are
attributed to the presence of aziridine ring in it. Similarly Azi-
cemicins A and B possess significant antimicrobial and anti-
bacterial activities owing to the presence of aziridine moiety.
Various N-substituted aziridines are versatile intermediates
for the synthesis of many biologically active compounds that
are valuable for new drug development. Buoyed from these
findings vis-a-vis keeping in view the unique reactivity feature
of the three-membered ring and in continuation of our previ-
ous work on various heterocyclic systems [18e21], herein,
we document a new route to synthesize analogues of biologi-
cally active aziridine carboxylate viz., 2-acetyl-2-ethoxy-
carbonyl-1-[4(40-arylazo)-phenyl]-N,N-dimethylaminophenyl
aziridine. These synthesized compounds were screened for
their antibacterial activities against a panel of Gram-positive
and Gram-negative bacteria and can be envisaged as the new
lead compounds for future perspectives.
The highly strained three-membered [1e3] aziridines have
been the synthetic targets as well as useful building blocks for
the synthesis of wide range of nitrogen containing heterocy-
cles due to their high regio- and stereoselective [4e8] proper-
ties. A systematic perusal of literature reveals that a variety of
methods have been developed for the synthesis of aziridines,
including ring formation of amino alcohols, ring opening of
epoxides with metal azides, addition of a-halo ester to imines
[9e11], transfer of nitrene group to olefin, etc. The clinical ac-
tivity of aziridine is very much included in the DNA modifica-
tion. Armstrong and co-workers reported that azinomycin B
containing aziridine nucleus interacts with duplex DNA in
the major groove. Aziridine nucleus forms a covalent inter-
strand cross-link via the N7 positions of suitably disposed
* Corresponding author. Tel.: þ91 7312460208; fax: þ91 7312470352.
E-mail address: drpratibhasharma@yahoo.com (P. Sharma).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.02.016

252
P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
2. Chemistry
3.1. QSAR analysis
An important preparative methodology for the synthesis
of 2-acetyl-2-ethoxycarbonyl-1-[4(40-arylazo)-phenyl]-N,N-
dimethylaminophenyl aziridine is described incorporating
ethyl acetoacetate and N,N-dimethyl amino benzaldehyde as
the substrates. In this strategy, ethyl acetoacetate was stirred
with N,N-dimethyl amino benzaldehyde under Knoevenagel
reaction conditions to give (6) in initial mechanistic steps.
The key compound (6) was further treated with freshly pre-
pared p-amino azobenzene under the oxidative influence of
lead tetraacetate in the presence of dichloromethane/pentane.
Upon gentle stirring for 10 min a solidified mass of 2-acetyl-
2-ethoxycarbonyl-1-[4(40-arylazo)-phenyl]-N,N-dimethylami-
nophenyl aziridine appeared in excellent (75e80%) yield. A
mechanistic overview of the synthetic pathway is depicted in
Scheme 1.
Conclusively, the most prominent cyclization step involves
nucleophilic attack of eNH2 fragment of p-amino azobenzene
on eC]Ce olefinic moiety of N,N-dimethyl amino-1-phenyl-
2-ethoxy carbonyl but-2-en-1-one (6) to form cyclized CeCe
N fraction of aziridine nucleus. Here, oxidative addition of
lead tetraacetate plays a very promising role in the ring clo-
sure. IR, 1H NMR and mass spectral data corroborated towards
the structure of the synthesized aziridines.
To obtain a significant correlation between structural fea-
tures and biological activities, QSAR studies were performed
using the linear free energy relationship (LFER) model of
Hansch and Fujita [46]. Biological activity data were reported
as ꢁlog MIC on molar basis and used as dependent variable to
get the linear relationship in the QSAR model. The physico-
chemical parameters taken from the list of Skagerberg et al.
[22] were then correlated with varied molecular descriptors
like log of octanolewater partition coefficient (log p), energy
of highest occupied molecular orbital (HOMO) and lowest un-
occupied molecular orbital (LUMO), molar refractivity (MR)
and Connolly accessible area (CAA), Connolly molecular
area (CMA), dipoleedipole energy (DDENE), Van der Waals
volume (VDW) and non-Van der Waals volume (NVDW).
All the calculations to figure out molecular descriptors were
done at SCF level using AM1 [23] Hamiltonian incorporated
in MOPAC 6.0 [24] package. Geometries were optimized at
minimum gradient level using CHEM 3D-6.0 [25] software.
In order to perform correlation studies for various descriptors,
intercorrelated parameters were discarded depending upon
their individual correlation with biological activities. Using
the stepwise selection and elimination procedures the resultant
parameters were subjected to MLR analysis with the help of
Valstat [26] software.
3. Biological studies
The best fit between ꢁlog MIC and these explaining pa-
rameters was obtained through multiple regression analysis
(MRA) using least square method as shown in Tables 2 and 3.
Out of a number of parametric evaluations, the best corre-
lation (r2 > 0.93) was found to exist between molar refractiv-
ity and biological activity. The resulting mono-parametric
models are displayed in Eqs. (1)e(4) (Table 4) with statistical
parameters of regression. No outliers have been detected and
these Eqs. (1)e(4) were derived using entire training data
set (n ¼ 11).
All the newly synthesized derivatives were screened for
their antibacterial activities against Escherichia coli ATCC
13067, Pseudomonas diminuta MTCC 3361, Staphylococcus
aureus ATCC 2943, and Bacillus subtilis ATCC 6633.
Nutrient agar media were prepared for bacterial growth.
Stock solution was prepared in DMF and suspension contain-
ing approximately 107 CFU/ml of bacteria was prepared from
broth culture in log phase growth. Bacterial plates were pre-
pared in triplicate and incubated at 37 ꢀC within 16e24 h
for bacteria. Also azinomycin was tested under similar condi-
tions as a control drug. Minimal inhibitory concentration
(MIC) was determined by means of standard twofolds serial
dilution method using agar media and reported in Table 1,
where MIC is defined as the lowest concentration of com-
pound that inhibited visible growth.
All the reported compounds exhibited remarkable in vitro
activity against the tested bacterial strains compared to refer-
ence drug. A systematic perusal of data depicted in Table 1
reveals significant antibacterial activities. In general antibacte-
rial profile of the tested compounds follows the pattern:
B. subtilis > P. diminuta > S. aureus > E. coli
Further, a close inspection of screening results reveals that
the substitution in aromatic ring attached with azo moiety of
aziridine 2-carboxylate exerted significant influence on the an-
tibacterial armament. It is deduced from the data presented in
Table 1 that the in vitro antibacterial activity is found to be in-
creased with the derivatives bearing eNO2 (8j), eCOOH (8f),
eOH (8i), and eCl (8b) substituents in the meta position of
the phenyl ring (Fig. 1).
The overall quality of the models is indicated by coefficient
of determination (r2), standard error of estimate (s), and Fisher
statistics (F ).
QSAR model for activity against B. subtilis:
ꢁlog MIC ¼ ½4:0362ð ꢂ 0:0904Þꢃ þ MR½0:7230ð ꢂ 0:1522Þꢃ
ð1Þ
n ¼ 11, r ¼ 0.96, r2 ¼ 0.93, variance ¼ 0.0022, std ¼ 0.0472,
F(1,9) ¼ 119.96.
QSAR model for activity against P. diminuta:
ꢁlog MIC ¼ ½4:0209ð ꢂ 0:0803Þꢃ þ MR½0:6591ð ꢂ 0:1352Þꢃ
ð2Þ
n ¼ 11, r ¼ 0.97, r2 ¼ 0.93, variance ¼ 0.0018, std ¼ 0.0420,
F(1,9) ¼ 126.34.
QSAR model for activity against E. coli:
ꢁlog MIC ¼ ½3:9657ð ꢂ 0:0585Þꢃ þ MR½0:5188ð ꢂ 0:0984Þꢃ
ð3Þ

P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
253
Scheme 1. Reagents and conditions: (i) (C2H5)2NH/0 ꢀC, (ii) stirring for 50 min, (iii) H2SO4 (2 M), (iv) (COOCH3)4Pb/CH2Cl2/pentane/stirring for 30 min at
25 ꢀC.

254
P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
Table 1
Antibacterial screening data for 2-acetyl-2-ethoxycarbonyl-1-[4-(40-arylazo)-
phenyl]-N,N-dimethylaminophenylaziridines
Table 2
Values of selected descriptors with correlation r > 0.45
MRa
HOMO (eV)
DDENE
VDW
NVDW
Compound MIC in mg/ml
8a
8b
8c
8d
8e
8f
8g
8h
8i
0.103
0.603
0.603
0.565
0.787
0.693
0.693
0.285
0.285
0.736
0.736
ꢁ7.823
ꢁ8.606
ꢁ8.737
ꢁ8.516
ꢁ8.486
ꢁ8.214
ꢁ8.775
ꢁ8.369
ꢁ8.482
ꢁ10.791
ꢁ10.484
3.176
3.599
3.185
3.011
2.081
2.812
4.209
3.298
2.003
3.747
2.443
33.530
28.101
19.988
20.159
22.249
1.165
9.561
11.082
9.801
Gram-negative bacteria
Gram-positive bacteria
S. aureus B. subtilis
E. coli
P. diminuta
9.941
MIC
ꢅ 10ꢁ5 MIC ꢅ 10ꢁ5 MIC ꢅ 10ꢁ5 MIC ꢅ 10ꢁ5 MIC
ꢁlog MIC
ꢁlog MIC
ꢁlog MIC
ꢁlog
14.852
1.121
7.288
28.760
132.442
18.285
25.159
22.563
8a
8b
8c
8d
8e
8f
8.995 4.046 7.447 4.128 8.337 4.079 7.014 4.154
5.297 4.276 3.872 4.412 4.688 4.329 3.467 4.460
5.916 4.228 4.487 4.348 5.297 4.276 4.074 4.390
5.741 4.241 4.256 4.371 5.105 4.292 3.614 4.442
4.325 4.364 2.884 4.540 3.707 4.431 2.472 4.607
4.602 4.337 3.199 4.495 3.999 4.398 2.799 4.553
5.000 4.301 3.597 4.444 4.395 4.357 3.199 4.495
8.054 4.094 6.561 4.183 7.413 4.130 6.138 4.212
7.621 4.118 6.138 4.212 6.998 4.155 5.715 4.243
3.990 4.399 2.594 4.586 3.396 4.469 2.198 4.658
4.188 4.378 2.992 4.524 3.589 4.445 2.594 4.586
13.851
11.061
5.762
8j
8k
a
10.521
MR is scaled by factor 0.1.
8g
8h
8i
ꢁlog MIC ¼½4:1781ð ꢂ 0:1610Þꢃ þ MR½0:6843ð ꢂ 0:1329Þꢃ
þ log p½ ꢁ 0:0206ð ꢂ 0:0207Þꢃ
8j
8k
ð5Þ
n ¼ 11, r ¼ 0.98, r2 ¼ 0.94, variance ¼ 0.0009, std ¼ 0.0305,
F(1,9) ¼ 147.65.
n ¼ 11, r ¼ 0.98, r2 ¼ 0.96, variance ¼ 0.0015, std ¼ 0.0385,
F(1,9) ¼ 93.
QSAR model for activity against S. aureus:
However, the results obtained from Eq. (5) are not statisti-
cally allowed which revealed the need of mono-parametric
model over bi- and tri-parametric models.
ꢁlog MIC ¼ ½3:9880ð ꢂ 0:0669Þꢃ þ MR½0:5736ð ꢂ 0:1126Þꢃ
ð4Þ
The predictive power of these equations was also checked
by leave one out (LOO) cross-validated r2CV values (>0.88).
The observed biological activities are also in accordance
with calculated and predictive activities as depicted in
Fig. 2, Tables 5 and 6.
n ¼ 11, r ¼ 0.97, r2 ¼ 0.94, variance ¼ 0.0012, std ¼ 0.0349,
F(1,9) ¼ 138.09.
The F value obtained in Eqs. (1)e(4) is found to be statis-
tically significant at 99% level.
To further validate our results, four compounds (entries
T1eT4) have been chosen as the test set molecules whose
ꢁlog MIC values range between 4.021 and 4.686 (which
were not included in the training set). Predicted and actual
biological activities of test set molecules are summarized in
Table 7. Predicted ꢁlog MIC values agree well with the exper-
imental ones, which suggests that our model is good for pre-
diction of the biological activity of related compounds.
PRESS (predicted residual sum of squares) is a cross-vali-
dation parameter whose value less than SSY (sum of the
squares of response value) points out that the model predicts
better than chance and can be considered statistically impor-
tant. Table 4 suggests that all the proposed models have
PRESS ꢄ SSY demonstrating them to be statistically signifi-
cant. Further, to be a reasonable QSAR model PRESS/SSY ra-
tio should be smaller than 0.4 and its value smaller than 0.11
indicates an excellent model. The data pertaining to Table 4
indicate that for all the four proposed models this ratio is
y0.1 suggesting all of them to be excellent models. Moreover,
the value of cross-validated correlation coefficient (r2CV) and
bootstrapping r2 are further supporting the predictive power
of these explaining models (Eqs. (1)e(4)).
Moreover, we have also tried to test bi- and tri-parametric
correlation statistically but we have not found any significant
result as can be illustrated in Eq. (5) which represents a bipara-
metric model for B. subtilis.
QSAR model (biparametric model) for activity against B.
subtilis:
Since molar refractivity accounts for the polarizability, size
and polarity of groups as displayed through Eqs. (1)e(4) sug-
gest that molar refractivity is a key factor to express biological
activities, which may be possible due to steric interaction oc-
curring in polar species.
Fig. 1. ORTEP diagram of 8a (PM3 optimized geometry) with atom number-
ing. Thermal ellipsoids are scaled to the 50% probability level. The atom num-
bering is arbitrary and has nothing to do with the IUPAC nomenclature.

P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
255
SA
Table 3
Correlation matrix of biological activitya with molecular descriptors
MR
HOMO
log p
CAA
CMA
DDENE
LUMO
VDW
NVDW
BS
PD
EC
MR
1.00
0.54
0.29
0.25
0.41
0.07
0.10
0.45
0.27
0.64
0.07
0.24
0.07
HOMO
log p
CAA
CMA
DDENE
LUMO
VDW
NVDW
BS
1.00
0.37
0.23
0.33
0.06
0.59
0.89
0.10
0.05
0.14
0.15
0.15
1.00
0.32
0.30
0.01
0.50
0.07
0.12
0.09
0.07
0.03
0.09
1.00
0.85
0.13
0.51
0.54
0.49
0.10
0.04
0.07
0.07
1.00
0.19
0.55
0.53
0.19
0.09
0.07
0.04
0.10
1.00
0.18
0.21
0.44
0.05
0.02
0.02
0.03
1.00
0.82
0.13
0.16
0.13
0.07
0.18
1.00
0.28
0.02
0.08
0.09
0.09
1.00
0.60
0.52
0.60
0.43
1.00
0.48
0.67
0.29
PD
EC
1.00
0.97
0.98
1.00
0.90
AS
1.00
a
EC ¼ E. coli, PD ¼ P. diminuta, SA ¼ S. aureus, BS ¼ B. subtilis.
4. Experimental
4.2.1. Synthesis of diazoaminobenzene (A)
The mixture of 6.5 ml (0.07 M) of aniline, 10.0 ml of
conc. hydrochloric acid and 40.0 ml of water was taken in
a 250 ml Erlenmeyer flask and stirred to make a homoge-
neous solution followed by the addition of 25 g of crushed
ice. Now, 2.6 g (0.037 M) of sodium nitrite solution in
6 ml of water was added slowly with constant shaking dur-
ing a period of 10e15 min. The contents were allowed to
stand for 10 min and 10.5 g (0.128 M) of sodium acetate
dissolved in 20 ml of water was added. A yellow precipitate
of diazoaminobenzene commences to appear which was kept
at 20 ꢀC with occasional shaking for 40 min. The yellow
solid thus formed was filtered on a Buchner funnel, washed
with 100 ml of cold water and recrystallized from light
petroleum.
All the chemicals used were of AR-grade purity. IR spectra
were recorded on Perkin Elmer model 377 spectrophotometer
1
in KBr pellets. H NMR spectra were recorded on a Bruker
DRX300 instrument. The FAB mass spectra were recorded
on a JEOLSX102/DA-6000 Mass Spectrometer using argon/
xenon (6 kV, 10 mA) as the FAB gas. Analytical thin layer
chromatography was performed using E. Merck silica gel G,
0.50 mm plates, (Merck No. 5700). The melting points were
determined on an electric melting point apparatus in open
capillaries and are uncorrected.
4.1. Synthesis of N,N-dimethyl amino-1-phenyl-2-
ethoxycarbonyl but-1-en-2-one (5)
The compound (5) was prepared by condensing together
N,N-dimethyl amino benzaldehyde (4.5 g, 0.03 M) and 1-eth-
oxy butane-1,3-dione (2.6 ml, 0.02 M) in the presence of cat-
alytic amount of diethyl amine and allowed to undergo stirring
at 0 ꢀC for 50 min followed by the addition of sulfuric acid
(50 ml, 2 M). On cooling the precipitate so obtained was fil-
tered, thoroughly washed with water and dried. As a result
N,N-dimethyl amino-1-phenyl-2-ethoxycarbonyl but-1-en-2-
one was obtained in good yield (80%) as a yellowish crystal-
line product. It was recrystallized from a mixture of ethanol
and DMF.
4.2.2. Conversion of diazoaminobenzene to p-aminoarylazo
benzene (B)
In an Erlenmeyer flask, a mixture of 2.5 g (0.0125 M) of di-
azoaminobenzene and 6.9 ml (0.07 M) of aniline was taken.
To the solution 1.3 g of finely powdered aniline hydrochloride
was added and the mixture was allowed to warm at 40e45 ꢀC
for 1 h on a water bath with occasional shaking. The reaction
mixture was permitted to stand for 15 min at room tempera-
ture. Now 15 ml of 1:1 glacial acetic acid was added and
shaken thoroughly to remove excess aniline as aniline acetate.
It was then allowed to stand for 15 min. The solid product thus
obtained was filtered on a Buchner funnel, washed with water,
recrystallized from carbon tetrachloride, and resulted in appre-
ciable yield.
4.2. Synthesis of p-aminoarylazo benzene (7aeo)
Preparation of this compound (7aeo) was accomplished
[27] in two steps viz., A and B as follows.
4.3. Synthesis of 2-acetyl-2-ethoxycarbonyl-1-[4(40-
arylazo)-phenyl]-N,N-dimethylaminophenyl
aziridines (8aeo)
Table 4
Cross-validation parameters
Equation Number of
compound used
PRESS SSY PRESS/ SPRESS SDEP r2CV rb2sp
SSY
A 500 cc, three-necked round-bottomed flask equipped
with an efficient mechanical stirrer was charged with a mix-
ture of a p-amino azobenzene (7aeo) (2.3 g, 0.12 M), N,N-
dimethyl amino-1-phenyl-2-ethoxycarbonyl but-1-en-2-one
(5) (1.4 g, 0.60 M) and 30 ml of dichloromethane. To the
(1)
(2)
(3)
(4)
11
0.032 0.288 0.111 0.059 0.054 0.889 0.922
0.025 0.238 0.105 0.053 0.048 0.895 0.925
0.013 0.146 0.089 0.038 0.035 0.911 0.931
0.017 0.179 0.095 0.044 0.040 0.905 0.934
11
11
11

256
P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
4.7
4.6
4.5
4.4
4.3
4.2
4.1
4.7
4.6
r2=0.92
r2=0.90
4.5
4.4
4.3
4.2
4.1
4.1
4.2
4.3
4.4
4.5
4.6
4.0
4.1
4.2
4.3
4.4
4.5
4.6
Calculated
Predicted
Fig. 2. Plots of observed versus calculated and observed versus predicted activities of 2-acetyl-2-ethoxycarbonyl-1-[4(40-arylazo)-phenyl]-N,N-dimethylamino-
phenyl aziridine derivatives (8aek) against B. subtilis.
resulting suspension was added 6.0 g (0.012 M) of lead
tetraacetate over a period of 10 min at room temperature
with vigorous stirring. Stirring was continued for an addi-
tional 30 min, after which time the mixture was filtered
through celite, which was washed twice with 25 ml partitions
of dichloromethane. The combined filtrates were transferred
to a 1-l beaker and 500 ml of pentane was added with gentle
stirring and cooling in an ice bath. The yellow precipitate
that formed after 15 min was suction filtered and redissolved
in 200 ml of dichloromethane. The solution obtained was
swirled for 5 min with 10 g of silica gel and filtered through
celite, which was washed twice with 50 ml portions of di-
chloromethane. To this dichloromethane solution was added
50.0 ml of pentane with cooling. The precipitate thus formed
after 30 min was dried under vacuum at room temperature
for 2 h, yielding appreciable percentage of 2-acetyl-2-ethox-
ycarbonyl-1-[4(40-arylazo)-phenyl]-N,N-dimethylaminophenyl
aziridines (8aeo). An overview of the synthetic scheme is
delineated in Scheme 1. Structures of the synthesized com-
pounds have been ascertained on the basis of spectroanalyti-
cal data.
4.3.1. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(200-phenyl)azo]-
phenyl}-3-N,N-dimethylaminophenyl aziridine [8a]
Prepared according to the general procedure as in Section
4.3.
IR (KBr) (cmꢁ1) 3110 (CeH three-membered ring), 3051
(]CeH, sp2), 2936 (CeH, sp3), 2371 (overtone, CO), 1763
(C]O ester), 1715 (C]O, acetyl), 1650 (C]C), 1575
(N]N), 1601, 1414, 1320 (CjC ring str.), 1261 (CeN),
ꢆ
1
1100 (CeO ), 819,668 (sub. phenyl); H NMR (d ppm) 1.30
(t, 3H, CH3CH2, J ¼ 7.1 Hz), 1.93 (s, 6H, (CH3)2N), 2.11 (s,
3H, CH3CO), 3.06 (s, CH, aziridine ring), 4.06 (q, 2H,
CH3CH2, J ¼ 7.1 Hz), 7.45e7.99 (m, 5H, AreH attached to
N]N moiety), 7.81 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 102e
104, yield 71%. Anal. Calcd for C27H28N4O3: C, 71.03; H,
6.18; N, 12.27. Found: C, 70.92; H, 6.11; N, 12.20.
4.3.2. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-chlorophenyl)-
azo]phenyl}-3-N,N-dimethylaminophenyl aziridine [8b]
Prepared according to the general procedure as in Section
4.3.
Table 5
Table 6
Observed versus calculated activity of 2-acetyl-2-ethoxycarbonyl-1-[4(40-ary-
lazo)-phenyl]-N,N-dimethylaminophenyl aziridine derivatives (8aek) against
B. subtilis
Observed versus predicted activity of 2-acetyl-2-ethoxycarbonyl-1-[4(40-ary-
lazo)-phenyl]-N,N-dimethylaminophenyl aziridine derivatives (8aek) against
B. subtilis
Entry
Observed
Calculated
Entry
Observed
Predicted
8a
8b
8c
8d
8e
8f
4.154
4.460
4.390
4.442
4.607
4.553
4.495
4.212
4.243
4.658
4.586
4.111
4.472
4.472
4.445
4.605
4.537
4.537
4.242
4.242
4.568
4.568
8a
8b
8c
8d
8e
8f
4.154
4.460
4.390
4.442
4.607
4.553
4.495
4.212
4.243
4.658
4.586
4.069
4.473
4.481
4.445
4.605
4.535
4.543
4.251
4.242
4.552
4.565
8g
8h
8i
8g
8h
8i
8j
8k
8j
8k

P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
257
IR (KBr) (cmꢁ1) 3101 (CeH three-membered ring), 3053
(]CeH, sp2), 2936 (CeH, sp3), 2369 (overtone, CO), 1762
(C]O ester), 1720 (C]O, acetyl), 1657 (C]C), 1556
(N]N), 1605, 1415, 1322 (CjC ring str.), 1262 (CeN),
Table 7
Observed versus predicted activity of 2-acetyl-2-ethoxycarbonyl-1-[4(40-ary-
lazo)-phenyl]-N,N-dimethylaminophenyl aziridine derivatives (T1eT4) for
test set
Entry
Compound
Observed
Predicted
Residuals
ꢆ
1
1101 (CeO ), 821,665 (sub. phenyl); H NMR (d ppm) 1.31
(t, 3H, CH3CH2, J ¼ 8.5 Hz), 1.91 (s, 6H, (CH3)2N), 2.10 (s,
3H, CH3CO), 2.34 (s, 3H, CH3 attached to phenyl ring),
3.01 (s, CH, aziridine ring), 3.98 (q, 2H, CH3CH2,
J ¼ 8.5 Hz), 7.26e7.73 (m, 4H, AreH attached to N]N moi-
ety), 7.80 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 112e113, yield
73%. Anal. Calcd for C28H30N4O3: C, 71.47; H, 6.43; N,
11.91. Found: C, 71.39; H, 6.39; N, 11.90.
B. subtilis
P. diminuta
E. coli
T1
T2
T3
T4
8l
4.079
4.329
4.686
4.481
4.111
4.472
4.472
4.445
ꢁ0.032
ꢁ0.143
0.214
8m
8n
8o
0.036
T1
T2
T3
T4
8l
4.121
4.378
4.421
4.591
4.089
4.418
4.418
4.393
0.032
ꢁ0.04
0.003
8m
8n
8o
0.198
T1
T2
T3
T4
8l
4.021
4.379
4.221
4.281
4.019
4.278
4.278
4.259
0.002
0.101
4.3.5. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-
methoxyphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8e]
8m
8n
8o
ꢁ0.057
0.022
S. aureus
T1
T2
T3
T4
8l
4.078
4.358
4.421
4.492
4.047
4.334
4.334
4.312
0.031
0.024
0.087
0.180
Prepared according to the general procedure as in Section
4.3.
8m
8n
8o
IR (KBr) (cmꢁ1) 3112 (CeH three-membered ring), 3044
(]CeH, sp2), 2932 (CeH, sp3), 2355 (overtone, CO), 1760
(C]O ester), 1715 (C]O, acetyl), 1646 (C]C), 1548
(N]N), 1601, 1412, 1321 (CjC ring str.), 1258 (CeN),
IR (KBr) (cmꢁ1) 3109 (CeH three-membered ring), 3052
(]CeH, sp2), 2930 (CeH, sp3), 2368 (overtone, CO), 1758
(C]O ester), 1711 (C]O, acetyl), 1651 (C]C), 1571
(N]N), 1595, 1457, 1321 (CjC ring str.), 1260 (CeN),
1098 (CeO ), 815,667 (sub. phenyl), 550 (CeCl); H NMR
(d ppm) 1.29 (t, 3H, CH3CH2, J ¼ 7.7 Hz), 1.91 (s, 6H,
(CH3)2N), 2.57 (s, 3H, CH3CO), 3.07 (s, CH, aziridine ring),
4.01 (q, 2H, CH3CH2, J ¼ 7.7 Hz), 7.40e7.93 (m, 4H, C6H5
attached to N]N moiety), 7.80 (m, 8H, 2 ꢅ CH, N-phenyl);
mp (ꢀC) 101e102, yield 67%. Anal. Calcd for C27H27ClN4O3:
C, 66.05; H, 5.54; N, 11.41. Found: C, 65.98; H, 5.48; N,
11.30.
ꢆ
1
1100 (CeO ), 818,662 (sub. phenyl); H NMR (d ppm) 1.28
(t, 3H, CH3CH2, J ¼ 9.1 Hz), 1.89 (s, 6H, (CH3)2N), 2.11 (s,
3H, CH3CO), 3.05 (s, CH, aziridine ring), 3.71 (s, 3H, Oe
CH3 attached to phenyl ring), 3.94 (q, 2H, CH3CH2,
J ¼ 9.1 Hz), 6.97e7.50 (m, 4H, C6H5 attached to N]N moi-
ety), 7.78 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 104e105, yield
62%. Anal. Calcd for C28H30N4O4: C, 69.12; H, 6.21; N,
11.51. Found: C, 69.10; H, 6.18; N, 11.48.
ꢆ
1
4.3.6. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-
carboxyphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8f]
4.3.3. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
chlorophenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8c]
Prepared according to the general procedure as in Section
4.3.
Prepared according to the general procedure as in Section
4.3.
IR (KBr) (cmꢁ1) 3510 (eOH str.), 3114 (CeH three-mem-
bered ring), 3043 (]CeH, sp2), 2934 (CeH, sp3), 2370 (over-
tone, CO), 1755 (C]O ester), 1717 (C]O, acetyl), 1710
(C]O acid), 1652 (C]C), 1566 (N]N), 1600, 1411, 1313
(CjC ring str.), 1259 (CeN), 1100 (CeOꢆ), 811,663 (sub.
phenyl); 1H NMR (d ppm) 1.28 (t, 3H, CH3CH2,
J ¼ 9.6 Hz), 1.91 (s, 6H, (CH3)2N), 2.12 (s, 3H, CH3CO),
2.99 (s, CH, aziridine ring), 4.01 (q, 2H, CH3CH2,
J ¼ 9.6 Hz), 7.67e7.99 (m, 5H, AreH attached to N]N moi-
ety), 7.78 (m, 8H, 2 ꢅ N-phenyl) 11.0 (br s, eOH str.); mp
(ꢀC) 113e114, yield 66%. Anal. Calcd for C28H28N4O5: C,
67.19; H, 5.64; N, 11.19. Found: C, 67.11; H, 5.56; N, 11.13.
IR (KBr) (cmꢁ1) 3110 (CeH three-membered ring), 3050
(]CeH, sp2), 2932 (CeH, sp3), 2366 (overtone, CO), 1755
(C]O ester), 1710 (C]O, acetyl), 1652 (C]C), 1570
(N]N), 1599, 1455, 1320 (CjC ring str.), 1261 (CeN),
ꢆ
1
1089 (CeO ), 812,665 (sub. phenyl), 556 (CeCl); H NMR
(d ppm) 1.31 (t, 3H, CH3CH2, J ¼ 7.9 Hz), 1.93 (s, 6H,
(CH3)2N), 2.55 (s, 3H, CH3CO), 3.05 (s, CH, aziridine ring),
4.05 (q, 2H, CH3CH2, J ¼ 7.9 Hz), 7.45 (d, 2H, AreHb at-
tached to N]N moiety), 7.86 (d, 2H, AreHa attached to
N]N moiety), 7.80 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 122e
124, yield 63%. Anal. Calcd for C27H27ClN4O3: C, 66.05;
H, 5.54; N, 11.41. Found: C, 66.01; H, 5.47; N, 11.39.
4.3.7. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
carboxyphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8g]
4.3.4. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-
methylphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8d]
Prepared according to the general procedure as in Section
4.3.
Prepared according to the general procedure as in Section
4.3.
IR (KBr) (cmꢁ1) 3512 (eOH str.), 3107 (CeH three-mem-
bered ring), 3041 (]CeH, sp2), 2935 (CeH, sp3), 2367 (over-
tone, CO), 1749 (C]O ester), 1715 (C]O, acetyl), 1711

258
P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
ꢆ
1258 (CeN), 1100 (CeO ), 818,662 (sub. phenyl); H NMR
1
(C]O acid), 1651 (C]C), 1563 (N]N), 1600, 1421, 1311
(CjC ring str.), 1257 (CeN), 1108 (CeOꢆ), 816,659 (sub.
phenyl); 1H NMR (d ppm) 1.26 (t, 3H, CH3CH2,
J ¼ 9.2 Hz), 1.90 (s, 6H, (CH3)2N), 2.08 (s, 3H, CH3CO),
2.97 (s, CH, aziridine ring), 3.99 (q, 2H, CH3CH2,
J ¼ 9.2 Hz), 8.30 (d, 2H, AreHb attached to N]N moiety),
8.11 (d, 2H, AreHa attached to N]N moiety), 7.82 (m, 8H,
2 ꢅ N-phenyl), 11.1 (br s, eOH str.); mp (ꢀC) 134e136, yield
60%. Anal. Calcd for C28H28N4O5: C, 67.19; H, 5.64; N,
11.19. Found: C, 67.13; H, 5.39; N, 11.11.
(d ppm) 1.28 (t, 3H, CH3CH2, J ¼ 7.8 Hz), 1.89 (s, 6H,
(CH3)2N), 2.11 (s, 3H, CH3CO), 3.05 (s, CH, aziridine ring),
3.94 (q, 2H, CH3CH2, J ¼ 7.8 Hz), 7.7e8.81 (m, 4H, AreH
attached to N]N moiety), 7.76 (m, 8H, 2 ꢅ N-phenyl); mp
(ꢀC) 105e106, yield 77%. Anal. Calcd for C27H27N5O5: C,
64.66; H, 5.43; N, 13.96. Found: C, 64.52; H, 5.39; N, 13.82.
4.3.11. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
nitrophenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8k]
4.3.8. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
hydroxyphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8h]
Prepared according to the general procedure as in Section
4.3.
Prepared according to the general procedure as in Section
4.3.
IR (KBr) (cmꢁ1) 3100 (CeH three-membered ring), 3052
(]CeH, sp2), 2934 (CeH, sp3), 2374 (overtone, CO), 1760
(C]O ester), 1719 (C]O, acetyl), 1658 (C]C), 1553
(N]N), 1600, 1412, 1320 (CjC ring str.), 1350 (NO2),
IR (KBr) (cmꢁ1) 3445 (eOH str.), 3281 (CeH three-mem-
bered ring), 3051 (]CeH, sp2), 2959 (CeH, sp3), 2373 (over-
tone, CO), 1753 (C]O ester), 1718 (C]O, acetyl), 1622
(C]C), 1529 (N]N), 1457, 1415, 1345 (CjC ring str.),
1282 (CeN), 1186 (CeOꢆ), 871,801 (sub. phenyl), 737 (e
ꢆ
1
1261 (CeN), 1100 (CeO ), 819,668 (sub. phenyl); H NMR
(d ppm) 1.29 (t, 3H, CH3CH2, J ¼ 8.9 Hz), 1.92 (s, 6H,
(CH3)2N), 2.14 (s, 3H, CH3CO), 3.05 (s, CH, aziridine ring),
4.06 (q, 2H, CH3CH2, J ¼ 7.8 Hz), 7.71 (d, 2H, AreHb at-
tached to N]N moiety), 7.98 (d, 2H, AreHa attached to
N]N moiety), 7.79 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 105e
106, yield 77%. Anal. Calcd for C27H27N5O5: C, 64.66; H,
5.43; N, 13.96. Found: C, 64.52; H, 5.38; N, 13.84.
1
CH2); H NMR (d ppm) 1.27 (t, 3H, CH3CH2, J ¼ 8.7 Hz),
1.84 (s, 6H, (CH3)2N), 2.55 (s, 3H, CH3CO), 3.06 (s, CH, azir-
idine ring), 3.39 (q, 2H, CH3CH2, J ¼ 8.7 Hz), 6.91 (d, 2H,
AreHb attached to N]N moiety), 7.74 (d, 2H, AreHa at-
tached to N]N moiety), 7.238 (m, 8H, 2 ꢅ N-phenyl),
12.78 (br s, eOH str.); mp (ꢀC) 112e113, yield 73%. Anal.
Calcd for C27H28N4O4: C, 68.63; H, 5.97; N, 11.86. Found:
C, 68.52; H, 5.91; N, 11.72.
4.3.12. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-
bromophenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8l]
Prepared according to the general procedure as in Section
4.3.
4.3.9. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-
hydroxyphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8i]
Prepared according to the general procedure as in Section
4.3.
IR (KBr) (cmꢁ1) 3110 (CeH three-membered ring), 3051
(]CeH, sp2), 2928 (CeH, sp3), 2361 (overtone, CO), 1754
(C]O ester), 1710 (C]O, acetyl), 1649 (C]C), 1570
(N]N), 1591, 1454, 1320 (CjC ring str.), 1256 (CeN),
ꢆ
1
IR (KBr) (cmꢁ1) 3441 (eOH str.), 3278 (CeH three-mem-
bered ring), 3046 (]CeH, sp2), 2951 (CeH, sp3), 2368 (over-
tone, CO), 1751 (C]O ester), 1715 (C]O, acetyl), 1621
(C]C), 1526 (N]N), 1455, 1411, 1341 (CjC ring str.),
1281 (CeN), 1181 (CeOꢆ), 862,811 (sub. phenyl), 735 (e
1094 (CeO ), 811,661 (sub. phenyl), 570 (CeBr); H NMR
(d ppm) 1.27 (t, 3H, CH3CH2, J ¼ 7.7 Hz), 1.90 (s, 6H,
(CH3)2N), 2.54 (s, 3H, CH3CO), 3.04 (s, CH, aziridine ring),
4.01 (q, 2H, CH3CH2, J ¼ 7.6 Hz), 7.37e7.83 (m, 4H, C6H5 at-
tached to N]N moiety), 7.74 (m, 8H, 2 ꢅ CH, N-phenyl); mp
(ꢀC) 114e115, yield 66%. Anal. Calcd for C27H27BrN4O3: C,
66.57; H, 5.08; N, 10.46. Found: C, 66.51; H, 5.04; N, 10.39.
1
CH2); H NMR (d ppm) 1.25 (t, 3H, CH3CH2, J ¼ 8.8 Hz),
1.81 (s, 6H, (CH3)2N), 2.52 (s, 3H, CH3CO), 2.99 (s, CH, azir-
idine ring), 5.34 (q, 2H, CH3CH2, J ¼ 8.8 Hz), 6.91e7.41 (m,
5H, AreH attached to N]N moiety), 7.214 (m, 8H, 2 ꢅ N-
phenyl), 12.80 (br s, eOH str.); mp (ꢀC) 123e124, yield
75%. Anal. Calcd for C27H28N4O4: C, 68.63; H, 5.97; N,
11.86. Found: C, 68.49; H, 5.88; N, 11.80.
4.3.13. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
bromophenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8m]
Prepared according to the general procedure as in Section
4.3.
4.3.10. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(300-
nitrophenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8j]
Prepared according to the general procedure as in Section
4.3.
IR (KBr) (cmꢁ1) 3101 (CeH three-membered ring), 3047
(]CeH, sp2), 2932 (CeH, sp3), 2365 (overtone, CO), 1760
(C]O ester), 1715 (C]O, acetyl), 1646 (C]C), 1548
(N]N), 1601, 1412, 1321 (CjC ring str.), 1345 (NO2),
IR (KBr) (cmꢁ1) 3112 (CeH three-membered ring), 3048
(]CeH, sp2), 2929 (CeH, sp3), 2364 (overtone, CO), 1753
(C]O ester), 1712 (C]O, acetyl), 1651 (C]C), 1568
(N]N), 1597, 1451, 1322 (CjC ring str.), 1262 (CeN),
1088 (CeO ), 814,662 (sub. phenyl), 568 (CeBr); H NMR
(d ppm) 1.25 (t, 3H, CH3CH2, J ¼ 7.9 Hz), 1.91 (s, 6H,
(CH3)2N), 2.53 (s, 3H, CH3CO), 3.03 (s, CH, aziridine ring),
4.01 (q, 2H, CH3CH2, J ¼ 7.9 Hz), 7.44 (d, 2H, AreHb at-
tached to N]N moiety), 7.81 (d, 2H, AreHa attached to
ꢆ
1

P. Sharma et al. / European Journal of Medicinal Chemistry 44 (2009) 251e259
259
N]N moiety), 7.84 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 121e
Acknowledgement
122, yield 63%. Anal. Calcd for C27H27BrN4O3: C, 66.57;
H, 5.08; N, 10.46. Found: C, 66.52; H, 5.02; N, 11.41.
We are grateful to Central Drug Research Institute, Luck-
now, India for providing spectroanalytical facilities and one
of the authors (V.S.) is thankful to Council of Scientific and
Industrial Research, New Delhi for providing financial
assistance.
4.3.14. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
methoxyphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8n]
Prepared according to the general procedure as in Section
4.3.
References
IR (KBr) (cmꢁ1) 3111 (CeH three-membered ring), 3041
(]CeH, sp2), 2930 (CeH, sp3), 2351 (overtone, CO), 1757
(C]O ester), 1711 (C]O, acetyl), 1641 (C]C), 1543
(N]N), 1600, 1411, 1321 (CjC ring str.), 1251 (CeN),
1100 (CeO ), 813,659 (sub. phenyl); H NMR (d ppm) 1.26
(t, 3H, CH3CH2, J ¼ 9.1 Hz), 1.88 (s, 6H, (CH3)2N), 2.12 (s,
3H, CH3CO), 3.01 (s, CH, aziridine ring), 3.67 (s, 3H, Oe
CH3 attached to phenyl ring), 3.92 (q, 2H, CH3CH2,
J ¼ 9.1 Hz), 6.95e7.47 (m, 4H, C6H5 attached to N]N moi-
ety), 7.76 (m, 8H, 2 ꢅ N-phenyl); mp (ꢀC) 101e102, yield
61%. Anal. Calcd for C28H30N4O4: C, 69.12; H, 6.21; N,
11.51. Found: C, 68.89; H, 6.15; N, 11.47.
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4.3.15. 2-Acetyl-2-ethoxycarbonyl-1-{4-[40(400-
methylphenyl)azo]phenyl}-3-N,N-dimethylaminophenyl
aziridine [8o]
Prepared according to the general procedure as in Section
4.3.
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IR (KBr) (cmꢁ1) 3100 (CeH three-membered ring), 3051
(]CeH, sp2), 2941 (CeH, sp3), 2362 (overtone, CO), 1761
(C]O ester), 1715 (C]O, acetyl), 1656 (C]C), 1553
(N]N), 1601, 1413, 1321 (CjC ring str.), 1261 (CeN),
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Cancer Chemotherapeutic Agents, American Chemical Society, Wash-
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ꢆ
1
1102 (CeO ), 815,661 (sub. phenyl); H NMR (d ppm) 1.32
(t, 3H, CH3CH2, J ¼ 8.5 Hz), 1.89 (s, 6H, (CH3)2N), 2.11 (s,
3H, CH3CO), 2.31 (s, 3H, CH3 attached to phenyl ring),
3.04 (s, CH, aziridine ring), 3.92 (q, 2H, CH3CH2,
J ¼ 8.5 Hz), 6.98 (d, 2H, AreHb attached to N]N moiety),
7.47 (d, 2H, AreHa attached to N]N moiety), 7.78 (m, 8H,
2 ꢅ N-phenyl); mp (ꢀC) 114e115, yield 71%. Anal. Calcd
for C28H30N4O3: C, 71.47; H, 6.43; N, 11.91. Found: C,
71.45; H, 6.38; N, 11.89.
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successfully synthesized in appreciable yields and screened
in vitro for their antimicrobial activities against both strains
of Gram-positive and Gram-negative bacteria. Moreover, mo-
lar refractivity and polarizability parameters were the main
governing physicochemical factors for the displayed antimi-
crobial activities of these synthesized compounds. Such
a QSAR evaluation would open future perspectives to use
these compounds as new lead compounds in clinical trials.
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