Studies on synthesis and evaluation of quantitative structure-activity relationship of 5-[(3′-chloro-4′,4′-disubstituted-2- oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphospholo[1,5-a] pyridin-1-yl-phosphorus dichlorides

Article abstract of DOI:10.1016/j.bmcl.2004.12.050

A new series of 5-[(3′-chloro-4′,4′-disubstituted-2- oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphospholo[1,5-a] pyridin-1-yl-phosphorus dichlorides has been synthesized and subjected to acute antibacterial and antifungal screening studies. All the derivatives belonging to this series delineated remarkable activity as compared to standard drugs (ampicillin and clotrimazole). Compounds are quantitatively analyzed in relation to their different physicochemical parameters. Significant correlations were obtained between biological activity and polarizability parameter (MR).

Full text of DOI:10.1016/j.bmcl.2004.12.050

Bioorganic & Medicinal Chemistry Letters 15 (2005) 937–943
Studies on synthesis and evaluation of quantitative
structure–activity relationship of 5-[(30-chloro-40,40-disubstituted-
2-oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]-
azaphospholo[1,5-a]pyridin-1-yl-phosphorus dichlorides
Pratibha Sharma,* Ashok Kumar, Shikha Sharma and Nilesh Rane
School of Chemical Sciences, Devi Ahilya University, Takshila Campus, Khandwa Road, Indore 452 017, India
Received 28 October 2004; revised 16 December 2004; accepted 17 December 2004
Available online 20 January 2005
Abstract—A new series of 5-[(30-chloro-40,40-disubstituted-2-oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphos-
pholo[1,5-a]pyridin-1-yl-phosphorus dichlorides has been synthesized and subjected to acute antibacterial and antifungal screening
studies. All the derivatives belonging to this series delineated remarkable activity as compared to standard drugs (ampicillin and
clotrimazole). Compounds are quantitatively analyzed in relation to their different physicochemical parameters. Significant correl-
ations were obtained between biological activity and polarizability parameter (MR).
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
can eradicate this problem easily. Based on these facts
and in continuation of our interest in developing simple
and efficient route for the synthesis of heterocycles,13–16
it was aimed to compose an elegant synthetic route
for condensed system containing both indolizine and
azetidine nuclei. We report herein the synthesis and
studies on biological evaluation of 5-[(30-chloro-40,40-
disubstituted-2-oxoazetidinyl)(N-nitro)amino]-6-hydroxy-
3-alkyl/aryl[1,3]azaphospholo[1,5-a]pyridin-1-yl-phos-
phorus dichlorides.
Indolizines and azetidines, the nitrogen containing het-
erocyclic systems, have been widely distributed in nat-
ure. In particular, indolizines have been the subject of
substantial attention by chemists due to their biological
properties such as antifungal,1 antimycobacterial,2 anti-
herpes3 and antineociceptive.4 The other well-known
pharmacological applications associated with this ring
compounds are well documented in the literature.5,6
This nucleus acts as the prototype molecule for the large
class of azolozines particularly, aza-indolizine. Likewise,
compounds containing azetidine ring are present in
many drugs exhibiting potent analgesics7 and antiviral
activities.8,9 Recent discoveries had also displayed other
pharmacological profile of these compounds.10 These
findings had led to a spate of synthetic studies of various
azetidine analogues.11,12
2. Chemistry
Initially, 1,3-disubstituted-propane-1,3-dione[(3-hydroxy-
pyridin-2-yl)hydrazones] 1a–r was prepared from
2-amino-3-hydroxypyridine under diazotization condi-
tions using hydrobromic acid according to the
reported17 procedure modified by us. Compounds 1a–r
were nitrated to provide yellowish crystals of N-pro-
tected derivatives, that is, 1,3-disubstituted 2[(3-
hydroxypyridin-2-yl)(N-nitro)hydrazono]propane-1,3-
diones 2a–r. It was then added to a constantly stirred
solution of 1,4-dioxan, triethylamine and chloroacetyl-
chloride to give disubstituted-3-chloro-1-[(3-hydroxy-
pyridin-2-yl)(N-nitro)amino]-4-oxoazetidine-2,2-dicarb-
oxylates 3a–r. Furthermore, treatment of 3a–r with a
pertinent alkyl/aryl halide and phosphorus trichloride
Although, a number of antimicrobial agents have been
developed in order to resist various pathogenic mi-
crobes, but still there is a lack of an ideal drug, which
Keywords: Indolizine; Azetidine; Synthesis; Antibacterial; Antifungal;
QSAR; Molar refractivity.
*
Corresponding author. Tel.: +917234160208; fax: +91
7312470372; e-mail: drpratibhasharma@yahoo.com
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.050

938
P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
resulted in the formation of a ylide as an intermediate,
which on treatment with phosphorus trichloride and
acetonitrile in presence of triethylamine yielded 5-[(30-
chloro-40,40-disubstituted-2-oxoazetidinyl)(N-nitro)ami-
no]-6-hydroxy-3-alkyl/aryl[1,3]azaphospholo[1,5-a]pyr-
idin-1-yl-phosphorus dichlorides 4a–r.
to show least to moderate activity on the growth of A.
niger. The pattern followed by tested compounds is
shown below:
S: aureus > B: subtilis > C: albicans > A: niger
3.1. QSAR analysis
In order to deduce the correlation of observed activity,
expressed in terms of MIC of reported compounds with
different structural parameters, systematic QSAR inves-
tigations have been carried out using the linear free en-
ergy relationship (LFER) model proposed by Hansch
and Leo.18
3. Biological activities
The in vitro antimicrobial activity of the 5-[(30-chloro-
40,40-disubstituted-2-oxoazetidinyl)(N-nitro)amino]-6-
hydroxy-3-alkyl/aryl[1,3]azaphospholo[1,5-a]pyridin-1-
yl-phosphorus dichlorides were investigated against
several representative pathogenic bacteria and fungi.
Nutrient agar media and saboured dextrose agar was
employed for bacterial and fungal growth, respectively.
Inocula containing approximately 107 CFUs/mL of bac-
teria and 106 CFUs/mL of fungi were prepared from
broth culture in log phase. Bacterial and fungal plate
was incubated at 37 ꢁC for 24 h for bacteria and 30 ꢁC
for 28 h for fungi. Four microbial strains including
Bacillus subtilis ATCC 6633, Staphylococcus aureus
ATCC 2943 as bacteria and Aspergillus niger ATCC
16404, Candida albicans ATCC10231 as fungus were
used in antimicrobial assay. Ampicillin and clotrimazole
were also screened under similar conditions as reference
antibacterial and antifungal drug, respectively. All the
synthesized compounds delineate profound antimicro-
bial potency on both bacteria and fungi as compared
to reference drugs, which is further supported by biologi-
cal investigations shown in Table 1. The screening
results reveals that reported compounds showed a
remarkable effect on the bacteriocidal/bacterostatic
potency. However, these compounds have been found
1
log ¼ k1a þ k2b þ k3
C
where C is molar dose that produces or prevents certain
biological response, a and b are the descriptors to be
investigated and k1, k2, k3 are the constants.
The activity data, MIC represents the minimal concen-
tration of compounds that inhibits visible growth. The
same are further expressed as ÀlogMIC on molar basis
and used as dependent variables to get linear relation-
ship in QSAR model. The calculated parameters used
in present studies include molar refractivity (MR), Van
der Waals volume (VDW), connolly accessible area
(CAA), connolly molecular area (CMA), connolly
solvent excluded area (CSEV), dipole–dipole energy
(DDENE), partition coefficient (PC). The above-men-
tioned parameters were calculated by using Chem 3D
6.0 software.19 Further, HOMO and LUMO energies
were calculated by semiempirical PM320 studies using
MOPAC 6.0 package.21 Some indicator variables were
Table 1. The in vitro antimicrobial activity of 5-[(30-chloro-40,40-disubstituted-2-oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphos-
pholo[1,5-a]pyridin-1-yl-phosphorus dichlorides 4a–r
Compound
R
R0
R00
ÀlogMIC (lg/mL)
Bacteria
Fungi
SA
BS
CA
AN
4a
4b
4c
4d
4e
4f
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
COOH
C6H5
C6H5
OC2H5
OC2H5
OCH3
OC2H5
NHC6H5
C6H5
CH3
C6H5
CH2Br
OC2H5
OCH3
CH3
4.980
4.367
4.304
4.147
4.179
4.549
4.870
4.246
4.201
4.107
4.115
4.406
4.745
4.191
4.128
4.036
4.043
4.373
4.649
4.171
4.109
4.020
4.034
4.342
CH3
CH3
4g
4h
4i
6
4.4514.31 4.262
4.063
4.208
4.250
CH3
4.045
4.154
4.067
4.008
4.083
4.016
3.972
4.073
4.000
CN
CH3
OC2H5
OCH3
CH2Br
OC2H5
CH3
4j
4.114
4k
4l
OC2H5
OC2H5
OC2H5
NHC6H5
C6H5
CH3
4.8814.794
4.689
4.703
4.6314.578
C6H5
C6H5
4.599
4.606
5.037
4.902
4.256
4.502
4.527
4.970
4.850
4.193
4.441
4.460
4.773
4.691
4.181
4m
4n
4o
4p
4q
4r
A
C6H5
C6H5
CH3
CH3
5.116
5.106
C6H5
C6H5
CH3
4.399
4.566
CN
CH3
OC2H5
OCH3
—
4.4914.408
4.372
C6H5
—
—
4.4714.3414.267
3.907
—
4.254
—
—
4.606
—
—
3.139
—
3.236
C
—
SA = S. aureus; BS = B. subtilis; CA = C. albicans; AN = A. niger; A = ampicillin; C = clotrimazole.

P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
939
also used to describe the effect of specific binary altera-
tions such as presence of –COOH (IN1) and –C6H5
(IN2).
mentioning that no outliers have been detected and the
equations were derived using the entire data set (n = 18).
QSAR model for S. aureus
All the calculated parameters were first subjected to cor-
relation studies and only those parameters considered
further with intercorrelation <0.5, depending on their
individual correlation with biological activity. The best
fit between ÀlogMIC values and these explaining
parameters were obtained through multiple regression
analysis (MRA) employing the method of least square
using VALSTAT software.22 Calculated parameters
and correlation matrix needed for MRA is shown in
Tables 2 and 3.
À log MIC ¼ ½1:4216ðÆ0:328851Þꢀ
þ MR ½0:228041ðÆ0:0241034Þꢀ
n ¼ 18; r2 ¼ 0:962; s ¼ 0:068; F ¼ 406:477
ð1Þ
QSAR model for B. subtilis
À log MIC ¼ ½1:56255ðÆ0:383329Þꢀ
þ MR ½0:210531ðÆ0:0280963Þꢀ
n ¼ 18; r2 ¼ 0:938; s ¼ 0:079; F ¼ 254:977
ð2Þ
Only, molar refractivity exhibited (r2 > 0.95) a good
correlation with biological activity (Table 3). The statis-
tical quality of the resulting models, as depicted in Eqs.
1–4, is determined by r2 (coefficient of determination), s
(standard error of estimate), F (F-statistics). It is worth
Table 2. Values of descriptors calculated for 5-[(30-chloro-40,40-disubstituted-2-oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphos-
pholo[1,5-a]pyridin-1-yl-phosphorus dichlorides 4a–r
Compound
HOMO
LUMO
VDW
DDENE
PC
3.456
CSEV
CMA
CAA
MR
IN1IN2
4a
4b
4c
4d
4e
4f
À9.198
À9.341
À9.337
À9.357
À9.344
À9.186
À9.235
À9.287
À9.433
À9.356
À8.512
À8.601
À8.575
À8.965
À8.834
À8.704
À8.669
À8.717
À9.337
À8.956
À1.592
À1.702
À1.704
À1.720
À1.707
À1.569
À1.620
À1.663
À1.787
À1.716
À1.029
À1.262
À2.044
À1.533
À1.478
À1.323
À1.367
À1.339
À0.827
À0.228
8.606
5.241
8.679
12.522
23.562
23.828
23.700
19.515
3.543
436.444
383.819
384.103
349.299
359.136
398.978
386.834
336.285
361.607
342.607
446.627
460.477
452.818
450.559
465.652
420.085
417.145
411.407
280.439
285.356
449.403
390.942
410.083
369.095
376.871
403.948
402.233
352.242
374.047
356.737
435.674
444.276
431.799
452.654
397.882
372.68
768.382
677.648
717.713
649.029
659.563
695.953
693.863
617.191
694.692
623.714
730.893
741.482
726.599
758.411
659.709
636.698
724.031
660.928
555.251
538.175
15.541
12.840
12.680
11.753
12.063
13.863
13.494
11.447
12.077
11.600
14.793
14.633
14.716
15.933
15.564
13.399
14.325
13.552
9.144
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
—
—
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
—
—
1.533
2.029
0.971
1.280
1.756
1.993
0.530
0.577
0.750
3.725
4.221
3.613
2.687
4.471
2.722
1.408
2.943
À1.204
5.254
7.483
5.068
2.037
5.734
4g
4h
4i
11.594
10.786
33.917
19.410
20.009
16.280
14.544
10.247
5.7062
10.312
23.404
13.247
0.675
2.714
4.950
4.510
4j
4k
4l
12.019
14.941
12.303
11.222
11.927
7.849
4m
4n
4o
4p
4q
4r
A
12.5969
10.171
7.445
422.921
386.837
304.619
295.911
C
14.212
2.072
10.395
A = ampicillin; C = clotrimazole.
Table 3. Correlation matrix of molecular descriptor calculated for 4a–r
SA
BS
CA
AN
MR
HOMO LUMO VDW DDENE PC
CSEV CMA CAA IN1IN2
SA
BS
1.000
0.993 1.000
0.993 0.996 1.000
CA
AN
0.996 0.996 0.995 1.000
0.9810.970 0.970 0.984 .0010
MR
HOMO
LUMO
VDW
0.586 0.579 0.557 0.594 0.659 1.000
0.388 0.378 0.344 0.3810.397 0.600
0.663 0.677 0.649 0.664 0.704 0.806
.0010
0.442
0.201
1.000
0.014
DDENE 0.464 0.419 0.465 0.454 0.472 0.299
1.000
0.458 .0010
PC
0.825 0.793 0.778 0.8010.835 0.744
0.915 0.896 0.888 0.910 0.949 0.804
0.223 0.208 0.206 0.195 0.148 0.087
0.153 0.179 0.135 0.165 0.163 0.140
0.342 0.356 0.329 0.342 0.338 0.124
0.501 0.483 0.505 0.500 0.578 0.775
0.447
0.765
CSEV
CMA
CAA
IN1
0.454
0.096
0.104
0.031
0.302
0.815
0.055
0.104
0.023
0.730
0.411
0.292
0.071
0.128
0.330
0.929 1.000
0.398 0.185
0.009 0.023
0.233 0.189
0.578 0.694
1.000
0.044 1.000
0.173 0.848 1.000
0.163 0.342 0.197
IN2
1

940
P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
5.2
4.8
4.6
4.4
4.2
4.0
5.0
4.8
4.6
4.4
4.2
4.0
4.0
4.2
4.4
4.6
4.8
5.0
5.2
4.0
4.2
4.4
4.6
4.8
CALCULATED
CALCULATED
5.2
5.0
4.8
4.6
4.4
4.2
4.0
4.8
4.6
4.4
4.2
4.0
4.0
4.2
4.4
4.6
4.8
5.0
5.2
4.0
4.2
4.4
4.6
4.8
PREDICTED
PREDICTED
Figure 2. Plots of observed versus calculated and observed versus
predicted activity of 4a–r against A. niger (Eq. 4).
Figure 1. Plots of observed versus calculated and observed versus
predicted activity of 4a–r against S. aureus (Eq. 1).
QSAR model for C. albicans
The F-value obtained in Eqs. 1–4 are found statisti-
cally significant at >99.90% level since all the calculated
F value are far higher as compared to tabulated value,
À log MIC ¼ ½1:61463ðÆ0:369476Þꢀ
þ MR ½0:20129ðÆ0:027081Þꢀ
n ¼ 18; r2 ¼ 0:940; s ¼ 0:076; F ¼ 250:889
ð3Þ
that is, F1,16a0.001 = 16.1. Similarly, cross validation of
obtained equations were subsequently checked by
employing the LOO method and calculation of all the
related cross-validation parameters viz. PRESS (pre-
dicted residual sum of the square), SPRESS (uncertainty
of prediction), SDEP (standard error of prediction),
r2CV (cross-validated correlation coefficient) and r2bsp
(bootstrapping r2). The calculated and predicted activi-
ties of the synthesized compounds were in good accor-
dance with the observed activities as shown in Figures
1,2.
QSAR model for A. niger
À log MIC ¼ ½1:95319ðÆ0:229365Þꢀ
þ MR ½0:172809ðÆ0:0168114Þꢀ
n ¼ 18; r2 ¼ 0:968; s ¼ 0:047; F ¼ 479:831
ð4Þ
Table 4. Cross-validation parameters
Eq.
Compds used
PRESS
SSY
PRESS/SSY
SPRESS
SDEP
r2
r2
bsp
CV
1
2
3
4
18
18
18
18
0.0934
0.1269
0.1237
0.0453
1.9236
1.6764
1.5334
1.0982
0.0486
0.0757
0.0807
0.0413
0.0765
0.0891
0.0879
0.0532
0.0721
0.0840
0.829
0.9514
0.9243
0.9193
0.9587
0.9525
0.9377
0.9375
0.9596
0.0502

P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
941
PRESS is a good estimate of the real prediction error of
the model. Its value less than SSY indicate that the pro-
posed model has good predictive power and is better
than chance. In this regard, all the four models proposed
by us (Eqs. 1–4) are statistically significant. Further,
to be a reasonable QSAR model PRESS/SSY ratio
should be smaller than 0.4, and its value smaller than
0.1indicates an excellent model. The data pertaining
to Table 4 indicate that for all the four proposed models
this ratio is ꢁ0.1suggesting all of them to be excellent
model. Moreover, the value of cross-validated correla-
tion coefficient (r2CV) and bootstrapping r2 are further
supporting the predictive power of these explaining
models (Eqs. 1–4).
Since, molar refractivity accounts for the polarizability
and thus for the size and polarity of the groups as
indicated by Eqs. 1–4, suggesting that MR plays a
significant role towards the expressed biological
activities, which is possible due to steric interactions
occurring in polar spaces. It can be suggested that the
presence of –COOH group at C-3 of indolizine nucleus
further increases the inhibitory action on the growth
of tested panel of bacteria and fungi as revealed by
Table 1.
4. Experimental
All the chemicals used are of analytical grade. Melting
points were taken in open capillary tubes using an
electric melting point apparatus. All the melting
points reported are uncorrected. 1H NMR spectra
were recorded at 300 MHz with a Bruker advance
DRX 300 instrument using TMS as an internal
stranded. IR spectra were run on a Perkin Elmer model
377-spectrophotometer using KBr pellets. Analytical
thin layer chromatography was performed using
E. Merck Silica gel a 0.50 mm plate (Merck no.
5700).
4.1. Synthesis of disubstituted-3-chloro-1-[(3-hydroxy-
pyridin-2-yl)(N-nitro)amino]-4-oxoazetidine-2,2-dicarb-
oxylates (3a–r)
2-Amino-3-hydroxypyridine (2.2 g, 0.02 M) was diazo-
tized by hydrobromic acid using different active methyl-
ene compound (0.02 M) as per the procedure reported17
and modified by us to give 1,3-disubstituted propane
1,3-dione[(3-hydroxypyridin-2-yl)hydrazones] 1a–r. In a
250 cm3 round-bottom flask, 3-disubstituted propane
2,4-dione[(3-hydroxypyridin2-yl)hydrazone] 1a–r (0.02
M), was taken and subjected to nitration to give
1,3-disubstituted
2[(3-hydroxypyridin-2-yl)(N-nitro)-
hydrazono]propane-1,3-diones 2a–r. To this, triethyl-
amine (2.4 mL, 0.02 M), chloroacetyl chloride (1mL,
0.02 M) and measured quantity of 1,4-dioxane (50 mL)
were added and all the contents were stirred for 4 h
to afford disubstituted-3-chloro-1-[(3-hydroxypyridin-
2-yl)(N-nitro)amino]-4-oxoazetidine-2,2-dicarboxylates
3a–r.

942
P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
4.2. Synthesis of 5-[(30-chloro-40,40-disubstituted-2-
oxoazetidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/
aryl[1,3]azaphospholo[1,5-a]pyridin-1-yl-phosphorus
dichlorides (4a–r)
hydrofuran (25 mL) was added. All the contents were
stirred for 30 min at room temperature and resulted in
the formation of a solid compound. It was then washed
with diethyl ether (10 mL), filtered and dried in vacuum.
The resultant compound (0.01M) thus obtained was
then suspended in acetonitrile (20 mL) in a beaker and
cooled to 0–5 ꢁC. To this, triethylamine (4 mL,
0.04 M) was added and the mixture was stirred for
30 min. Further, a solution of phosphorus trichloride
(0.02 M) in acetonitrile (1mL) was added dropwise.
The reaction mixture gradually changes from pale yel-
low to brown and allowed to stand at room temperature
for 30 min and then stirred further for 10 h. The
compounds 5-[(30-chloro-40,40-disubstituted-2-oxoaze-
tidinyl)(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]aza-
Disubstituted-3-chloro-1-[(3-hydroxypyridin-2-yl)(N-ni-
tro)amino]-4-oxoazetidine-2,2-dicarboxylates 3a–r (0.01
M) was taken in 250 cm3 round-bottom flask and an
equimolar quantity of a solution of an alkylating agent
viz. benzyl chloride, monochloroacetic acid in tetra-
O
OH
R'
N
NH
R"
phospholo[1,5-a]pyridin-1-yl-phosphorus
dichlorides
N
O
(4a–r) obtained were recrystallized from methanol.
Structures of all the synthesized compounds have been
ascertained on the basis of consistent physical and spec-
troanalytical data (Table 5). Synthetic pathway of all
sequential steps is depicted in Scheme 1.
1a-r
(i)
O
O
OH
R'
Conclusively, a series of compounds incorporating
azetidine and phosphaindolizine heterocyclic nuclei
viz., 5-[(30-chloro-40,40-disubstituted-2-oxoazetidinyl)-
(N-nitro)amino]-6-hydroxy-3-alkyl/aryl[1,3]azaphospho-
lo[1,5-a]pyridin-1-yl-phosphorus dichlorides has been
synthesized as potent antimicrobial agents. Further-
more, QSAR studies performed on these compounds
have revealed that the substitution of bulky group with
higher polarizability probably enhances the potency of
these compounds as antibacterial and antifungal agents.
Influence of other substituents at this site will be the
matter of further investigation.
N
N
R"
N
NO2
2a-r
(ii)
OH
R'
NO2
N
O
R"
N
N
O
O
Cl
3a-r
(iii)
References and notes
1. Akinori, K.; Tastuya, N.; Koizumi, K.; Yoshiyasu, K.;
Naoki, S. Heterocycles 1996, 42, 195.
2. Gundersen, L. L.; Negussie, A. H.; Rise, F.; Ostby, O. B.
Arch. Pharm. 2003, 336, 191.
3. Foster, C.; Ritchie, M.; Selwood, D. I.; Snowden, W.
Antiviral. Chem. Chemother. 1995, 6, 289.
4. Vaught, V. L.; Carson, J. R.; Carmosin, R. J.; Blum, P. S.;
Perisco, F. J.; Hageman, W. E.; Shank, R. P.; Raffa, R. B.
J. Pharmacol. Exp. Ther. 1990, 255, 1 .
5. Coutre, A.; Deniau, E.; Grandclaudon, P.; Leburn, S.;
Leonce, S.; Renard, P.; Pfeiffer, B. Bioorg. Med. Chem.
2000, 8, 2113.
OH
R'
Cl
NO2
O
R"
N
N
+
N
O
+
H2C
H
C
2
O
Cl -
R
Cl2P
6. Jorgenson, A. S.; Jacobson, P.; Chirstiansen, L. B.; Bury,
P. S.; Kanstrup, A.; Throp, S. M.; Bain, S.; Naerum, L.;
Wassermann, K. Bioorg. Med. Chem. Lett. 2000, 10, 399.
7. Holladay, M. W.; Bai, H.; Li, Y.; Lin, N. H.; Daanen, J.
F.; Ryther, K. B.; Wasicak, J. T.; Kincaid, J. F.; He, Y.;
Hettinger, A. M. Bioorg. Med. Chem. Lett. 1998, 8, 2797.
8. Nishiyama, S.; Kikuchi, Y.; Kurata, H.; Yamamura, S.;
Izawa, T.; Nagahata, T.; Ikeda, R.; Kato, K. Bioorg. Med.
Chem. Lett. 1995, 5, 2273.
9. Hosono, F.; Nishiyama, S.; Yamamura, S.; Izawa, T.;
Kato, K.; Terada, Y. Tetrahedron 1994, 50, 1335.
10. Cheng, Q.; Kiyota, H.; Yamaguchi, M.; Horiguchi, M.;
Oritani, T. Bioorg. Med. Chem. Lett. 2003, 13, 1075.
11. Smaele, D. D.; Dejaegher, Y.; Duvey, G.; Kimpe, N. D.
Tetrahedron Lett. 2001, 42, 2373.
(iv)
OH
R'
NO2
N
O
R"
N
N
O
Cl2P
R
O
P
Cl
4a-r
Scheme 1. Reagents and conditions: (i) HNO3/H2SO4, 0–5 ꢁC; (ii)
(C2H5)3N, 1,4-dioxane, ClCOCH2Cl, stirring, 4 h; (iii) RX, THF, PCl3;
(iv) CH3CN, PCl3, (C2H5)3N, stirring, 10 h.

P. Sharma et al. / Bioorg. Med. Chem. Lett. 15(2005) 937–943
943
12. Barrett, A. J. M.; Dozzo, P.; White, A. J. P.; Williams,
D. J. Tetrahedron 2002, 58, 7303.
13. Sharma, P.; Sharma, S.; Rane, N. Bioorg. Med. Chem.
2004, 12, 3135.
14. Sharma, P.; Rane, N.; Gurram, V. K. Bioorg. Med. Chem.
Lett. 2004, 14, 4185.
18. Hansch, C.; Leo, A. Exploring QSAR, Fundamentals and
Applications in Chemistry and Biology; ACS: Washington,
DC, 1995.
19. Software Chem 3D 6.0, CambridgeSoft Corporation, 100
Cambridge Park, MA 02140-2317, USA www.
cambridgesoft.com.
15. Sharma, P.; Kumar, A.; Mandloi, A. Synth. Commun.
2003, 33, 3.
16. Sharma, P.; Kumar, A.; Pandey, P. Phosphorus Sulfur
Silicon 2003, 178, 583.
17. Sharma, P.; Kumar, A.; Sharma, S. Indian J. Chem. 2004,
43B, 385.
20. Stewart, J. J. P. J. Comput. Chem. 1991, 12, 320.
21. Stewart, J. J. P. MOPAC 6.0. QCPE 455; Indiana
University: Bloomington, IN 47405, 1990.
22. Valstat software developed at department of pharmacy, Shri
Govindram Sekseria Institute of Technology and Sciences,
23, Park Road, Indore 452 017, Madhya Pradesh, India.