QSAR analysis of 2-oxo-1,2,3,4-tetrahydropyrimidine analogues of antibacterials

Article abstract of DOI:10.1135/cccc2009054

QSAR analysis of two sets of analogues of 2-oxo-1,2,3,4- tetrahydropyrimidine was performed to investigate the relationship between their physicochemical parameters and antibacterial activity. Predictive and statistically significant models were generated

Full text of DOI:10.1135/cccc2009054

QSAR Analysis
1361
QSAR ANALYSIS OF 2-OXO-1,2,3,4-TETRAHYDROPYRIMIDINE
ANALOGUES OF ANTIBACTERIALS
a,
b
Ramesh L. SAWANT * and Manish S. BHATIA
a
Department of Pharmaceutical Chemistry,
Pd. Dr. Vithalrao Vikhe Patil Foundation’s College of Pharmacy,
Vilad Ghat, Post-MIDC, Ahmednagar-414111, Maharashtra, India; e-mail: sawantrl@yahoo.com
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy,
Near Chitranagari, Kolhapur-416013, Maharashtra, India; e-mail: drmsb13@yahoo.com
b
Received April 18, 2009
Accepted Jun e 22, 2009
Publish ed on lin e Septem ber 16, 2009
QSAR an alysis of two sets of an alogues of 2-oxo-1,2,3,4-tetrah ydropyrim idin e was perform ed
to in vestigate th e relation sh ip between th eir ph ysicoch em ical param eters an d an tibacterial
activity. Predictive an d statistically sign ifican t m odels were gen erated. On th e basis of th ese
m odels n ew com poun ds were syn th esized, structurally ch aracterized an d evaluated for th eir
an tibacterial poten tial. Th e poten tial of n ewly syn th esized com poun ds was h igh er th an th e
train in g set of com poun ds, in close agreem en t with QSAR prediction .
Keyw ord s: QSAR; 2-Oxo-1,2,3,4-tetrah ydropyrim idin e; An tibacterial activity; Electron ic fea-
tures; Steric features.
Microbial in fection s are th e m ost com m on cause of th e diseased state. Most
widely used an tibacterials are an tibiotics but recen tly fluoroquin olon es an d
oth er syn th etics are used to com bat n ewer an d resistan t m icrobial in fec-
tion s1. Man y research program m e efforts are directed to th e design of n ew
an d available drugs because of th e un satisfactory status of side effects of
presen t drugs an d th e acquisition of resistan ce of th e in fectin g organ ism s to
th e presen t drugs. Th e em ergen ce an d spread of bacterial resistan ce are a se-
vere global problem . Path ogen ic m icroorgan ism s develop ph ysiological
m ech an ism s to block th e action s of repeatedly used an tim icrobial agen ts
an d, after a period of tim e, th e n ewly in troduced com poun ds becom e less
effective in producin g m icrobicidal or static respon se. Th e escalatin g resis-
tan ce h as led to th e appearan ce of m ultiresistan t Staphylococci, Enterococci
an d Pneumococci in n osocom ial an d com m un ity acquired in fection s2. Th ere
is a real perceived n eed for th e discovery of n ew com poun ds en dowed with
an tibacterial properties, possibly actin g th rough m ech an ism s th at are dis-
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373
© 2009 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2009054

1362
Sawant, Bhatia:
tin ct from th ose of th e well-kn own classes of an tibacterial agen ts to wh ich
m an y clin ically relevan t path ogen s are n ow resistan t.
QSAR studies of an tim icrobial activity are an exception ally im portan t
topic in th e area of com puter-aided drug design 3,4. Alth ough th e dem an d
for in-silico discovery is clear in all areas of h um an th erapeutics, th e field of
an ti-in fective drugs sh ows a particular n eed for com putation al solution s en -
ablin g rapid iden tification of n ovel th erapeutic leads. As a result, th ere is an
urge for n ew an tim icrobials driven by critical situation , such as in creased
prevalen ce of m ultidrug-resistan t bacteria an d em ergen ce of deadly in fec-
tious diseases.
Pyrim idin e derivatives play a vital role in m an y biological processes, th e
rin g system bein g presen t in n ucleic acids, several vitam in s an d coen zym es,
uric acid an d oth er purin es. Man y syn th etics of th e group are also im por-
tan t as drugs an d ch em oth erapeutic agen ts. In recen t years, substituted
2-oxo-1,2,3,4-tetrah ydropyrim idin es received sign ifican t atten tion , owin g
to th eir diverse ran ge of biological properties, such as calcium ch an n el m o-
dulator5, selective 1-adren oreceptor an tagon ist6, HIV gpl20-CD4 in h ibitior7,
an tiviral8, an tican cer drug with m itotic kin esin in h ibition 9, oral an tih yper-
ten sive10, blood platelet aggregation in h ibitor11, drug for th e treatm en t of
ben ign prostatic h yperplasia12, an ti-in flam m atory13, m uscarin ic14, an ti-
fun gal an d an tibacterial drugs15. Th e presen ce of several in teractin g fun c-
tion al groups in th e pyrim idin e com poun ds also determ in es th eir great
syn th etic poten tial.
RESULTS AND DISCUSSION
In both sets th e m in im um in h ibitory con cen tration (MIC) data (in m g/m l)
again st Staphylococcus aureus was con verted to n egative logarith m ic dose
in m oles (pMIC) for QSAR an alysis (Table I). Th e values of descriptors
(Table II) th at are sign ifican t in th e m odel sh ow h igh correlation with bio-
logical activity. Th e correlation am on g th e descriptors an d th eir correlation
with an tibacterial activity is dem on strated by con struction of correlation
m atrix (Table III).
Perform in g stepwise m ultiple lin ear regression an alysis in set 1 results in
several equation s. Th e followin g four of wh ich are statistically sign ifican t
QSAR m odels.
pMIC = 4.97312 + 0.04823 (±0.0231)* PEOE_VSA_PNEG – 0.02076 (±0.0061)*
PEOE_VSA_PPOS – 1.85275 (±0.3356)* FCASA-
n = 18, r2 = 0.73706, q2 = 0.564376, SE = 0.2372, F = 13.08, p = 0.0002 (1a)
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

QSAR Analysis
1363
pMIC = 4.95113 – 0.31731 (±0.1341)* PC+ – 0.02626 (±0.0130)* Q_VSA_PNEG +
0.01250 (±0.0029)* SMR_VSA7
n = 18, r2 = 0.76165, q2 = 0.584635, SE = 0.2258, F = 14.91, p = 0.0001 (1b)
pMIC = 4.96716 – 0.32007 (±0.1361)* PC+ + 0.01163 (±0.0032)* SMR_VSA7 –
0.70285 (±0.3643)* FCASA-
n = 18, r2 = 0.75649, q2 = 0.588355, SE = 0.2243, F = 14.50, p = 0.0001 (1c)
pMIC = 4.35070 + 0.01201 (±0.0077)* PEOE_VSA_PPOS – 0.63991 (±0.1704)*
PC+ + 0.01820 (±0.0033)* SMR_VSA7
n = 18, r2 = 0.73685, q2 = 0.553238, SE = 0.2373, F = 13.07, p = 0.0002 (1d)
For set 2, followin g statistically sign ifican t QSAR m odels are obtain ed.
pMIC = –6.65726 + 2.91592 (±0.6572)* GCUT_SLOGP_3 – 0.01920 (±0.0042)*
MNDO_HF
n = 12, r2 = 0.75998, q2 = 0.484092, SE = 0.3037, F = 14.25, p = 0.0016 (2a)
pMIC = –7.83838 + 1.55969 (±0.3908)* VadjMa – 0.01907 (±0.0044)* PM3_HF
n = 12, r2 = 0.73514, q2 = 0.460294, SE = 0.3191, F = 12.49, p = 0.0025 (2b)
pMIC = –1.92407 + 0.02605 (±0.0061)* zagreb – 0.01955 (±0.0044)* MNDO_HF
n = 12, r2 = 0.74517, q2 = 0.459367, SE = 0.3130, F = 13.16, p = 0.0021 (2c)
pMIC = –3.15816 + 1.99980 (±0.4663)* PEOE_PC+ – 0.01528 (±0.0040)* PM3_HF
n = 12, r2 = 0.75896, q2 = 0.499449, SE = 0.3044, F = 14.17, p = 0.0017 (2d)
pMIC = –0.74566 – 0.01642 (±0.0038)* MNDO_HF + 1.42990 (±0.2930)* std_dim3
n = 12, r2 = 0.79023, q2 = 0.548233, SE = 0.2840, F = 16.95, p = 0.0009 (2e)
Out of th ese m odels m odel (1b) of set 1 an d m odel (2e) of set 2 were se-
lected on th e basis of statistical criteria. Th e in tern al predictivity of th e
m odel was assessed by cross-validated squared correlation coefficien t (q2).
Th e h igh q2 in both th e m odels are in dicative of its reliability in prediction
of an tibacterial activity in th e series. Predictin g th e an tibacterial activity
validated th e predictive ability. Th e low residual activity observed (Table IV)
in dicates th e reliability of th e selected QSAR m odel.
In th e case of set 1, it is eviden t from th e selected best QSAR m odel th at
th e total positive partial ch arge (PC+) an d th e total polar n egative van der
Waals surface area (Q_VSA_PNEG) con tribute n egatively wh ereas th e con -
tribution of th e van der Waals surface area to m olar refractivity
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

1364
Sawant, Bhatia:
(SMR_VSA7) to an tibacterial activity is positive. Th e n ew com poun ds h av-
in g less positive partial ch arge an d polar n egative van der Waals surface
area with h igh er con tribution of van der Waals surface area to m olar
refractivity m ay lead to im proved an tibacterial activity from th is series.
TABLE Ia
An tibacterial (S. Aureus) activity of set 1 com poun ds
O
Ar
O
O
R1
N
Ph
Me
N
H
Com poun d
Ar
R1
MIC, µg/m l
pMIC
6b
6c
6d
6e
6f
Ph
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3
250
125
62
3.1636
3.4991
3.8177
2.5916
2.8813
2.8517
3.3413
3.1466
2.8767
2.8650
2.8342
3.6197
3.1263
4.0564
3.4799
2.5568
2.8456
3.4154
4-MeOC6H4
4-Me2NC6H4
4-CH2=CHC6H4
2-OHC6H4
2-furyl
1000
500
500
125
250
500
500
500
62
6h
7a
7b
7e
7f
H
Ph
4-CH2=CHC6H4
2-OHC6H4
2-furyl
7h
8a
8b
8c
8d
8e
8f
H
Ph
CH3
250
32
4-MeOC6H4
4-Me2NC6H4
4-CH2=CHC6H4
2-OHC6H4
2-furyl
CH3
CH3
125
1000
500
125
CH3
CH3
8h
CH3
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

QSAR Analysis
1365
In th e case of set 2, it is eviden t from th e selected best QSAR m odel th at
h eat of form ation (MNDO_HF) an d stan dard dim en sion 3 (std_dim 3) are re-
spon sible for th e activity. Heat of form ation con tributes n egatively an d
stan dard dim en sion 3 con tributes positively to biological activity, wh ich
in dicates th at m in im izin g th e h eat of form ation an d in creasin g th e surface
area probably lead to better an tibacterial com poun ds of th is series.
TABLE Ib
An tibacterial (S. Aureus) activity of set 2 com poun ds
O
Ar
O
O
R1
N
Me
N
H
Com poun d
Ar
R1
MIC, µg/m l
pMIC
4a
4b
4c
4d
4f
H
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
C2H5O
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
1000
500
250
500
250
500
1000
500
16
2.3268
2.7609
3.1049
2.8213
3.0854
2.7455
2.2971
2.7392
4.2792
2.8026
2.4776
3.6296
Ph
4-MeOC6H4
4-Me2NC6H4
2-OHC6H4
2-furyl
4h
5a
5b
5c
5d
5e
5h
H
Ph
4-MeOC6H4
4-Me2NC6H4
4-CH2=CHC6H4
2-furyl
500
1000
62
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

1366
Sawant, Bhatia:
Based on th e QSAR studies data, th e n ew com poun ds were design ed tak-
in g in to accoun t th e exten t to wh ich particular descriptors govern ed an ti-
bacterial activity. It is eviden t from th e QSAR studies th at electron ic
descriptors con tribute n egatively wh ereas spatial descriptors con tribute pos-
itively to an tibacterial activity. Con siderin g th e above fact n ew com poun ds
TABLE IIa
Calculated m olecular descriptors of set 1 com poun ds
PEOE_VSA_
PNEGa
PEOE_VSA_
PPOSb
Q_VSA_
PNEGd
Com pd.
PC+c
SMR_VSA7e
FCASA-f
6b
6c
6d
6e
6f
43.3414
45.8452
43.3414
43.3414
51.1090
43.3414
43.3414
43.3414
43.3414
51.1090
43.3414
40.8377
40.8377
43.3414
40.8377
40.8377
48.6052
40.8377
45.0986
45.0986
45.0986
45.0986
55.4227
63.8813
45.0986
45.0986
45.0986
55.4227
63.8813
30.3901
30.3901
30.3901
30.3901
30.3901
40.7142
49.1728
4.8960
5.1080
5.5840
5.2180
5.2780
5.3040
4.0020
4.8960
5.2180
5.2780
5.3040
3.5720
4.4660
4.6780
5.1540
4.7880
4.8480
4.8740
43.3414
45.8452
43.3414
55.5963
51.1090
43.3414
43.3414
43.3414
55.5963
51.1090
43.3414
40.8377
40.8377
43.3414
40.8377
53.0926
48.6052
40.8377
66.6520
102.0359
132.4464
66.6520
66.6520
66.6520
68.7099
68.7099
68.7090
68.7099
68.7090
66.6520
66.6520
102.0359
132.4464
66.6520
66.6520
66.6520
1.6270
1.4768
1.4232
1.8380
1.7826
1.4479
1.4326
1.7299
1.9344
1.9028
1.5176
1.3479
1.6847
1.5140
1.4465
1.8762
1.8224
1.4325
6h
7a
7b
7e
7f
7h
8a
8b
8c
8d
8e
8f
8h
a
b
c
Total polar n egative vdw surface area. Total polar positive vdw surface area. Total posi-
d
e
tive partial ch arge. Total polar n egative vdw surface area. vdw surface area in m olar re-
fractivity (SMR). Fraction al ch arge-weigh ed n egative surface area.
f
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

QSAR Analysis
1367
were design ed con tain in g trim eth oxyph en yl substituen t at Ar position in
th e gen eral structure of both th e series. Th e an tibacterial activity of th ese
n ew com poun ds was predicted by evaluatin g selected m ost sign ifican t
QSAR m odels of th e series. Th e activity prediction for th e n ew com poun ds
was don e by com pute-m odel evaluate m odule of th e MOE 2006.08 soft-
ware16. Th e predicted activity of th e n ew com poun ds was h igh er th an th e
m ost active com poun d of th e series. Subsequen tly, th ese n ew com poun ds
were syn th esized, ch aracterized an d screen ed for th eir an tibacterial activity.
Th e observed activity was h igh er th an th at of train in g set com poun ds, in
close agreem en t with QSAR prediction an d com parable to th e curren tly
clin ically used pyrim idin e an tim icrobial trim eth oprim (Table V).
TABLE IIb
Calculated m olecular descriptors of set 2 com poun ds
GCUT_
PEOE_
PC+d
Com pd.
VAdjMab zagrebc
MNDO_HFe PM3_HFf
std_dim 3g
SLOGP_3a
4a
4b
4c
4d
4f
2.2665
2.6026
2.6466
2.6950
2.6358
2.5316
2.2128
2.5726
2.6191
2.6701
2.5356
2.4978
4.9069
5.4594
5.5850
5.6439
5.5236
5.3923
4.8074
5.3923
5.5236
5.5850
5.5236
5.3219
70.0000 1.7181
104.0000 2.0422
114.0000 2.2488
120.0000 2.2236
110.0000 2.2762
100.0000 2.2149
66.0000 1.6947
100.0000 2.0043
110.0000 2.2253
116.0000 2.2002
108.0000 2.1188
96.0000 2.1915
–112.9104
–112.8434
–118.6648
–65.1793
–121.4409
–111.5959
–140.3118
–92.3657
–146.9882
–96.3653
–96.2787
–142.5653
–119.6412
–125.5291
–122.7770
–86.3890
0.7310
1.2300
1.4817
1.4778
1.4361
1.3175
0.5784
1.2418
1.5095
1.5033
1.3602
1.3291
–131.4696
–112.4507
–152.0492
–120.8682
–158.0519
–124.7239
–81.0662
4h
5a
5b
5c
5d
5e
5h
–147.9133
a
b
c
d
Log P GCUT (3/3). Vertex adjacen cy in form ation (m ag). Zagreb in dex. Total positive
e
f
g
partial ch arge. MNDO h eat of form ation (kcal). PM3 h eat of form ation (kcal). Stan dard
dim en sion 3.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

1368
Sawant, Bhatia:
TABLE IIIa
Correlation m atrix set 1
PEOE_VSA_ PEOE_VSA_
Q_VSA_ SMR_
pMIC
PC+
FCASA-
PNEG
PPOS
PNEG
VSA7
pMIC
1.0000
PEOE_VSA_
PNEG
–0.2753
1.0000
0.4660
PEOE_VSA_
PPOS
–0.3750
1.0000
PC+
–0.2163
0.3324
0.4457
0.4763
0.1359
–0.2380
0.0233
1.0000
0.3277
Q_VSA_PNEG –0.5668
1.0000
SMR_VSA7
FCASA-
0.4055 –0.1111
–0.5315 0.4305
0.4278 –0.2923
0.3333
1.0000
0.8257 –0.3773 1.0000
TABLE IIIb
Correlation m atrix set 2
GCUT_
SLOGP_3
PEOE_ MNDO_
PC+ HF
std_
dim 3
pMIC
VAdjMa zagreb
PM3_HF
pMIC
1.0000
0.4487
GCUT_
1.0000
SLOGP_3
VAdjMa
zagreb
0.4403
0.4360
0.5713
0.9677
0.9737
0.8942
1.0000
0.9956
0.8951
1.0000
0.8957 1.0000
PEOE_
PC+
MNDO_
HF
0.3985
0.3092
0.3397
0.3483 0.0349 1.0000
PM3_HF
0.3095
0.5763
0.1876
0.9556
0.3582
0.9649
0.3341 0.0667 0.8939
0.9633 0.9601 0.1908
1.0000
0.1789
std_
1.0000
dim 3
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

QSAR Analysis
1369
EXPERIMENTAL
Selection of Com poun ds
Data set for 18 an alogues of 3-ben zoyl-2-oxo-1,2,3,4-tetrah ydropyrim idin e (set 1) an d 12 an -
alogues of 3-form yl-2-oxo-1,2,3,4-tetrah ydropyrim idin e (set 2) from our previously pub-
lish ed work were used17,18. An tibacterial activity was tested in vitro again st Gram -positive
bacteria Staphylococcus aureus (NCIM-2079) by th e cup-plate agar diffusion m eth od, usin g
dim eth yl sulfoxide as solven t an d trim eth oprim as stan dard drug. Min im um in h ibitory con -
cen tration s (MIC) of all th ese com poun ds were determ in ed by th e double dilution
m eth od19. Th e biological data MIC in m g/m l were con verted to n egative logarith m ic doses
in m oles (pMIC) for QSAR an alysis.
TABLE IVa
Observed, predicted pMIC an d residuals for set 1 com poun ds
Com poun d
pMIC observed
pMIC predicted
Residuals
6b
6c
6d
6e
6f
3.1636
3.4991
3.8177
2.5916
2.8813
2.8517
3.3413
3.1466
2.8767
2.8650
2.8342
3.6197
3.1263
4.0564
3.4799
2.5568
2.8456
3.4154
3.0926
3.4018
3.6966
2.6687
2.7674
2.9631
3.4020
3.1183
2.6944
2.7932
2.9889
3.5785
3.2948
3.6040
3.8988
2.8780
2.9696
3.1653
0.0710
0.0972
0.1211
–0.0771
0.1138
–0.1114
–0.0607
0.0283
0.1823
0.0718
–0.1546
0.0412
–0.1685
0.4524
–0.4188
–0.3140
–0.1241
0.2501
6h
7a
7b
7e
7f
7h
8a
8b
8c
8d
8e
8f
8h
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

1370
Sawant, Bhatia:
TABLE IVb
Observed, predicted pMIC an d residuals for set 2 com poun ds
Com poun d
pMIC observed
pMIC predicted
Residuals
4a
4b
4c
4d
4f
2.3268
2.7609
3.1049
2.8213
3.0854
2.7455
2.2971
2.7392
4.2792
2.8026
2.4776
3.6296
2.1535
2.8658
3.3213
2.4375
3.3017
2.9705
2.3852
2.5466
3.8261
2.9861
2.7800
3.4956
0.1733
–0.1049
–0.2164
0.3838
–0.2163
–0.2250
–0.0881
0.1926
4h
5a
5b
5c
5d
5e
5h
0.4530
–0.1835
–0.3025
0.1340
TABLE V
An tibacterial (S. Aureus) activity of lead com poun ds an d stan dard drug
Com poun d
MIC, µg/m l
pMIC observed
pMIC predicted
Residuals
4g
8
8
4.6748
4.6584
4.4534
4.4398
–
5.0171
4.9665
4.2134
4.2224
–
–0.3423
–0.3081
0.2400
0.2174
–
5g
6g
16
16
8
7g
Trim eth oprim
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

QSAR Analysis
1371
QSAR An alysis
Th e series were subjected to QSAR an alysis usin g MOE 2006.08 run n in g on P-IV processor.
Structures of all th e com poun ds were sketch ed usin g th e builder m odule of th e program m e.
Th ese structures were th en subjected to en ergy m in im ization usin g Ham ilton ian force field
m olecular m ech an ics MMFF 94X by fixin g root-m ean -square (RMS) gradien t as 0.01 kcal/m ol Å.
Th e descriptor values for all th e com poun ds were calculated usin g th e “com pute descriptor”
m odule of th e program m e. All th e calculated descriptors were con sidered as in depen den t
variables an d biological activity (pMIC) as th e depen den t variable. Stepwise m ultiple lin ear
regression an alysis was used to perform QSAR an alysis to gen erate several m odels. Th e best
m odel was selected on th e basis of various statistical param eters such as squared correlation
coefficien t (r2), stan dard error of estim ation (SE), sequen tial Fisch er test (F). Quality an d pre-
dictability of th e m odel was estim ated20 from th e cross-validated squared correlation coeffi-
cien t (q2).
Meth ods
Meltin g poin ts of th e syn th esized com poun ds were determ in ed in an open capillary tube
an d h en ce are un corrected. Th e structures of th e title com poun ds were establish ed on th e
basis of spectral data. Th e IR spectra (KBr; ν, cm –1) were recorded on a Jasco FTIR 4100
spectroph otom eter. 1H NMR spectra (δ, ppm ; J, Hz) were recorded on a Varian NMR 400 MHz
spectrom eter usin g CDCl3 as solven t with TMS as an in tern al stan dard. Mass spectra were re-
corded to kn ow th e M + 1 peak on an LC-MS Th erm ofin igen spectrom eter. Purity of th e syn -
th esized com poun ds was ch ecked by silica gel G plate usin g ben zen e an d eth yl acetate as
m obile ph ases.
O
Ar
O
R1
Me
N
DMF,
POCl3
Ar
N
H
O
O
Ar
O
R1
4,5
70 °C
AlCl3, HCl
4 h
O
O
R1
Me
NH
H2N
H2N
O
N
H
O
O
Ar
O
Me
R1
Me
N
Ph
PhCOCl, Py
PhH
1–3
N
H
O
1,4,6 (R1 = EtO)
2,5,7 (R1 = MeO)
3,8 (R1 = Me)
6–8
Ar
a
b
c
d
e
f
H
Ph
4-MeOC6H4
4-Me2NC6H4
4-CH2=CHC6H4
2-OHC6H4
3,4,5-(MeO)3C6H2
furyl
g
h
SCHEME 1
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

1372
Sawant, Bhatia:
Syn th esis of New Com poun ds
Ethyl 6-methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(1g)21,22. A m ixture of 3,4,5-trim eth oxyben zaldeh yde (0.02 m ol), eth yl acetoacetate (0.02 m ol),
urea (0.03 m ol), alum in ium ch loride (0.01 m ol), an d few drops of con cen trated h ydroch loric
acid in m eth an ol was refluxed for 4 h . Th e solid separated on coolin g was filtered, wash ed
with cold m eth an ol, dried an d recrystallized from m eth an ol.
Methyl 6-methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate
(2g)21,22. Th e sam e procedure was followed as for 1g. In stead of eth yl acetoacetate m eth yl
acetoacetate was used.
Ethyl 3-formyl-6-methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylate (4g). To a suspen sion of 1g (0.02 m ol) in 20 m l of dry dim eth ylform am ide, ph osph o-
rus oxych loride (0.02 m ol) was added in ice bath . Th e resultin g solution was h eated at 70 °C
an d kept th ere for 40 m in . Th en it was poured in to 150 m l of ice-water to yield th e solid
product. Th e product th us separated was filtered, wash ed with cold water, air dried an d
recrystallized from eth an ol. Yield 66.7%; m .p. 176 °C. IR: 3240, 3140 (N–H), 2943 (C–H),
1703 (C=O), 1687 (C=O), 1674 (C=O). 1H NMR (400 MHz, CDCl3): 1.20 (t, J = 7, 3 H, eth yl
CH3), 2.38 (s, 3 H, C6-CH3), 3.80 (s, 9 H, OCH3), 4.10 (q, J = 7, 2 H, OCH2), 6.43 (s, 1 H,
CH), 6.96 (s, 2 H, Ph ), 7.22 (s, 1 H, NH), 8.20 (s, 1 H, form yl CH). LC-MS (M + 1): 379.590.
Methyl 3-formyl-6-methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylate (5g). Th e sam e procedure was followed as for 4g. In stead of 1g, 2g were used. Yield
69.1%; m .p. 194 °C. IR: 3210, 3097 (N–H), 2943 (C–H), 1701 (C=O), 1643 (C=O), 1593
(C=O). 1H NMR (400 MHz, CDCl3): 2.38 (s, 3 H, C6-CH3), 3.70 (s, 3 H, COOCH3), 3.83 (s,
9 H, OCH3), 6.43 (s, 1 H, CH), 6.96 (s, 2 H, Ph ), 7.23 (s, 1 H, NH), 8.40 (s, 1 H, form yl CH).
LC-MS (M + 1): 365.077.
Ethyl 3-benzoyl-6-methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylate (6g). To a suspen sion of 1g (0.02 m ol) an d 4 m l of pyridin e in 20 m l of dry ben zen e,
ben zoyl ch loride (0.03 m ol) was added dropwise at room tem perature. Th e resultin g solution
was h eated to reflux for 2 h . After coolin g 80 m l of water was added an d th e ben zen e layer
was allowed to separate. Th e ben zen e layer was wash ed with 5% sodium carbon ate followed
by water an d dried with an h ydrous m agn esium sulfate. Th e ben zen e solution was con cen -
trated to obtain oily residue wh ich on crystallization from m eth an ol yielded a solid product.
Yield 62.9%; m .p. 96 °C. IR: 3230, 3097 (N–H), 2948 (C–H), 1724 (C=O), 1708 (C=O), 1653
(C=O). 1H NMR (400 MHz, CDCl3): 1.21 (t, J = 7, 3 H, eth yl CH3), 2.40 (s, 3 H, C6-CH3),
3.83 (s, 9 H, OCH3), 4.18 (q, J = 7, 2 H, OCH2), 6.57 (s, 1 H, CH), 6.62 (s, 2 H, Ph ),
7.77–7.88 (m , 5 H, COPh ), 7.18 (s, 1 H, NH). LC-MS (M + 1): 455.019.
Methyl 3-benzoyl-6-methyl-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (7g). Th e sam e procedure was followed as for 6g. In stead of 1g, 2g were used.
Yield 64.3%; m .p. 110 °C. IR: 3220, 3180 (N–H), 2945 (C–H), 1733 (C=O), 1703 (C=O), 1685
(C=O). 1H NMR (400 MHz, CDCl3): 2.27 (s, 3 H, C6-CH3), 3.62 (s, 3 H, COOCH3), 3.83 (s,
9 H, OCH3), 6.50 (s, 1 H, CH), 7.10 (s, 2 H, Ph ), 7.76–7.88 (m , 5 H, COPh ), 7.08 (s, 1 H,
NH). LC-MS (M + 1): 441.007.
CONCLUSION
QSAR an alysis reveals th at electron ic an d steric features govern th e an tibac-
terial poten tial of 2-oxo-1,2,3,4-tetrah ydropyrim idin es. Th e design ed an d
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373

QSAR Analysis
1373
syn th esized com poun ds based on th ese observation s are good an ti-
bacterials. QSAR m odels gen erated are h igh ly sign ifican t. Th is study could
h elp in design an d developm en t of prom isin g an tibacterials.
The authors thank Dr. H. N. More, Bharti Vidyapeeth College of Pharmacy, Kolhapur, for providing
facilities.
REFERENCES
1. Rao G. K., Sen S., Rajendra B.: Indian Drugs 2004, 41, 524.
2. Cohen M. L.: Science 1992, 257, 1050.
3. Gonzalez D. H., Prado P. F., Ubeira F. M.: Curr. Top. Med. Chem. 2008, 8, 1676.
4. Gonzalez D. H., Vilar S., Santana L., Uriarte E.: Curr. Top. Med. Chem. 2007, 7, 1015.
5. Kappe C. O.: Molecules 1998, 3, 1.
6. Barrow J. C., Glass K. L., Selnick H. G., Freidinger R. M., Chang R. S. L., O’Malley S. S.,
Woyden C.: Bioorg. Med. Chem. Lett. 2000, 10, 1917.
7. Patil A. D., Kumar N. V., Kokke W. C., Bean M. F., Freyer A. J., Debrose C., Mai S.,
Trunch A., Falkner D. J., Carte B., Breen A. L., Hertzberg R. P., Johnston R. K., Westely
J. W., Ports B. C. M.: J. Org. Chem. 1995, 60, 1182.
8. Hurst E. W., Hull R.: J. Med. Pharm. Chem. 1961, 3, 215.
9. Kappe C. O., Shishkin O. V., Uray G., Verdino P.: Tetrahedron 2000, 56, 1859.
10. Kappe C. O.: Acc. Chem. Res. 2000, 33, 879.
11. Tozkoparan B., Akgun H., Ertan M., Sara Y., Ertekin N.: Arch. Pharm. 1995, 328, 169.
12. Nagarathnam D., Wetzel J. M., Miao S. W., Marzabad M. R., Chiu G., Wang W. C.,
Hong X., Fang J., Forry C., Branchek T. A., Heydora W. E., Chang R. S. L., Broten T.,
Schora T., Gluchowski C.: J. Med. Chem. 1998, 41, 5320.
13. Tozkoparan B., Yarim M., Sarac S., Ertan M., Kelicen P., Altinok G., Demirdamar R.: Arch.
Pharm. 2000, 333, 415.
14. Jung M. H., Park J. G., Lee M. J.: Arch. Pharm. 2001, 334, 79.
15. Kappe C. O.: Eur. J. Med. Chem. 2000, 35, 1043.
16. Vilar S., Cozz G., Moro S.: Curr. Top. Med. Chem. 2008, 8, 1555.
17. Sawant R. L., Bhatia M. S.: Bull. Chem. Soc. Ethiopia 2008, 22, 391.
18. Sawant R. L., Bhatia M. S.: Int. J. Chem. Sci. 2008, 6, 45.
19. Kirven L. A., Thornsberry C.: Antimicrob. Agents Chemother. 1978, 10, 335.
20. Narasimhan B., Kumari M., Dhake A., Sundaravelan C.: Arkivoc 2006, 13, 73.
21. Russowsky D., Lopes F. A., Da Silva V. S. S., Canto K. F. S., Montes M. G., D’Oca, Godoi
M. N.: J. Braz. Chem. Soc. 2004, 15, 165.
22. Kumar S., Saini A., Sandhu J. S.: Indian J. Chem., B 2004, 43, 1485.
Collect. Czech. Chem. Commun. 2009, Vol. 74, No. 9, pp. 1361–1373