Synthesis and antibacterial evaluation of ureides of Baylis-Hillman derivatives

Article abstract of DOI:10.1016/j.bmcl.2006.04.020

The synthesis of several 1-(2-cyano-3-aryl-allyl)-3-aryl-urea(thiourea) constructed from the reaction between allylamines generated from Baylis-Hillman acetates and substituted isocyanates and isothiocyanates has been described. Further, their cyclization in the presence of a base led to the formation of 5-arylmethyl-4-imino-3-aryl-3,4-dihydro-1H-pyrimidin-2-ones. All compounds were tested for their antibacterial activity. Few of the compounds showed superior activity or were equipotent to the standard antibacterial agents.

Full text of DOI:10.1016/j.bmcl.2006.04.020

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3824–3828
Synthesis and antibacterial evaluation of ureides of
Baylis–Hillman derivativesq
Somnath Nag,a Richa Pathak,a Manish Kumar,b P. K. Shuklab and Sanjay Batraa,*
aMedicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226 001, India
bFermentation Technology Division, Central Drug Research Institute, PO Box 173, Lucknow 226 001, India
Received 23 February 2006; revised 21 March 2006; accepted 11 April 2006
Available online 2 May 2006
Abstract—The synthesis of several 1-(2-cyano-3-aryl-allyl)-3-aryl-urea(thiourea) constructed from the reaction between allylamines
generated from Baylis–Hillman acetates and substituted isocyanates and isothiocyanates has been described. Further, their cycliza-
tion in the presence of a base led to the formation of 5-arylmethyl-4-imino-3-aryl-3,4-dihydro-1H-pyrimidin-2-ones. All compounds
were tested for their antibacterial activity. Few of the compounds showed superior activity or were equipotent to the standard anti-
bacterial agents.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The emergence of resistant strains of bacteria has
renewed the interest of several research groups in the
development of new antibacterial compounds. The aryl
ureas remain one of the simplest of chemicals to be used
as antibacterials in clinics. For instance, diaryl urea tri-
Figure 1. Triclocarban.
clocarban (Fig. 1) is essentially used in the disinfecting
solutions in hospitals and households. The significance
of ureides as antiinfectives including antibacterials was
tetrahydro-pyrimidin-2-ones. These compounds were
recently reviewed by us.1 In our efforts concentrated to-
evaluated for their antibacterial activity. During the pre-
ward generation of compounds of medicinal importance
liminary in vitro screening, a few of the compounds
using Baylis–Hillman reaction as the key step, we envi-
exhibited significant antibacterial activity against several
sioned the synthesis of new aryl urea derivatives in a
strains of bacteria, which prompted us to report our
straightforward manner by the reaction between the
findings in this communication.
amines afforded by the Michael addition of ammonia
or primary amine on the Baylis–Hillman derivatives
Initially, the Baylis–Hillman adducts 1a and 1b were
and the commercially available aryl isocyanates. In prin-
prepared following the literature procedure.2 Treatment
ciple, these open-chain aryl ureas can be easily cyclized
of these compounds with methanolic ammonia or benzyl
amine gave the corresponding amino derivatives 2a, 3a
in the presence of a base to yield the tetrahydropyrimi-
din-2-ones, the cyclic ureide analog. Such a synthetic
and 3b as illustrated in Scheme 1.3 The reaction of
amines 2a, 3a, and 3b with different isocyanates yielded
the required urea derivatives (4–7). Interestingly, these
ureas during the cyclization reaction in the presence of
K2CO3 or NaH afforded products 8–11. The loss of
strategy would give a library of novel ureides for anti-
bacterial evaluation. In studies aimed toward these
objectives, we have carried out the synthesis of several
urea derivatives from the allylamines obtained from
the acetates of the Baylis–Hillman adducts of acryloni-
the benzyl moiety in these compounds was conclusively
supported by spectroscopic data. Further support for
trile and successfully cyclized them to the corresponding
the assigned structure of products 8–11 was made on
the basis of alternate synthesis as outlined in Scheme
2. Treatment of acrylonitrile with benzyl amine in
methanol led to the product 12 which was reacted with
substituted isocyanate to give the urea derivative 13.
Keywords: Ureides; Baylis–Hillman; Antibacterial.
q
CDRI Communication No. 6933.
Corresponding author. Tel.: +91 522 262411 18x4368; fax: +91 522
2623405/2623938; e-mail: batra_san@yahoo.co.uk
*
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.04.020

S. Nag et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3824–3828
3825
Scheme 1. Reagents and conditions: (i) methanolic ammonia, rt 8 h or BnNH2, MeOH, rt 8 h; (ii) R2NCO, THF, rt, 1.5–2 h; (iii) K2CO3, MeOH,
reflux, 8–9 h or NaH, toluene, reflux, 8–9 h.
Scheme 2. Reagents and conditions: (i) BnNH2, MeOH, rt, 3.5 h; (ii) R2NCO, THF, rt, 1 h; (iii) NaH, toluene, reflux, 9 h.
Subsequently, the reaction between the urea 12 and
NaH in refluxing toluene afforded the cyclized derivative
9. It was presumed that in the presence of strong base
such as K2CO3 or NaH the hydroxyl group present at
the benzylic position triggers off the loss of the benzyl
group as benzaldehyde. In order to validate, in a repre-
sentative compound 1a the hydroxyl group was convert-
ed to the methoxy group 14.4 Subsequently, it was
reacted with benzyl amine and converted to the urea
derivative 16. The cyclization of urea 16 with NaH led
to isolation of the methoxy derivative 17 in moderate
yields as depicted in Scheme 3. This clearly showed that
the elimination of the benzyl group is due to the pres-
ence of the hydroxyl moiety. In the light of these results
Scheme 3. Reagents and conditions: (i) Ag2O, MeI, CH2Cl2, rt, 5 h; (ii) BnNH2, MeOH, rt, 6 h; (iii) 3,4-(Cl)2–C6H3NCO, THF, 45 min; (iv) NaH,
toluene, reflux, 8 h.
Scheme 4. Reagents and conditions: (i) AcCl, pyridine, CH2Cl2, rt, 3 h; (ii) methanolic ammonia, rt, 1 h; (iii) R1NCO, THF, rt, 1 h; (iv) K2CO3,
MeOH, reflux, 8–9 h or NaH, toluene, reflux, 8–9 h.

3826
S. Nag et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3824–3828
it was decided to evaluate the analogous reactions on the
acetates of the Baylis–Hillman adducts as shown in
Scheme 4. Accordingly, the Baylis–Hillman adducts
1a–d were prepared and acetylated in the presence of
pyridine and acetyl chloride. Treatment of acetates
18a–d with methanolic ammonia furnished the allylam-
ines 19a–d as Z-isomer.3a The reaction between the
allylamines and several commercially available
iso(thio)cyanates yielded the required (thio)urea deriva-
tives 20–36 in good yields as solids. These products (20–
36) were cyclized in the basic medium to yield the respec-
tive 4-imino-tetrahydro-pyrimidin-2-ones 37–53 in mod-
erate yields. The tautomerization of the benzylidene
double bond from an exocyclic to an endocyclic position
was supported by the NMR data. All the compounds
generated during the study gave satisfactory spectro-
scopic and analytical data.5 The ureas 4–7, 16, 20–36,
and cyclized products 17 and 37–53 were evaluated
6
against the susceptible Gram-positive and the Gram-
negative bacteria including Staphylococcus aureus,
Streptococcus faecalis, Klebsiella pneumoniae, Escherich-
ia coli, and Pseudomonas aeruginosa strains and the re-
sults are summarized in Table 1. Among all the
compounds screened, 16, 17, 30, 32, and 46 exhibited
significant antibacterial activity with low MIC values.
Only two other compounds, 25 and 29, show prominent
activity against the E. coli.
It was interesting to discover that all active compounds
bear 3,4-dichloro-phenyl group which is a sub-structure
Table 1. Yields, physical characteristics and antibacterial activities of reported compounds
Compound
Yield (%)
Physical state, mp (ꢁC)
Antibacterial activity MIC (lg mLÀ1
)
Sa
Sf
Kp
Ec
Pa
4
81
79
51
59
82
77
38
66
70
54
72
74
78
60
60
73
63
63
77
60
58
62
55
62
58
63
60
44
65
40
43
58
57
59
40
43
51
40
39
55
50
White solid, 160–162
White solid, 142–144
White solid, 86–88
>50
>50
25
>50
>50
50
>50
>50
50
>50
>50
12.5
>50
25
>50
>50
50
5
6
7
White solid, 168–169
White solid, 208–210
Yellow oil
>50
50
>50
50
>50
50
>50
50
8
16
3.12
1.56
>50
>50
50
6.25
3.12
>50
>50
50
3.12
3.12
>50
>50
50
3.12
1.56
50
50
50
17
20
Brown solid, 140–144
White solid, 173–175
White solid, 173–174
White solid, 148–149
White solid, 212–213
White solid, 214–216
White solid, 185–186
White solid, 165–166
White solid, 150–152
White solid, 203–205
White solid, 205–206
White solid, 201–202
White solid, 176–177
White solid, 160–161
White solid, 212–213
White solid, 206–207
White solid, 220–221
White solid, 161–163
White solid, 207–210
White solid, 185–187
White solid, 210–212
White solid, 197–199
White solid, 204–206
White solid, 214–215
White solid, 216–217
Pale yellow solid, 212–213
White solid, 208–209
White solid, 147–149
White solid, 199–200
White solid, 210–211
Pale yellow solid, 205–206
White solid, 197–199
White solid, 118–120
White solid, 190–192
Pale yellow solid, 210–212
>50
>50
50
21
22
>50
50
23
24
>50
>50
>50
>50
>50
>50
>50
1.56
>50
1.56
>50
>50
>50
>50
50
>50
>50
>50
>50
>50
>50
>50
1.56
>50
3.12
>50
>50
>50
>50
25
>50
>50
>50
>50
50
>50
>50
1.56
>50
>50
>50
6.25
0.78
>50
1.56
>50
>50
>50
>50
50
>50
>50
>50
>50
>50
>50
>50
50
25
26
27
28
>50
>50
1.56
>50
3.12
>50
>50
>50
50
29
30
31
32
>50
25
33
34
>50
>50
>50
>50
50
35
36
37
38
50
50
50
50
50
50
39
40
>50
>50
>50
>50
50
>50
>50
>50
50
>50
>50
50
>50
>50
>50
50
>50
>50
>50
>50
50
41
42
>50
>50
>50
>50
3.12
50
43
44
50
25
50
>50
>50
3.12
25
>50
>50
3.12
25
>50
>50
25
45
46
>50
3.12
25
47
48
50
>50
>50
>50
>50
>50
>50
0.3
50
25
50
>50
>50
>50
>50
>50
>50
0.36
0.02
0.02
>50
>50
>50
>50
>50
>50
0.78
25.0
50.0
49
50
50.0
>50
>50
>50
>50
0.36
0.78
0.01
>50
>50
50
51
52
53
>50
0.78
0.78
0.02
Norfloxacin
Gentamycin sulfate
Ampicillin
6.25
0.09
Sa, Staphylococus aureus; Sf, Streptococcus fecaelis; Kpn, Klebsiella pneumoniae; Ec, Escherichia coli; Pa, Pseudomonas aeruginosa.
ND, not done.

S. Nag et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3824–3828
3827
unit of triclocarban. Compound 16, an open-chain urea
References and notes
derivative, showed significant antibacterial effect with 2-
fold better activity than the standard gentamycin for S.
aureus. In comparison, the cyclized derivative 17 showed
marked activity against S. aureus with MIC of
1.56 lg mLÀ1, which was 2-fold better than 16 and 4-
fold better than the standard gentamycin. Both these
compounds also elicit significant antibacterial activity
against other P. aeruginosa and were found to be equi-
potent to the ampicillin. In the series represented by
compounds 20–53, the open-chain urea analogs were
found to show better antibacterial activity than the cyc-
lic dihydro-pyrimidin-2-one system. Within the urea
derivatives, the most potent in vitro antibacterial effect
was demonstrated by compounds 30 and 32 in relation
to all evaluated strains of bacteria, while compounds
25 and 29 show potent responses against E. coli only.
Although compounds 30 and 32 were equipotent against
S. aureus, compound 30 was 2-fold more active for S.
fecaelis, K. pneumoniae, and E. coli and was 2-fold less
active for P. aeruginosa than compound 32. Compounds
25 and 29 with MIC of 1.56 and 6.25 lg mLÀ1, respec-
tively, against E. coli were the only other actives in the
series. These results indicated that in open chain aryl
ureas, in comparison to the thiourea group, only the
compounds bearing urea moiety show antibacterial ef-
fect. On the other hand, the presence of 3,4-dichloro-
phenyl group was essential for antibacterial activity in
this class of compounds. The replacement of the phenyl
group with a heteroaryl group has negative effect on the
antibacterial activity. Unfortunately except for com-
pound 46, most of the cylclic ureide analogs were found
to be inactive. Compound 46 with MIC of 3.12 lg mLÀ1
against S. aureus was 2-fold more active than gentamy-
cin and with MIC of 25 lg mLÀ1 against P. aeruginosa
was equipotent to the same drug. Compound 47, the
cyclic derivative of urea 30, shows mild activity only
thereby indicating that even the presence of two 3,4-
dichlorophenyl groups did not have influence on anti-
bacterial activity. The biological evaluation of this limit-
ed set of compounds shows that the cyclized compound
1-benzyl-3-(3,4-dichloro-phenyl)-4-imino-5-(methoxy-
phenyl-methyl)-tetrahydro-pyrimidin-2-one (17) elicits
better antibacterial activity than its open chain urea pre-
cursor (16). On the contrary, the 1-(2-cyano-3-aryl-al-
lyl)-3-aryl-ureas (20–35) were better antibacterial as
compared to their cyclic analogs 5-arylmethyl-4-imino-
3-aryl-3,4-dihydro-1H-pyrimidin-2-ones (36–53).
1. Batra, S.; Tusi, Z.; Madapa, S. Curr. Med. Chem.–Anti-
Infective Agents. 2006, 5, 135.
2. (a) Baylis, A. B.; Hillman, M. E. D. German Patent
2155113, 1972, CA, 1972, 77, 34174q; (b) Patra, A.; Batra,
S.; Kundu, B.; Joshi, B. S.; Roy, R.; Bhaduri, A. P.
Synthesis 2001, 276; (c) Cai, J.; Zhou, Z.; Zhao, G.; Tang,
C. Org. Lett. 2002, 4, 4723.
3. (a) Pathak, R.; Singh, V.; Nag, S.; Kanojiya, S.; Batra, S.
Synthesis 2006, 813; (b) Batra, S.; Roy, A. K.; Patra, A.;
Bhaduri, A. P.; Surin, W. S.; Raghvan, S. A. V.; Sharma,
P.; Kapoor, K.; Dikshit, M. Bioorg. Med. Chem. 2004, 12,
2059.
4. B’Ouzide, A. Org. Lett. 2002, 4, 1347.
5. 1-Benzyl-1-[3-(4-chloro-phenyl)-2-cyano-3-methoxy-pro-
pyl]-3-(3,4-dichloro-phenyl)-urea (16). mmax (neat) 1663
;
(CONH), 2248 (CN), 3401 (NH) cmÀ1 1H NMR
(DMSO-d6, 200 MHz) d = 3.25 (s, 3H, OCH3), 3.47–3.56
(m, 2H, CH2), 3.80–3.84 (m, 1H, CHCN), 3.87–3.90 (m,
1H, CHOCH3), 4.79 (s, 2H, CH2Ph), 7.24–7.69 (m, 12H,
ArH), 9.07 (s, 1H, NH); mass (FAB+) m/z 502 (M++1), 504
(M++3); EI-HRMS, calcd for C25H22Cl3N3O2 501.0778,
found: 501.0782.
1-Benzyl-5-[(4-chloro-phenyl)-methoxy-methyl]-3-(3,4-di-
chloro-phenyl)-4-imino-tetrahydro-pyrimidin-2-one (17).
mmax (KBr) 1640 (CONH), 3317 (NH) cmÀ1 1H NMR
,
(DMSO-d6, 200 MHz) d = 3.24 (m, 1H, CHCH2), 3.32 (s,
3H, OCH3), 3.34 (d, 2H, J = 4.0 Hz, CH2N), 3.62 (d, 1H,
J = 6.1 Hz, CHOCH3), 4.33 (s, 2H, CH2Ph), 6.90 (br s, 1H,
ArH), 7.10 (s, 1H, ArH), 7.30–7.36 (m, 8H, ArH), 9.02 (s,
1H, NH); mass (FAB+) m/z 502 (M++1); EI-HRMS, calcd
for C25H22Cl3N3O2 501.0778, found: 501.0787.
1-[3-(2-Chloro-phenyl)-2-cyano-allyl]-3-(3,4-dichloro-phen-
yl)-urea (25). mmax (KBr) 1649 (CONH), 2214 (CN), 3343
(NH) cmÀ1 1H NMR (DMSO-d6, 200 MHz) d = 4.14 (d,
;
2H, J = 5.4 Hz, CH2NH), 6.96 (br, 1H, CH2NH), 7.34 (s,
1H, ArH), 7.45–7.51 (m, 5H, @CH and ArH), 7.84–7.86
(m, 2H, ArH), 9.11 (s, 1H, CONH); 13C NMR (DMSO-d6,
50.32 MHz) d = 42.9, 114.6, 117.6, 118.4, 119.4, 123.1,
127.9, 129.6, 130.1, 130.8, 131.3, 132.0, 133.2, 140.3, 140.7,
155.0; mass (FAB+) m/z 381 (M++1); EI-HRMS, calcd for
C17H12Cl3N3O 379.0046, found: 379.0055.
1-[2-Cyano-3-(3,4-dichloro-phenyl)-allyl]-3-(3,4-dichloro-
phenyl)-urea (30). mmax (KBr) 1684 (CONH), 2219 (CN),
3322 (NH) cmÀ1; 1H NMR (DMSO-d6, 200 MHz) d = 4.09
(d, 2H, J = 5.4 Hz, CH2NH), 6.92 (t, 1H, J = 6.0 Hz,
CH2NH), 7.28 (dd, 1H, J1 = 2.2 Hz, J2 = 8.0 Hz, ArH),
7.37 (s, 1H, @CH), 7.48 (d,1H, J = 8.0 Hz, ArH), 7.77 (s, 2H,
ArH), 7.85 (d, 1H, J = 2.2 Hz, ArH), 7.98 (s, 1H, ArH), 9.16
(s, 1H, NH), mass (FAB+) m/z 416 (M++1); EI-HRMS, calcd
for C17H11Cl4N3O 412.9656, found: 412.9655.
1-[2-Cyano-3-(3,4-dichloro-phenyl)-allyl]-3-phenyl-thiourea
(32). mmax (KBr) 1593 (CSNH), 2210 (CN), 3167 (NH) cmÀ1
,
1H NMR (DMSO-d6, 200 MHz) d = 4.65 (d, 2H, J = 6.0 Hz,
CH2NH), 6.35 (t, 1H, J = 6.0 Hz, CH2NH, replaceable with
D2O), 7.28 (s, 1H, @CH), 7.32–7.49 (m, 5H, ArH), 7.59 (s,
1H, ArH), 7.93–7.97 (m, 2H, ArH); mass (FAB+) m/z 362
(M++1), 364 (M++3); EI-HRMS, calcd for C17H11Cl4N3S
361.0207, found: 361.0214.
In summary, we have discovered potent antibacterial
activity in new aryl ureas which can be easily afforded
from the Baylis–Hillman chemistry. Further work is
underway to optimize the SAR in the related structures
by introducing more diversity.
5-(3,4-Dichloro-benzyl)-3-(2,4-dichloro-phenyl)-4-imino-
3,4-dihydro-1H-pyrimidin-2-one (46). mmax (KBr) 1656
Acknowledgments
(CONH), 3308 (NH) cmÀ1
;
1H NMR (DMSO-d6,
200 MHz) d = 3.73 (s, 2H, CH2), 7.29 (d, 1H, @CH), 7.56–
7.60 (m, 5H, ArH), 7.86 (s, 1H, ArH); 13C NMR (DMSO-d6,
50.32 MHz) d = 31.5, 129.0, 130.3, 130.5, 130.7, 131.2, 133.0,
134.6, 141.3, 156.9; mass (FAB+) m/z 414 (M+), 416 (M++2);
EI-HRMS, calcd for C17H11Cl4N3O 412.9656, found:
412.9658.
Three of the authors (S.N.N., R.P., and M.K.) grate-
fully acknowledge the financial support from UGC
and CSIR, New Delhi, in the form of fellowship.
The work was supported by a financial grant from
DST, India.

3828
S. Nag et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3824–3828
6. Bacterial strains: five pathogenic bacteria namely Strepto-
coccus faecalis, Klebsiella pneumoniae, Escherichia coli,
Pseudomonas aeruginosa, and Staphylococcus aureus were
obtained from our departmental culture collection and
maintained on nutrient agar slants at 37 ꢁC.7 The purity of
all the cultures was checked before MIC determination.
MIC determination. Minimum inhibitory concentration of
compounds was tested by standard micro broth dilution
method. Briefly, testing was performed in flat bottom 96
well tissue culture plates (CELLSTARꢂ Greiner bio-one
GmbH, Germany) in Muller Hinton broth (Titan biotech
Ltd, India) for bacterial strains. Initial inoculum of
bacterial strains was maintained at 1–5 · 103 cells/ml. The
plates were incubated in a moist chamber at 37 ꢁC and
absorbance at 492 nm was recorded on VersaMax micro-
plate reader (Molecular Devices, Sunnyvale, USA) after for
24 h. MIC was determined as 90% inhibition of growth with
respect to the growth control by using SOFTmax Pro 4.3
Software (Molecular Devices, Sunnyvale, USA).
7. Yadav, P. P.; Gupta, P.; Chaturvedi, A. K.; Shukla,
P. K.; Maurya, R. Bioorg. Med. Chem. 2005, 13,
1497.