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.