The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: Synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation

Article abstract of DOI:10.1016/j.bmcl.2011.03.062

A series of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of biological interest were prepared by sequential Bigineli's reaction, reduction followed by reaction of resulting amines with different arylisocynates. All the synthesized (1-23) compound

Full text of DOI:10.1016/j.bmcl.2011.03.062

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4648–4651
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea:
Synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation
Rajesh H. Tale a, , Atish H. Rodge a, Girish D. Hatnapure b, Ashish P. Keche b
⇑
a Department of Chemistry, School of Chemical Sciences, Swami Ramanand Teerth University (SRTM), Nanded, India
b Department of Chemistry, Udaygiri Mahavidayla, Udgir, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of biological interest were prepared by
sequential Bigineli’s reaction, reduction followed by reaction of resulting amines with different aryliso-
cynates. All the synthesized (1–23) compounds were screened against the pro-inflammatory cytokines
Received 21 December 2010
Revised 2 March 2011
Accepted 16 March 2011
Available online 21 March 2011
(TNF-
study reveled that among all the compounds screened, compounds 12 and 17 found to have promising
anti-inflammatory activity (68–62% TNF- and 92–86% IL-6 inhibitory activity at 10 M). Interestingly
a and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological activity evaluation
a
l
Keywords:
compounds 3, 4, 5, 6, 15, 22 and 23 revealed promising antimicrobial activity at MIC of 10–30 lg/mL
against selected pathogenic bacteria and fungi.
3,4-Dihydropyrimidin-2(1H)-ones
Urea derivatives
Anti-inflammatory
Anti-bacterial
Ó 2011 Elsevier Ltd. All rights reserved.
Anti-fungal
Due to their broad range of pharmacological properties such as
calcium channels blockers, antioxidant, anticancer, and anti-
inflammatory activity of 3,4-dihydropyrimidin-2(1H)-one nucleus
have increasingly attracted the attention of synthetic chemists.1–5
Moreover, the dihydropyrimidine-5-carboxylate core has been
found in several marine natural products which are potent HIV-
gp-120-CD4 inhibitors.6,7 In addition, antimicrobial activity of
3,4-dihydropyrimidone derivatives have been extensively studied
and well established in the literature.8–14 However, relatively there
are very few reports on the anti-inflammatory activity of the 3,4-
dihydropyrimidin-2(1H)-one derivatives,5,15 and most impor-
tantly, the potential of 3,4-dihydropyrimidin-2(1H)-one nucleus
as to their anti-inflammatory activity against the pro-inflamma-
signaling pathways.17,18 IL-6 contributes to the initiation and
extension of the inflammatory process and considered as a central
mediator in a range of inflammatory diseases but has not received
the desired attention in drug discovery.19 TNF-
a and IL-6 are thus
pharmaceutically important molecular targets for the treatment of
the above-mentioned diseases.
Biological importance of heterocyclic derivatives of aryl ureas
have been reported in the literature. For example, N-2,4-
pyrimidine-N,N-phenyl/alkyl ureas were reported to be inhibitor
of tumor necrosis factor alpha (TNF-
urea derivatives is reported as a potent inhibitor of TNF-
a
),20,21 SA13353, substituted
produc-
a
tion,22 pyrido-quinazolone analogues reported as antifungal, anti-
bacterial and anticancer agents.23 However, to the best of our
knowledge, there has been no report on synthesis and evaluation
of biological activities of 3,4-dihydropyrimidinone urea derivatives
despite of their easy synthetic access.
tory cytokines (TNF-a and IL-6) hitherto remained untested.
Non-steroidal anti-inflammatory drugs (NSADs) are therapeuti-
cally important in the treatment of rheumatic arthritis and in var-
ious types of inflammatory conditions, but their therapeutic utility
has been limited due to their frequently observed gastrointestinal
side effects. Thus, there is an urgent need for new targets that are
required for the design and development of novel anti-inflamma-
tory agents as an alternative to NSAIDs.16 Tumor necrosis factor al-
In present study, in order to further expand the scope of
3,4-dihydropyrimidone derivatives as antimicrobial agents and
due to surprise lack of literature on their anti-inflammatory activ-
ity against TNF-a and IL-6, we report herein for the first time our
results on anti-inflammatory activity study of novel 3,4-dihydro-
pha (TNF-
a
)
and interleukin-6 (IL-6), the two important
pyrimidinone urea derivatives against for TNF-
with antimicrobial activities.
a and IL-6 along
multifunctional proinflammatory cytokines are involved in the
pathogenesis of autoimmune, inflammatory, cardiovascular, neu-
rodegenerative and cancer diseases through a series of cytokine
In an attempt to design and develop new potential biological
active compounds, we undertook the synthesis of some series of
novel 3,4-dihydropyrimidin-2(1H)-ones derivatives viz. N-aryl-N0-
[4-(3,4-dihydropyridin-2-(1H)-one] derivatives and evaluation of
their anti-inflammatory and antimicrobial activities.
⇑
Corresponding author. Tel.: +91 2462 229346; fax: +91 0 2462 229245.
E-mail address: rkht_2008@rediffmail.com (R.H. Tale).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.062

R. H. Tale et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4648–4651
4649
Table 1
Our synthetic strategy for 3,4-dihydropyrimidin-2(1H)-ones
Anti-inflammatory activity of 3,4-dihydropyrimidin-
2(1H)-ones urea derivatives
urea derivatives is illustrated in Scheme 1. A key intermediate
ethyl 6-methyl-4-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydropyr-
imidine-5-carboxylate 1 for the proposed synthesis was synthe-
Compound
% Inhibition at 10 lM
sized by heating
a mixture of p-nitrobenzaldehyde, ethyl
TNF-
a
IL-6
acetoacetate and thiourea in ethanol at 80 °C for 8 h using catalytic
amount of PTSA. Reduction of nitro group using SnCl2 in ethyl ace-
tate at room temperature followed by treatment of resulting amine
with different substituted isocynates in THF afforded the structur-
ally diverse 3,4-dihydropyrimidin-2(1H)-one urea derivatives
(3–23) in 70–90% yields.
Having secured the series of the novel 3,4-dihydropyrimidin-
2(1H)-one urea derivatives of N-aryl urea, next in order to search
for the potent compounds from these newly synthesized 3,
4-dihydropyrimidin-2(1H)-ones urea derivatives, compounds 1–
23 were evaluated for in vitro anti-inflammatory, antibacterial
and antifungal activity against various Gram-positive, Gram-nega-
tive bacteria and fungal strains using agar well diffusion method.
SAR of 3,4-dihydropyrimidin-2(1H)-one urea derivatives has
been presented in Tables 1–3 and some interesting trend was ob-
served as to the effect of substituent present on terminal ring of
urea moiety on various activities. It is found from our results
(Tables 1–3) that the lipophilicity as well as nature of the substitu-
ent affecting the biological activity of the synthesized analogues.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0
0
0
8
3
40
43
27
60
36
6
27
11
39
92
73
36
11
40
86
2
0
10
20
0
0
0
2
0
68
16
0
0
3
62
0
0
30
0
3
0
71
16
65
10
55
42
84
Thus, from the TNF-
it is observed that a majority of the analogues of this series found
to be active as IL-6 inhibitor while very few exhibited TNF- inhib-
itory activity. As can be seen from Table 1, compounds 12 and 17
exhibited the good (68% and 62%) TNF- and IL-6 (92% and 86%)
inhibitory activity as compared to the standard dexamethasone
but at higher concentration (10 M) and found to be moderately
potent anti-inflammatory agents.
a and IL-6 inhibitory activity data (Table 1),
Dexamethasone (1
lM)
a
Compounds 6, 13, 20 and 22 exhibited moderate activity
(55–73% inhibition) while other compounds 8, 10, 15 and 18
exhibited low inhibitory activity at same level of concentration.
It is also observed that the two-potent compounds in this series
12 and 17 present no or very low anti-microbial activity, which
a
l
NO2
NO2
S
O
O
a
O
H2N
NH2
O
R
O
NH
CHO
N
H
S
1
b
O
NH2
N
H
NH
c
O
O
O
NH
O
NH
N
H
2
S
N
H
S
3: 2-F
21: 4-butyl
22: 4-CF3
12: 2-Cl, 5-CF3
13: 2-Cl, 4-CF3
14: 2-Cl, 6-F
15: 3-CF3
4: 2-Cl
5: 2-CF3
6: 2-OCF3
7: 2-OC6H5
23: 4-OCH3
16: 3-Cl, 4-F
17: 3,5-F
8: 2-F, 6-CH3
9: 2-F, 6-CF3
18: 3,4-CH3
19: 4-F, 3-CH3
20: 4-isopropyl
10: 2-Cl, 6-CH3
11: 2-Cl, 6-CF3
Scheme 1. Synthesis of novel series of 3,4-dihydropyrimidin-2(1H)-ones urea derivatives. Reagents and conditions: (a) PTSA, EtOH, reflux, 8 h; (b) SnCl2, EtOAc, rt, 4 h; (c)
different substituted isocynates, THF, rt, 6 h.

4650
R. H. Tale et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4648–4651
Table 2
favourable site for the higher potency. Evidently, the compound
12 with Cl and CF3 at 2- and 5-positions, respectively, exhibiting
Antibacterial activity of 3,4-dihydropyrimidin-2(1H)-ones urea derivatives (MICa
values
lg/mL)
highest TNF-a and IL-6 inhibitory activity, while presence of Cl at
Compound
Gram-positive
Gram-negative
2-position and CF3 group at 6-position 11 exhibits no TNF-
a
activity or low IL-6 inhibitory activity. The compound 17 with flu-
oro group at 3- and 5-position of terminal benzene ring showed
Staphylococcus
aureus
Bacillus
subtilis
Escherichia Salmonella
coli
typhimurium
better TNF-
a (62% at 10 lM) and IL-6 (86% at 10 lM) inhibitory
1
2
3
4
5
6
7
8
35
40
10
10
25
30
40
60
55
40
40
55
35
65
40
60
90
90
65
85
—
45
55
15
20
25
30
55
65
40
65
85
85
35
55
55
—
30
40
10
10
15
25
35
30
40
55
60
80
25
85
20
85
—
50
60
40
40
30
20
40
30
60
80
90
90
55
85
40
—
activity. Interestingly, the large bulky lipophilic group such as
isopropyl at 4-position generated compound 20 that was found
to be moderate TNF-
isopropyl group with n-butyl group at 4-position has detrimental
effect on inhibition as it exhibits no TNF-
IL-6 inhibitory activity.
a or IL-6 inhibitor. However, replacement of
a activity or very low
9
The antibacterial activity data is represented in Table 2. As
shown in our results, some analogues of this series were found
to have even more potency than the standard drug ciprofloxacin
while some of them have comparable potency. The compounds
3 and 4 bearing F, Cl group at 2-position are most potent followed
by compounds 5, 6, 22 and 23 bearing CF3, OCF3 and OMe at 2- or
4-position. Thus compounds bearing substituent such as CF3,
OCF3 and OMe at 2- or 4-position of the terminal benzene ring
of urea part found to have higher potency than the compounds
bearing such a group at 3- or 5-positions or at both. Explicitly,
2- or 4-position is the favourable site for high antibacterial activ-
ity. The high potency of 3, 4, 22, and 23 may be attributed to the
presence of lipophilic or H-bond acceptor type group’s placement
such as F, Cl, CF3, OCF3 and OCH3 at 2- or 4-positions. This is fur-
ther supported by the fact that the presence of nonpolar lipo-
philic groups such as isopropyl, n-butyl etc. at 4-position,
compounds 20 and 21, respectively, has no major effect on the
activity. Rest of the compounds bearing substituent such as F,
Cl, CF3, OCF3, OCH3 and OPh at position 3 or 4 or both showed
moderate or no activity with respect to standard drug against
the test strains. No activity was observed in case of compounds
10
11
12
13
14
15
16
17
18
19
20
21
22
23
—
—
—
95
90
85
—
25
20
25
—
—
90
95
—
30
45
25
55
95
10
15
15
20
15
Ciprofloxacin 25
—: No activity was observed up to 200
l
g/mL.
a
Values are the average of three reading.
Table 3
Antifungal activity of 3,4-dihydropyrimidin-2(1H)-ones urea derivatives (MICa values
g/mL)
l
16–19 up to concentration of 200 lg/mL against some bacteria
and fungi.
Compound
Candida
albicans
Aspergillus
niger
Fusarium
solani
Aspergillus
flavus
It is clear from our results (Table 2 vs Table 3) that the SAR of
3,4-dihydropyrimidin-2(1H)-one urea derivatives for antibacterial
activity strongly correlates with their SAR of antifungal activity.
Again the position 2 and 4 of terminal benzene ring is favorable
site for high activity. The compounds 3 and 4 found to be 2.5-fold
more potent than the standard drug Micanazole while 22 and 23
exhibited comparable antifungal activity. Similar to the antibacte-
rial activity trend, nonpolar lipophilic groups such as isopropyl or
n-butyl at 4-position, compounds 20 and 21, respectively, has no
major effect on the antifungal activity also.
1
2
3
4
5
6
7
8
30
55
10
10
25
15
40
50
55
40
60
60
35
40
25
80
95
95
80
90
—
50
40
10
15
40
20
60
35
30
55
65
80
40
60
20
—
60
45
15
15
30
15
30
40
60
40
80
85
60
80
15
95
—
60
60
10
30
30
15
30
40
60
40
55
90
35
90
15
—
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
In conclusion, we have synthesized
a novel series of 3,
4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea in
convenient and atom economic and ecological manner and evalu-
ated their anti-inflammatory and antimicrobial activity. It was
found that amongst all the compounds screened, compounds 12
and 17 showed promising anti-inflammatory activity against
—
—
—
—
—
—
95
90
—
15
25
20
95
95
—
25
30
20
80
—
10
30
15
TNF-a and IL-6. The antimicrobial evaluation study of the synthe-
sized compounds shows moderate high activity against tested bac-
teria and fungi. Most importantly some of the compounds from
this newly synthesised series of 3,4-dihydropyrimidin-2(1H)-one
urea derivatives of N-aryl urea viz. compounds 3 and 4 found to
be much more potent antibacterial and antifungal agents (1.5–
2.5-fold more potent) than the standard drug Ciprofloxacin and
Micanozole, respectively.
15
10
Miconazole 25
—: No activity was observed up to 200
l
/mL.
a
Values are the average of three reading.
could indicate low toxicity associated and should be considered as
ideal anti-inflammatory agents.
Acknowledgments
It is observed that the position of the substituent on terminal
benzene ring of urea moiety has profound effect on the activity.
The 2- and 5-positions on the terminal benzene ring are the
The authors would like to thank Mr. R. B. Ingle department of
microbiology, Shri Shivaji Collage, Akola for biological screening
studies of the newly synthesized compounds.

R. H. Tale et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4648–4651
4651
11. Anil, K. C.; Pragya, A.; Chandrani, M.; Pankaj, K.; Yogesh, Y.; Ajendra, K. S.;
Vibha, Y.; Jyotsana, G.; Rajesh, D.; Hirday, N. J.; Arthur, C. W.; Virinder, S. P.;
Ashok, K. P.; Gainda, L. S. Bioorg. Med. Chem. 2006, 14, 973.
12. Mithun, A.; Bantwal, S. H.; Nalilu, S. K. Eur. J. Med. Chem. 2007, 42, 380.
13. Atul, R. G.; Kiran, S. T.; Fazal, S.; Mukund, V. D.; Kumar, V. S. Tetrahedron 2008,
64, 10214.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.03.062.
14. Chitra, S.; Devanathan, D.; Pandiarajan, K. Eur. J. Med. Chem. 2010, 45, 367.
15. Santosh, N. M.; Sandeep, S. S.; Rupali, D. E.; Jaiprakash, N. S.; Devanand, B. S.
Bioorg. Med. Chem Lett. 2010, 20, 4424.
References and notes
16. Shishoo, C. J.; Ravikumar, T.; Jain, K. S.; Rathod, I. S.; Gandhi, T. P.; Satia, M. C.
Ind. J. Chem. 1999, 38, 1075.
1. Inca, S. Z.; Selma, S.; Semra, C.; Kevser, E. Bioorg. Med. Chem. 2006, 14, 8582.
2. Zamanova, A. V.; Kurbanova, M. M.; Rzaeva, I. A.; Farzaliev, V. M.;
Allakhverdiev, M. A. Russ. J. Appl. Chem. 2010, 83, 293.
3. Hélio, A. S.; Carlindo, B. O.; Roberta, B. A.; Claudio, M. P. P.; Rodolpho, C. B.;
Rodrigo, C.; Vanessa, C. B.; Lucielli, S.; Cristina, W. N. Eur. J. Med. Chem. 2006, 41,
513.
17. Papadakis, K. A.; Targan, S. R. Inflamm. Bowel. Dis. 2000, 6, 303.
18. Krishnamoorthy, S.; Honn, K. V. Cancer Metast. Rev. 2006, 25, 481.
19. Dominic, S. C.; Raj, M. D. Semin. Arthritis Rheum. 2009, 38, 382.
20. Todd, A. B.; Jennifer, A. M.; Michael, P. C.; Mark, S.; Adam, G.; Roger, G. B.;
Matthew, J. L.; Steven, K. L.; John, C. V.; Biswanath, D.; Lily, C. H.; Marlene, J. M.;
Michael, J. J. Bioorg. Med. Chem Lett. 2006, 16, 3510.
4. Prashantha Kumar, B. R.; Gopu, S.; Nasir Baig, R. B.; Srinivasan, C. Eur. J. Med.
Chem. 2009, 44, 4192.
21. Jennifer, A. M.; Todd, A. B.; Michael, P. C.; Mark, S.; Adam, G.; Roger, G. B.;
Matthew, J. L.; Steven, K. L.; John, C. V.; Biswanath, D.; Lily, C. H.; Kimberly, K.
B.; Karen, J.; Richard, L. W.; Michael, J. J. Bioorg. Med. Chem Lett. 2006, 16, 3514.
22. Hiroshi, E.; Ayako, S.; Hiroshi, S.; Noriyoshi, Y.; Hiroyuki, I.; Chikako, S.; Fumio,
T.; Masahiro, O.; Yoshimasa, S.; Masato, H.; Masakazu, B. Bioorg. Med. Chem
Lett. 2010, 20, 4479.
5. Sushilkumar, S. B.; Devanand, B. S. Bioorg. Med. Chem. Lett. 2004, 14, 1733.
6. Heys, L.; Moore, C. G.; Murphy, P. Chem. Soc. Rev. 2000, 29, 57.
7. Aron, Z. D.; Overman, L. E. Chem. Commun. 2004, 253.
8. Nandakumar, A.; Prakasam, T.; Paramasivan, T. P.; Vembu, P.; Ponnuswamy, M.
N.; Ramesh, P. Bioorg. Med. Chem. Lett. 2010, 20, 4252.
9. Pratibha, S.; Nilesh, R.; Gurram, V. K. Bioorg. Med. Chem Lett. 2004, 14, 4185.
10. Kidwai, M.; Saxena, S.; Khalilur, R. K. M.; Thukral, S. S. Eur. J. Med. Chem. 2005,
40, 816.
23. Anjani, K. T.; Mishra, A. K.; Aruna, B.; Pushpa, M.; Sharma, R. K.; Pandey, V. K.;
Vinay, K. S. Bioorg. Med. Chem Lett. 2006, 16, 4581.