A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide moieties: Synthesis, anti-inflammatory and antimicrobial evaluation

Article abstract of DOI:10.1016/j.bmcl.2012.03.092

A series of novel 4-(3-(trifluoromethyl)phenylamino-6-(4-(3-arylureiodo/ arylthioureido/arylsulfonamido)-pyrimidine derivatives of biological interest were prepared by the sequential Suzuki cross coupling, acid amination, reduction followed by reaction of

Full text of DOI:10.1016/j.bmcl.2012.03.092

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3445–3448
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A novel pyrimidine derivatives with aryl urea, thiourea and sulfonamide
moieties: Synthesis, anti-inflammatory and antimicrobial evaluation
Ashish P. Keche a, Girish D. Hatnapure a, Rajesh H. Tale c, Atish H. Rodge c, Satish S. Birajdar a,
Vandana M. Kamble a,b,
⇑
a Department of Chemistry, Maharashtra Udaygiri Mahavidayla, Udgir, India
b Department of Chemistry, The Institute of Science, Bombay, India
c Dendrimer and Bio-organic Chemistry Laboratory, School of Chemical Science, S. R. T. M. University, Nanded, 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 4-(3-(trifluoromethyl)phenylamino-6-(4-(3-arylureiodo/arylthioureido/arylsulfonami-
do)-pyrimidine derivatives of biological interest were prepared by the sequential Suzuki cross coupling,
acid amination, reduction followed by reaction of resulting amine with different arylisocyantes or
arylisothiocyantes or arylsulfonyl chlorides. All the synthesized compounds (1–25) were screened for
Received 1 January 2012
Revised 15 March 2012
Accepted 27 March 2012
Available online 1 April 2012
their pro-inflammatory cytokines (TNF-
fungal). Biological data revealed that among all the compounds screened, compounds 5, 6, 11, 12, 16
and 20 were found to have moderate to potent anti-inflammatory activity (up to 48–78% TNF- and
56–96% IL-6 inhibitory activity) with reference to standard dexamethasone at 10 M. The compounds
a and IL-6) and antimicrobial activity (antibacterial and anti-
Keywords:
Pyrimidine
Urea
Thiourea and sulfonamide derivatives
Anti-inflammatory
Anti-bacterial
a
l
10, 12, 13, 18, 20, 22, 24 and 25 found to have promising antimicrobial activity against all the selected
pathogenic bacteria and fungi.
Ó 2012 Elsevier Ltd. All rights reserved.
Anti-fungal
The treatment of bacterial infections remains a challenging
therapeutic problem because of emerging infectious diseases and
the increasing number of multidrug-resistant microbial pathogens.
Despite the many antibiotics and chemotherapeutics available, the
emergence of old and new antibiotic-resistant bacterial strains in
the last decades leads to a substantial need for new classes of
anti-bacterial agents.1
Pyrimidine and their derivatives are continuously attracting
attention of the medicinal chemists in view of their profound range
of biological activities, anti-HIV-1,2 analgesic agents,3 antiprolifer-
ative,4 and antitumor.5 The pyrimidine nucleus has increasingly
attracted the attention of synthetic chemists. Though the antimi-
crobial activity of pyrimidine derivatives has been extensively
studied and well documented in the literature,6–8 however, rela-
tively reports on the anti-inflammatory activity of the pyrimidine
derivatives,3,9–11 are scare. Moreover, the potential of pyrimidine
derivatives bearing urea, thiourea and sulfonamide moieties as to
their anti-inflammatory activity against the pro-inflammatory
utility has been limited due to their frequently observed gastroin-
testinal side effects. Thus, there is an urgent need for new targets
that are required for the design and development of novel anti-
inflammatory agents as an alternative to NSAIDs.12 Tumor necrosis
factor alpha (TNF-a) and interleukin-6 (IL-6), the two important
multifunctional pro-inflammatory cytokines are involved in the
pathogenesis of autoimmune, inflammatory, cardiovascular, neu-
rodegenerative and cancer diseases through a series of cytokine
signaling pathways.13,14 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 it has not re-
ceived the desired attention in drug discovery.15 TNF-
a and IL-6
are thus pharmaceutically important molecular targets for the
treatment of the above-mentioned diseases.
In recent years we have been engaged in design, synthesis and
anti-inflammatory and antimicrobial activity evaluation of novel
urea, thiourea and sulfonamide derivatives of different heterocy-
cles. We have previously reported the synthesis, anti-inflammatory
and antimicrobial activity evaluation of novel 3,4-dihydropyrimi-
din-2(1H)-ones urea derivatives.16 Encouraged by the results of
our previous work, and in order to further expand the scope of
pyrimidine derivatives as privileged medicinal scaffold, herein we
disclose our results on the anti-inflammatory and antimicrobial
activity evaluation of novel pyrimidine derivatives bearing urea,
thiourea and sulfonamide moieties. Thus a large number 4-(3-(tri-
fluoromethyl)phenylamino-6-(4-(3-arylureiodo/arylthioureido/
cytokines (TNF-a and IL-6) hitherto remained untested.
Non-steroidal anti-inflammatory drugs (NSAIDs) are therapeu-
tically important in the treatment of rheumatoid arthritis and in
various types of inflammatory conditions, but their therapeutic
⇑
Corresponding author. Tel.: +91 022829293; fax: +91 022047962.
E-mail address: m.vandana248@gmail.com (V.M. Kamble).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.092

3446
A. P. Keche et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3445–3448
arylsulfonamido)-pyrimidine derivatives were conveniently syn-
thesized and evaluated for their anti-inflammatory and antimicro-
bial activity.
temperature in 67% yield. The purity of the compounds was
checked by TLC and HPLC. Spectral data 1H NMR, 13C NMR, IR
and MS of the newly synthesized compounds 1–25 was consistent
with the proposed structures.
Our synthetic strategy for the novel 4-(3-(trifluoromethyl)
phenylamino-6-(4-(3-arylureiodo/arylthioureido/arylsulfonamido)-
pyrimidine derivatives is illustrated in Scheme 1. The key interme-
diates 4-chloro-6-(4-nitrophenyl) pyrimidine (2) was synthesized
by Suzuki cross coupling,17 between 4,4,5,5-tetramethyl-2-(4-
nitrophenyl)-1,3,2-dioxaborolane (1) and 2,4-dichloropyrimidine,
in 53% yield. The microwave assisted amination of (2) with 3-(tri-
fluoromethyl) aniline in 2-propanol, under acidic conditions affor-
ded 4-(3-(trifluoromethyl) phenyl amino)-6-(4-nitrophenyl)
pyrimidin (3) in 73% yield.17 The desired amino analog (4) to be
used in subsequent nucleophlic addition reaction, was
obatined by reduction of (3) using SnCl2 in ethyl acetate at room
Having secured a series of structurally diverse 4-(3-(trifluoro-
methyl)
phenyl
amino-6-(4-(3-arylureiodo/arylthioureido/
arylsulfonamido)-pyrimidine derivatives, next in-vitro anti-
inflammatory and antimicrobial activity has been screened for
the new compounds. The results of the anti-inflammatory,
antibacterial and antifungal activity are collected in Tables 1–3
respectively. As shown in Table 1 six compounds, 5, 6, 11, 12, 16
and 20 found to be active against proactive kinas TNF-a and inter-
leukin-6. Especially, compound 5, found to be more active while 6
exhibited similar activity with respect to the standard dexametha-
sone at 10
lM concentration. The compounds 11, 12, 16 and 20
Cl
N
O
B
Br
O
a
b
N
O2N
O2N
O2N
1
2
c
F
F
HN
N
F
N
O2N
3
d
F
F
HN
N
F
N
H2N
4
g
e
F
F
HN
N
F
F
f
HN
F
N
F
N
O
S
O
N
R
N
H
N
H
N
H
F
F
R
O
HN
F
R = 5) 2-F, 3-Cl
6) 4-CH(Me)2
7) 4-SMe
5-11
N
R = 19) 4-Br
19-25
S
N
20) 2-Me,5-F
R
21) 3-Me
22) 4-OCF3
23) 3-CN
24) 2-OF3
8) 3-OMe
N
H
N
H
9) 3, 4-di-Me
10) 3-CF3
12-18 R = 12) 2-CF3
13) 3-CN
11) 4-CN
25) 2,5-di-OMe
14) 4-OMe
15) 4-Cl
16) 2-F
17) 2-Me
18) 3,5-di-CF3
Reagents andConditions :- a) Bis-pinacoloto diborane, Potassium acetate, Pd(OAc)2, DMF, 80 oC, 2 h.
b) 2,4-dichloropyrimidine/Sodiumo carbonate, Pd(PPh3)2Cl2, DME/EtOH/Water.
MW 120 C, 20 min.
c) 3-(trifluoromethyl)aniline/Iso-propanol, conc. HCl, MW 100 oC, 20 min.
d) SnCl2/EtOAc, r.t. 12 h. e) Isocynate/THF, r.t. 1-2 h.
f) Isothiocynate/THF, r.t. 1-2 h. g) Solfonyl chlorides /DCM, Et3N, r.t. 1-2 h.
Scheme 1. Synthesis of novel pyrimidine derivatives containing urea, thiourea, sulfonamide moieties.

A. P. Keche et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3445–3448
3447
Table 1
Table 3
Anti-inflammatory activity of novel pyrimidine derivatives containing urea, thiourea,
sulfonamide moieties
Antifungal activity of novel pyrimidine derivatives containing urea, thiourea,
sulfonamide moieties (MICa values
lg/mL)
Compounds
% Inhibition at 10
l
M NF-
a
IL-6
Compounds
C. albicans
A. niger
F. solani
A. flavus
1
2
3
0
0
0
0
0
0
1
2
3
90
90
—
—
90
—
—
—
—
—
90
—
4
5
6
7
8
9
10
11
12
13
14
15
16
17
0
6
4
5
6
7
8
9
10
11
12
13
14
15
16
17
80
90
—
80
—
—
90
—
—
80
—
—
78
71
0
11
16
28
61
68
11
3
96
90
0
18
27
40
80
82
16
8
90
55
40
25
80
15
20
80
—
—
90
20
60
20
75
15
20
90
90
90
—
90
20
30
20
80
15
20
90
—
35
75
35
90
25
40
—
—
—
—
23
50
0
28
62
0
90
—
90
—
18
19
20
21
0
6
48
14
0
0
18
19
20
21
90
80
90
—
—
95
—
—
—
75
0
90
—
—
11
56
25
8
95
90
—
22
22
—
—
—
23
24
25
0
0
8
72
12
0
26
86
23
24
25
55
30
25
20
20
60
15
15
20
20
15
15
35
20
40
20
Dexamethasone(1
lMl)
Miconazole
No activity was observed up to 200
l
g/ml.
a
Values are the average of three reading.
Table 2
Antibacterial activity of novel pyrimidine derivatives containing urea, thiourea,
sulfonamide moieties (MICa values
g/mL)
l
candidate for drug discovery. The compounds 8, 9, 10, 13, 15, 21
exhibited low to very low anti-inflammatory activity and remain-
ing compounds found to be ineffective as anti-inflammatory
agents. It is to be noted that with only exception of compound 20
all of these active compounds viz., 5, 6, 11, 12 and 16 from the new-
ly synthesized series are either urea or thiourea derivatives and
unfortunately almost no compounds from the corresponding sul-
Compounds
Gram-positive
S. aureus B. subtilis
Gram-negative
S. typhimurium
E. coli
1
—
—
—
—
2
—
—
—
—
3
—
—
—
—
4
—
—
—
—
5
6
7
8
9
10
11
90
25
75
35
90
25
—
—
—
—
fonamide series was found to be effective TNF-a or IL-6 inhibitor.
40
90
30
90
40
—
20
90
30
—
35
—
40
90
30
—
80
—
In order to serach for the potent compound from these newly
synthesized compounds 1–25 were evaluated for in vitro antibac-
terial and antifungal activity against various Gram-positive, Gram-
negative bacteria and fungal strains using agar well diffusion
method. The antimicrobial evaluation data is represented in Tables
2 and 3. As can be seen from our results, many compounds from
the newly synthesized series found to be potent antibacterial and
antifungal agents. Thus the compounds 10, 12, 13, 18, 20, 22, 24
and 25 (Tables 2 and 3) exhibited comparable to or even higher
antibacterial and antifungal activity than the standard Ciprofloxa-
cin and Miconazole respectively almost against all the tested bac-
teria or fungi. Interestingly, the compounds 12, 20, 22, 24 and 25
exhibited potent to same antibacterial and antifungal activity
respectively as that of the standard Ciprofloxacin and Miconazole.
Thus the compounds 20, 22 and 24 found to be most potent among
the series and even more potent than standard ciprofloxacin as
antibacterial agent. Moreover, compounds 22 and 24 were found
to be more potent antibacterial agents than the standard drug
against some bacteria Viz. Staphylococcus aureus, Bacillus subtilis
and Salmonella typhimurium. Compounds 12 and 25 found to be
good antifungal agents as compared to standard Miconazole. To
our surprise, none of the most active anti-inflammatory agents 5,
6, 11, 12, 16, and 20 was found to be active antibacterial or anti-
fungal agents against all the bacteria or fungi screened. The
remaining compounds of this series were found to have moderate
or low activity or no activity.
12
—
—
—
—
13
14
90
—
—
—
90
—
90
—
15
16
17
35
90
—
35
90
—
30
90
—
30
—
—
18
19
20
21
22
23
24
25
20
80
15
90
15
40
10
45
20
25
—
10
—
20
65
10
30
15
25
—
25
—
15
90
15
25
20
25
15
15
90
10
45
10
35
20
Ciprofloxacin
No activity was observed up to 200
l
g/ml.
a
Values are the average of three reading.
were found to have moderate to good activity. TNF-
kin-6 inhibitory activity of thses compounds was in the range of
48–78% and 56–96% respectively but at 10 M and as compared
to the standard (dexamethasone, at 1 g/ml) they found to be
a and interleu-
l
l
moderately potent anti-inflammatory agents. Thus, the compound
5 found to be most potent anti-inflammatory agent amongst the
series of compounds 1–25 and could prove to be promising
The structural–activity relationship of these newly synthesized
compounds is represented in Tables 1–3. It can be seen from our

3448
A. P. Keche et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3445–3448
result (Table 1) that anti-inflammatory activity can be attributed to
the presence of urea or thiourea moiety in the pyrimidine scaffold.
This is due to the fact that bearing one exception (compound 20)
all the active candidates, compound 5, 6, 11, 12 and 16 are the
pyrimidine derivatives bearing either urea or thiourea moiety
and none of the members from the corresponding sulfonamide ser-
ies (compounds 19–25) found to be a potent anti-inflammatory
agent. This is further supported by the fact that compounds 1–3,
devoid of these functionalities found to be ineffective as the anti-
inflammatory agents. The nature of the substituent on benzene
ring of ureido or thioureido terminus found to have strong rele-
vance to the biological activities. Thus the presence of functional-
ities such F, CF3, Cl and isopropyl etc. were found to be suitable
for high potency. Interestingly, in contrast to our previous results,
here the presence of bulky lipophilic isopropyl group (compound
In conclusion, we have synthesized and evaluated the anti-
inflammatory and antimicrobial activity of a novel series pyrimi-
dine derivatives with aryl urea, aryl thiourea and aryl sulfonamide
moieties. The compound 5, 6, 11 and 12 found to be promising
anti-inflammatory agents while compounds 10, 12 and 25 were
found to active antibacterial and antifungal agents. With few
exceptions, overall it has been observed that the urea or thiourea
moiety found to be favorable structural feature for the aninflmma-
tory activity. Thus the presence of functionalities such as F, CF3, Cl
and isopropyl on benzene ring of ureido or thioureido terminus
found to have strong relevance to the anti-inflammatory activity
and Isopropyl, CF3, OCF3, CN, and OMe etc at 2, 3 or 4-position
on benzene ring of ureido, thioureido and sulfonamide terminus
found to be effective antimicrobial and antifungal agents.
6, 71% and 90% TNF-
a
and IL-6 inhibition respectively) found to
Acknowledgments
have strong positive effect on the present activity. The position
of F or CF3 group on the ureido or thioureido terminal ring has dra-
matic effect on the said activity. Our anti-inflammatory activity
data confirmed that the substitution of CF3 at o-position is more
relevant for increasing the biological activity than at m and p posi-
tions. Thus, while the compound 12 with o-CF3 exhibited 68% and
The authors would like to thank Mr. R. B. Ingle department of
microbiology, Shri Shivaji Science College, Akola for biological
screening studies of the newly synthesized compounds.
Supplementary data
82% TNF-
be a potent antiinflammatrory agent, the compound 18 with 3,5-
di-CF3 groups found to have no TNF- or IL-6 inhibitory activity
a and IL-6 inhibitory activity respectively and proved to
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.03.
092.
a
at all. Though we have not a concrete evidence in hand in support
of the actual role of urea or thiourea moiety on the activity at this
time, we can at least speculate that the H-bond donor ability of the
urea or thiourea (not present in sulfonamide framework) along
with the electronic effect of ortho or para substituent might be
responsible for their high anti-inflammatory activity.
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The structural–activity relationship of antibacterial and anti-
fungal activity is represented in Tables 2 and 3 respectively. The
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