Urea/thiourea derivatives of quinazolinone-lysine conjugates: Synthesis and structure-activity relationships of a new series of antimicrobials

Article abstract of DOI:10.1016/j.ejmech.2011.03.041

Synthesis of a series of urea/thiourea/acetamide/sulphonamide derivatives of quinazolinones conjugated lysine has been reported. Structures of the products have been determined by standard spectroscopical studies. All the compounds have been screened for

Full text of DOI:10.1016/j.ejmech.2011.03.041

European Journal of Medicinal Chemistry 46 (2011) 2530e2540
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Urea/thiourea derivatives of quinazolinoneelysine conjugates: Synthesis
and structureeactivity relationships of a new series of antimicrobials
*
G.P. Suresha, R. Suhas, Wethroe Kapfo, D. Channe Gowda
Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570 006, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a series of urea/thiourea/acetamide/sulphonamide derivatives of quinazolinones conjugated
lysine has been reported. Structures of the products have been determined by standard spectroscopical
studies. All the compounds have been screened for their antibacterial studies and structureeactivity
relationship has been developed. The activity profile revealed that the compounds containing urea and
thiourea functionalities along with fluoro group have exerted a highly potent activity. Thus, the title
compounds represent a novel class of potent antimicrobial agents.
Received 17 January 2011
Received in revised form
4 March 2011
Accepted 19 March 2011
Available online 8 April 2011
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
Quinazolinoneelysine conjugates
Urea
Thiourea
Potent microbe inhibitors
1. Introduction
In particular; substituted ureas have attracted attention due to their
range of applications as agricultural pesticides [12] and anti-
Despite a number of antibiotics available for the treatment of
bacterial infections, emergence of multi-drug resistant organisms
has posed a great challenge to the scientists. There appears to be
a need for the development of new drugs with improved efficacy and
better toxicity profile [1]. One of the most frequently encountered
heterocycle in medicinal chemistry is quinazolin-4(3H)-one and its
derivatives are reported to possess diverse biological applications
including antimicrobial [2], analgesic and anti-inflammatory [3],
anti-convulsant [4], anti-cancer [5] and anti-tubercular [6] activities.
The therapeutical applications of essential amino acids have
received a considerable attention in respiratory physiology, cardi-
ology, renal failure, neurological disorders, and congenital defects.
Amongst, lysine is pharmacologically and medicinally significant
because lysine acetylsalicylate (lysine aspirin) and bendazac lysine (a
lysine salt), both derivatives of lysine, have been investigated for their
therapeutical effects on migraine headaches [7], acute respiratory
infections [8] and rheumatoid arthritis [9]. Lysine has been used in
the treatment of recurrent herpetic lesions and aphthous ulcers [10].
Urea is a functional moiety that is commonly found in the natural
products and often displays a wide range of biological activities [11].
convulsants [13]. An unsymmetrically substituted urea is a common
structural feature of many biologically active compounds such as
enzyme inhibitors and pseudopeptides [14]. Unsymmetrically
substituted ureas at amino groups have also been shown to have
a potent HIV-1 protease inhibitory activity [13,14] equipotent
towards both wild and mutant types [14]. Sulfonylureas have been
found to have applications as oral antidiabetic drugs and as herbi-
cides. Some urea derivatives are useful as active ingredients in
antimicrobial, antifungal and algaecides agents [15]. A series of
ureas and thioureas was synthesized, and their inhibitory activities
against NOꢀ production in lipopolysaccharide-activated macro-
phages were evaluated [[16] and references cited therein].
Prompted by the above observations and keeping in mind that
amino acids are known to enhance the physiological effects of some
other drugs when given in together [17] and also in continuation of
our earlier work [2,18,19], we envisioned our approach towards the
synthesis of a novel series of quinazolinone conjugated lysine and
their urea/thiourea/acetamide and methyl sulphonamide deriva-
tives followed by the biological evaluation.
2. Results and discussion
Abbreviations: Boc, t-Butoxycarbonyl; DCM, Dichloromethane; DIEA, Diisopro-
pylethylamine; EDCI, 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide.HCl; HOBt,
1-Hydroxybenzotriazole; TFA, Trifluoro acetic acid.
2.1. Chemistry
Quinazolinones were coupled to lysine using EDCI/HOBt as
a coupling agent and DIEA as a base. The € amino group of lysine
* Corresponding author. Tel.: þ91 821 2419664/þ91 94498 34348 (Mobile).
E-mail address: dchannegowda@yahoo.co.in (D. Channe Gowda).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.03.041

G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
2531
was converted to substituted urea, thiourea, acetamide and methyl
sulphonamide derivatives using isocyanates, isothiocyanates,
acetyl chloride and methyl sulphonyl chloride respectively. The
yields of the synthesized compounds were found to be good and
characterized by M.P., 1H NMR, 13C NMR and mass spectroscopical
techniques. The physical and analytical data of the synthesized
compounds are provided in Table 1. 1H NMR of 4 and 5 showed the
as standard drugs for the assay. The concentration used for the test
compounds and that of the standard drugs remains the same.
It is observed from Table 2 that quinazolinoneelysine conju-
gates (4, 5) have exhibited moderate activity. When C terminal
protected methyl ester was deblocked (8, 9) there is a slight
enhancement in the activity. On the other hand, retaining of C
terminal protection and deblocking of Boc group of Lys led to
a slight decrease in the activity (6, 7). When both the protecting
groups were cleaved (10, 11) it resulted in the scattered activity
than their counter parts.
We took the advantage of € amino group of lysine to convert it
into urea/thiourea/acetamide/sulphonamide derivatives as these
functionalities were found to be essential in the lead pharmaco-
phores like PNU-100480, linezolid etc [24e26]. Further, these
functionalities were substituted with various groups like F, Cl, OMe
and Me since in the earlier studies it has been shown that the
presence of one or more of the aforesaid would lead to the
improvement of the activity [[27] and references cited therein].
As a result, urea (aec of 13, 14, 15, 16) and thiourea (aec of 18,
19, 20, 21) containing compounds have exhibited a highly potent
activity against all the five pathogens tested. But when the € amino
group of Lys was acetylated (23e26) and sulphonated (28e31),
there is a dramatic decrease in the activity. Hence, substitution by
acetylation or sulphonation leads to reduction of the antibacterial
activity. Earlier report [28] described that when O of urea was
replaced by S, the antibacterial activity decreased. But in the
signal at
d 8.15e8.30 doublet (1H) indicating the formation of
amide bond between heterocycle and lysine. The formation of urea/
thiourea derivatives was confirmed by d w8.0e9.5 singlet (1H) and
w6.0e7.2 multiplet (1H) in the 1H NMR spectra and all the aromatic
protons exactly matching the structure. Deprotection of methyl
ester resulted in the formation of COOH group which showed signal
at
d 11.80e12.00 singlet (1H) and all other peaks exactly matching
its structure. Further all the synthesized compounds were
confirmed by mass spectra which are in accordance with their
molecular formulae.
2.2. Biology
Antibacterial activity of the synthesized compounds were tested
against different strains of both gram positive bacteria namely
Bacillus substilis and gram negative bacteria like Escherichia coli,
Pseudomonas fluorescens, Xanthomonas campestris pvs. and Xan-
thomonas oryzae. The results obtained as zone of inhibition (mm)
are presented in Table 2. Streptomycin and tetracycline were used
Table 1
Physical and analytical data of the synthesized compounds.
Entry
Appearance
Yield (%)
M.P. (ꢁC)
Molecular Formula
23H32N4O6
C24H34N4O6
C20H25F3N4O6
C21H27F3N4O6
Theoretical Mol. Wt.
Actual mass values (Mþ
)
4
5
6
7
8
9
10
11
White solid
87
93
86
88
85
84
87
86
80
82
83
81
81
82
96
86
96
91
90
94
83
85
84
82
83
82
92
95
90
94
93
90
84
82
89
88
84
85
86
85
160e162
167e169
e
C
460.23
474.25
474
459.7 (Mꢀ
473.7 (Mꢀ
361.3
)
)
Off white solid
Brownish gummy
Brownish gummy
Off white solid
Off white solid
Brownish gummy
Brownish gummy
Off white solid
Off white solid
Off white solid
Pale yellow solid
White solid
Off white solid
Pale yellow solid
White solid
Off white solid
Pale yellow solid
White solid
e
488
375.4
150e152
156e157
e
C22H30N4O6
446.22
460.23
460.16
474.17
513.18
509.23
497.21
527.19
523.24
511.22
499.16
495.21
483.19
513.18
509.23
497.21
527.2
445.1 (Mꢀ
459.1 (Mꢀ
347.3
)
)
C23H32N4O6
C19H23F3N4O6
C20H25F3N4O6
C25H28ClN5O5
C26H31N5O6
e
359.3 (Mꢀ
515.2
)
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
21c
23
130e132
127e129
140e141
135e136
130e132
139e140
140e142
139e141
149e150
136e137
140e141
150e152
165e167
157e158
158e159
168e170
140e141
150e152
163e165
e
510.8
498.8
529.2
524.4
512.3
501.3
C25H28FN5O5
C26H30ClN5O5
C27H33N5O6
C26H30FN5O5
C24H26ClN5O5
C25H29N5O6
C24H26FN5O5
C25H28ClN5O5
C26H31N5O6
494.1 (Mꢀ
482.2 (Mꢀ
515.2
)
)
510.1
Off white solid
Off white solid
White solid
Off white solid
Off white solid
White solid
C25H28FN5O5
496.3 (Mꢀ
528.2
)
C26H30FN5O4S
C26H31N5O4S
C25H28FN5O4S
C27H32FN5O4S
C27H33N5O4S
C26H30FN5O4S
C25H28FN5O4S
509.21
513.18
541.22
523.23
527.2
510.1
514.7
542.2
522.3 (Mꢀ
528.3
)
Off white solid
Off white solid
Colourless gummy
Colourless gummy
Off white solid
White solid
Off white solid
Colourless gummy
Colourless gummy
Pale yellow gummy
Pale yellow gummy
Off white solid
Off white solid
Brownish gummy
Brownish gummy
513.18
495.19
499.17
527.20
509.21
513.18
402.19
416.21
388.17
402.19
438.16
452.17
424.14
438.16
512.3 (Mꢀ
494.1 (Mꢀ
498.2 (Mꢀ
528.2
)
)
)
C25H29N5O4S
e
C24H26FN5O4S
C26H30FN5O4S
C26H31N5O4S
C25H28FN5O4S
C20H26N4O5
169e170
156e158
167e169
e
508.3 (Mꢀ
512.3 (Mꢀ
403.3
)
)
24
25
26
28
29
30
31
e
C21H28N4O5
417.3
389.2
403.2
439.3
e
C19H24N4O5
e
C20H26N4O5
C19H26N4O6S
C20H28N4O6S
C18H24N4O6S
C19H26N4O6S
120e122
127e129
e
453.1
423.3 (Mꢀ
437.1 (Mꢀ
)
)
e

2532
G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
Table 2
enhancement in the activity than their counter parts. This is due to
the increase of the polarity of these compounds [2] which would
help the molecules to interact or penetrate more through the cell
membranes of microbes and there by inactivating them. This
indicates that increase in the polarity has an impact on the activity.
Also activity towards gram negative bacteria was more compared to
gram positive microorganisms.
Further, increasing the alkyl chain length of quinazolinone
moiety from 2 to 3 carbon atoms causes a slight decrease in the
activity except 7, 11, 25 and 27. Hence, the presence of a propyl
group is found to be essential in exerting more activity compared to
butyl chain which is in good agreement with our earlier reports
[2,29] which describes the conjugation with peptides.
Inhibitory zone (diameter) mm of the synthesized compounds against tested
bacterial strains by disc diffusion method.
Entry
Zone of inhibitiona (mm) ꢂ SD (n ¼ 3)
B.
E.
P.
X.
X.
oryzae
substilis
coli
fluorescens
campestris
pvs.
4
5
6
7
8
9
10
11
8 ꢂ 1.1
6 ꢂ 1.2
9 ꢂ 1.3
11 ꢂ 1.2
8 ꢂ 0.8
12 ꢂ 1.1
7 ꢂ 0.4
12 ꢂ 0.9
9 ꢂ 0.5
8 ꢂ 0.8
8 ꢂ 0.4
6 ꢂ 0.5
10 ꢂ 0.3
10 ꢂ 1.2
14 ꢂ 0.4
11 ꢂ 1.4
10 ꢂ 0.7
12 ꢂ 1.2
29 ꢂ 0.8
25 ꢂ 0.9
36 ꢂ 1.2
29 ꢂ 0.6
22 ꢂ 0.9
34 ꢂ 0.8
32 ꢂ 1.2
27 ꢂ 0.8
34 ꢂ 0.4
30 ꢂ 0.5
23 ꢂ 1.0
35 ꢂ 1.4
34 ꢂ 0.9
24 ꢂ 0.8
36 ꢂ 0.3
33 ꢂ 1.4
23 ꢂ 1.3
33 ꢂ 1.2
35 ꢂ 1.1
25 ꢂ 1.0
34 ꢂ 0.7
34 ꢂ 1.2
25 ꢂ 1.2
32 ꢂ 1.2
12 ꢂ 1.1
7 ꢂ 0.9
9 ꢂ 0.5
10 ꢂ 0.3
12 ꢂ 1.3
14 ꢂ 0.4
11 ꢂ 1.1
9 ꢂ 0.8
10 ꢂ 1.0
10 ꢂ 0.4
9 ꢂ 1.1
9 ꢂ 1.1
12 ꢂ 1.2
13 ꢂ 0.6
12 ꢂ 1.2
10 ꢂ 0.4
13 ꢂ 1.1
28 ꢂ 0.9
26 ꢂ 0.8
37 ꢂ 1.1
28 ꢂ 0.4
24 ꢂ 0.9
36 ꢂ 0.4
30 ꢂ 1.1
28 ꢂ 0.7
33 ꢂ 0.6
28 ꢂ 0.8
25 ꢂ 1.2
34 ꢂ 1.2
33 ꢂ 0.8
27 ꢂ 0.7
38 ꢂ 0.5
30 ꢂ 1.2
25 ꢂ 1.1
34 ꢂ 1.2
34 ꢂ 1.2
28 ꢂ 1.0
36 ꢂ 0.4
32 ꢂ 1.3
26 ꢂ 1.3
33 ꢂ 1.1
11 ꢂ 1.0
6 ꢂ 0.7
11 ꢂ 0.5
10 ꢂ 1.3
9 ꢂ 0.7
8 ꢂ 0.6
14 ꢂ 0.8
24 ꢂ 0.6
22 ꢂ 0.8
35 ꢂ 1.1
25 ꢂ 0.8
20 ꢂ 1.1
36 ꢂ 1.2
28 ꢂ 0.8
24 ꢂ 0.7
35 ꢂ 0.4
29 ꢂ 0.6
22 ꢂ 1.1
35 ꢂ 1.1
33 ꢂ 0.6
23 ꢂ 0.4
36 ꢂ 0.5
32 ꢂ 1.2
22 ꢂ 1.4
34 ꢂ 1.0
34 ꢂ 1.1
23 ꢂ 1.2
36 ꢂ 0.6
33 ꢂ 1.0
23 ꢂ 1.0
34 ꢂ 0.8
9 ꢂ 1.0
10 ꢂ 1.0
28 ꢂ 0.6
23 ꢂ 0.8
36 ꢂ 1.3
26 ꢂ 0.9
21 ꢂ 1.1
35 ꢂ 0.8
30 ꢂ 1.1
25 ꢂ 0.9
35 ꢂ 0.5
28 ꢂ 0.4
24 ꢂ 0.9
36 ꢂ 1.3
32 ꢂ 0.7
22 ꢂ 0.5
38 ꢂ 0.4
33 ꢂ 1.4
23 ꢂ 1.5
35 ꢂ 1.1
33 ꢂ 1.3
23 ꢂ 1.2
38 ꢂ 0.7
34 ꢂ 1.4
24 ꢂ 1.4
32 ꢂ 1.0
10 ꢂ 1.2
9 ꢂ 0.6
12 ꢂ 1.2
29 ꢂ 0.9
28 ꢂ 0.7
36 ꢂ 0.9
30 ꢂ 0.5
25 ꢂ 0.8
35 ꢂ 0.5
30 ꢂ 1.3
28 ꢂ 0.8
34 ꢂ 0.4
29 ꢂ 0.7
26 ꢂ 1.1
36 ꢂ 1.1
34 ꢂ 1.2
26 ꢂ 1.1
35 ꢂ 0.3
32 ꢂ 1.4
24 ꢂ 1.5
36 ꢂ 1.3
35 ꢂ 1.4
28 ꢂ 1.1
36 ꢂ 0.8
33 ꢂ 1.0
25 ꢂ 1.0
34 ꢂ 1.2
12 ꢂ 0.8
8 ꢂ 0.6
Quinazolinones when taken in isolation were inactive against
the panel of organisms, but have shown enhanced activity when
conjugated to Lys and in turn their urea/thiourea derivatives have
exerted high potency revealing the latter’s importance in arresting/
inhibiting the microbial growth.
13a
13b
13c
14a
14b
14c
15a
15b
15c
16a
16b
16c
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
21c
23
3. Conclusion
We have successfully synthesized a series of propyl and butyl
groups containing quinazolinoneelysine conjugates and converted
them to compounds containing C]O, C]S, NHeCOeCH3 and
NHeSO2eCH3 functional groups. The antibacterial activity of the
synthesized compounds showed that the urea and thiourea moie-
ties play a major role in enhancing the activity. Further, it is inter-
esting to note that F attached to the phenyl ring of the conjugates
acts as an active moiety in arresting the growth of the microbes.
Thus the nature of the substituent was found to be crucial to
improve the activity. Also, increasing the alkyl chain length of
quinazolinones from two to three carbon atoms resulted in slight
decrease in the activity. This study extends the knowledge of
different substituents at phenyl ring which might be of interest for
the identification of novel class of antimicrobials.
24
25
26
28
29
30
31
8 ꢂ 1.1
11 ꢂ 0.8
10 ꢂ 1.3
8 ꢂ 0.8
10 ꢂ 0.4
11 ꢂ 1.4
6 ꢂ 0.9
13 ꢂ 0.6
10 ꢂ 1.5
9 ꢂ 0.7
12 ꢂ 0.9
14 ꢂ 1.1
8 ꢂ 0.6
14 ꢂ 0.8
12 ꢂ 1.2
11 ꢂ 0.8
11 ꢂ 1.3
10 ꢂ 0.4
10 ꢂ 1.2
e
4. Experimental
11 ꢂ 1.0
9 ꢂ 0.9
9 ꢂ 1.4
11 ꢂ 1.2
12 ꢂ 0.6
12 ꢂ 1.2
23 ꢂ 0.8
e
12 ꢂ 1.0
10 ꢂ 0.6
11 ꢂ 1.1
e
9 ꢂ 0.8
4.1. Materials
12 ꢂ 0.8
17 ꢂ 0.5
e
11 ꢂ 1.0
21 ꢂ 0.6
e
Streptomycin
Tetracyclin
All chemicals and reagents were obtained from Aldrich (USA),
Spectrochem Pvt. Ltd. (India) and Rankem Pvt. Ltd. (India) and were
used without further purification. Lysine used was of L-configura-
tion and purchased from Advanced Chem. Tech. (Louisville, Ken-
tucky, USA). Silica gel (100e200 mesh) for column chromatography
was purchased from Sisco Research Laboratories Pvt. Ltd., (Mumbai,
India). Melting points were determined on a Thomas Hoover
melting point apparatus and are uncorrected. The 1H NMR spectra
were recorded on 400 MHz Bruker FT-NMR Spectrometer. 13C NMR
spectra were recorded in DMSO-d6 at 100 MHz. The chemical shifts
19 ꢂ 0.6
18 ꢂ 0.5
a
Values are mean of three determinations, the ranges of which are < 5% of the
mean in all cases.
present investigation, it was found that the presence of S is also
equally important which resulted in a highly potent activity. This
may be due to more nucleophilic character of sulphur. The charge
present in the molecule might help in penetrating through the
bacterial cell wall easily there by arresting its growth.
were reported as parts per million (d ppm) using TMS as an internal
Among the halogen substituted compounds, F containing mole-
cules have shown more potent activity which is analogues to earlier
study [27] compared to Cl containing molecules. This could be
attributed to the high electronegative nature of F compared to Cl.
Further, when an H atom of the phenyl ring was replaced by
a methyl group (18a, 19a, 20a, 21a) in F containing compounds, the
activity was slightly decreased. On the other hand, both Me and OMe
containing compounds of urea and thiourea derivatives have shown
equipotency in arresting the growth of pathogens which could be
due to their more electron donating effect. Thus, the order of activity
based on the groups attached to the phenyl ring of ureido and thi-
ouriedo derivatives was found to be F > FeMe > Cl > OMe z Me.
standard. Mass spectra were obtained on LCMSDTrap - XCT instru-
ment. The progress of the reaction was monitored on pre-coated
silica gel plates (Merck) using chloroform/methanol/acetic acid
(8.7:1:0.3) as an eluent system. The bacterial strains used were
obtained from Department of Studies in Biotechnology, University of
Mysore, India. All the chemicals and reagents used for antimicrobial
studies were of bacteriological grade unless otherwise indicated and
were purchased from Hi-media chemicals (Mumbai, India).
4.2. Synthesis
The 3-(4-oxo-3,4-dihydroquinazolin-2-yl)propanoic acid 1 and
When
C
terminal methyl ester of all the compounds is
4-(4-oxo-3,4-dihydroquinazolin-2-yl)butanoic
acid
2
were
deblocked, the resultant COOH containing compounds showed an
synthesized as previously reported using anthranilide, succinic

G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
2533
anhydride and dihydro-3H-pyran-2,6-dione [11,20,21]. Lysine 3
was coupled with aforesaid heterocyclic precursors 1 and 2 using
EDCI/HOBt as a coupling agent and DIEA as a base to get 4 and 5.
The carboxylic group was protected by methyl ester and its removal
was effected by hydrolysis using LiOH. The Boc group was used for
temporary Na protection and its removal was achieved with TFA.
Urea 13 (aec), 14 (aec); thiourea 18 (aec), 19 (aec); acetamide (23,
24) and methyl sulphonamide (28, 29) derivatives of heterocyclic
conjugates of lysine were synthesized by reacting 6 and 7 with
isocyanates 12 (aec), isothiocyanates 17 (aec), acetyl chloride 22,
methyl sulphonyl chloride 27 respectively in presence of DIEA as
a base [22]. The methyl ester group was removed by hydrolysing
with LiOH to obtain respective free acids 15 (aec), 16 (aec); 20
(aec), 21 (aec); 25, 26 and 30, 31. Synthetic structural frame works
of heterocyclic conjugates of lysine and their derivatives such as
urea, thiourea, acetamide and sulphonamide are presented in
Scheme 1 and 2 respectively.
The residue was extracted with EtOAc (30 mL) and the organic layer
was washed with 1N HCl (1 ꢃ 200 mL), water (1 ꢃ 200 mL), satu-
rated NaHCO3 solution (1 ꢃ 200 mL) and brine (1 ꢃ 200 mL). The
organic layer was dried over anhydrous MgSO4 and concentrated at
high vacuum. Chromatography (20% EtOAc-Hexane) over silica gel
(100e200 mesh) provided compound 4 as white powder. 1H NMR
(DMSO-D6, 400 MHz):
d
12.12 (s, 1H), 8.29e8.28 (d, 1H, J ¼ 7.6 Hz),
8.06e8.04 (d, 1H, J ¼ 8.0 Hz), 7.76e7.73 (t, 1H, J ¼ 7.4 Hz), 7.55e7.53
(d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t,1H, J ¼ 7.4 Hz), 6.71 (s, 1H), 4.21e4.16
(m, 1H), 3.57 (s, 3H), 2.84e2.81 (m, 4H), 2.67e2.65 (m, 2H),
1.65e1.50 (m, 2H), 1.34 (s, 9H), 1.32e1.30 (m, 2H), 1.24e1.22 (m, 2H).
13C NMR (DMSO-D6, 100 MHz):
d 173.2, 171.7, 171.0, 162.2, 158.5,
149.0, 134.6, 128.4, 127.6, 126.2, 126.0, 80.2, 52.5, 51.9, 40.4, 31.4, 31.1,
30.2, 30.0, 29.1, 23.9.
4.2.2. Methyl 6-(tert-butoxycarbonylamino)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl)butanamido) hexanoate (5)
The compound 5 was synthesized by following the procedure
described forthe compound 4 using 4-(4-oxo-3,4-dihydroquinazolin-
2-yl)butanoic acid (2.00 g, 8.62 mmol) in DMF (25 mL), H-Lys(Boc)-
OMe.HCl(2.50 g, 8.62mmol), DIEA(6.1mL,34.48mmol), HOBt(1.75g,
12.93 mmol), EDCI (3.50 g, 18.1 mmol) and THF (25 mL). 1H NMR
4.2.1. Methyl 6-(tert-butoxycarbonylamino)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoate (4)
To a stirred solution of 3-(4-oxo-3,4-dihydroquinazolin-2-yl)
propanoic acid (2.00 g, 9.17 mmol) in DMF (25 mL) cooled to 0 ꢁC,
a mixture of H-Lys(Boc)-OMe.HCl (2.71 g, 9.17 mmol), DIEA (6.5 mL,
36.7 mmol), HOBt (1.85 g,13.76 mmol), EDCI (3.70 g,19.2 mmol) and
THF (25 mL) was added. The reaction mixture was stirred overnight
while slowly warming to room temperature. The reaction mixture
was quenched with H2O (10 mL) and the solvent was evaporated.
(DMSO-D6, 400 MHz):
d
12.11 (s, 1H), 8.16e8.14 (d, 1H, J ¼ 7.6 Hz),
8.07e8.05 (d, 1H, J ¼ 7.2 Hz), 7.77e7.73 (t, 1H, J ¼ 8.4 Hz), 7.59e7.57
(d, 1H, J ¼ 8.4 Hz), 7.46e7.42 (t, 1H, J ¼ 7.2 Hz), 6.71 (s, 1H), 4.19e4.13
(m, 1H), 3.59 (s, 3H), 2.87e2.85 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.4 Hz),
2.21e2.18 (t, 2H, J ¼ 7.4 Hz), 1.95e1.92 (m, 2H),1.64e1.49 (m, 2H),1.33
O
HClH2N
O
O
O
O
O
N
O
NH
O
n
NH HN
N
H
O
a
+
OH
N
O
HN
O
n
n=2
n=3
4
O
n=2
n=3
1
5
3
b
2
c
HO
HN
O
O
O
O
O
O
N
NH
N
H
O
NH HN
NH2 .TFA
O
N
O
n
n=2
n
n=2
6
8
n=3
n=3
7
9
b
HO
O
O
N
NH HN
NH2 .TFA
O
n
n=2
10
11
n=3
Scheme 1. Synthesis of heterocyclic conjugates of lysine and their deprotection Reagents and conditions: (a) EDCI/HOBt, DIEA, 0 ꢁC, overnight at rt (b) 50% TFA in DCM, 1 h, rt
(c) LiOH/H2O/MeOH/THF, overnight at rt.

2534
G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
HO
NH HN
n
O
O
O
HO
O
S
O
N
O
N
O
N
O
S
O
O
S
R1
b
N
H
NH HN
NH
NH HN
NH
O
O
O
O
n
n
n=2
n=2
n=3
20(a-c)
21(a-c)
n=2
28
30
31
n=3
n=3
29
b
a(iv)
O
O
O
O
O
O
O
S
O
N
O
N
O
R
R1
a(i)
a(ii)
NH HN
n
N
H
NH HN
N
H
HN
NH
NH2 .TFA
O
O
O
N
n
n
n=2
13(a-c)
14(a-c)
n=2
n=3
18(a-c)
19(a-c)
n=2
n=3
6
7
n=3
a(iii)
b
HO
O
O
O
HO
O
O
O
N
O
O
O
O
R
NH HN
N
H
HN
NH
NH
NH HN
n
NH
b
O
O
N
N
O
n
n
n=2
n=3
15(a-c)
16(a-c)
n=2
n=3
23
24
n=2
n=3
25
26
Scheme 2. Synthesis of urea/thiourea/acetamide/sulphonamide derivatives of the conjugates 6 and 7 where R ¼ 4-Cl, 4-OMe, 5-F and R1 ¼ 4-Fþ6-Me, 2-Me, 3-F; Reagents and
conditions: (a) DIEA/THF, 8h, 0 ꢁC to rt; (i) ReN]C]O, (ii) R1eN]C]S, (iii) CH3eCOeCl, (iv) CH3eSO2eCl, (b) LiOH/H2O/MeOH/THF, overnight at rt.
(s, 9H), 1.32e1.30 (m, 2H), 1.24e1.22 (m, 2H). 13C NMR (DMSO-D6,
100 MHz): 173.4, 171.6, 169.9, 162.5, 158.0, 149.2, 134.3, 128.4, 127.5,
(m, 1H), 2.84e2.81 (m, 4H), 2.67e2.65 (m, 2H), 1.65e1.50 (m, 2H),
1.34 (s, 9H), 1.32e1.30 (m, 2H), 1.24e1.22 (m, 2H). 13C NMR
d
126.3,126.0, 80.0, 52.2, 51.9, 40.5, 34.4, 34.3, 31.2, 29.7, 29.0, 23.2, 23.1.
(DMSO-D6, 100 MHz): d 175.6, 171.6, 171.2, 162.4, 158.3, 149.1,
134.5, 128.2, 127.5, 126.2, 126.0, 80.1, 52.6, 40.3, 31.3, 31.0, 30.3,
29.9, 29.0, 23.5.
4.2.3. Methyl 6-amino-2-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)
propanamido)hexanoate trifluoro acetic acid salt (6)
To a stirred solution of 4 (2.00 g, 4.34 mmol) in DCM (10 mL)
cooled to 0 ꢁC was added 50% TFA in DCM (15 mL) and stirred for 1 h
at the same temperature. The reaction mixture was concentrated at
high vacuum to get the product 6 as TFA salt which was then
recrystallized using hexane and ethyl acetate.
4.2.6. 6-(tert-Butoxycarbonylamino)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl)butanamido) hexanoic acid (9)
The compound 9 was synthesized by following the procedure
described for compound 8 using 5 (0.20 g, 0.42 mmol) in methanol
(0.5 mL), water (0.5 mL), THF (0.5 mL) and LiOH (0.02 g, 0.84 mmol).
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 12.01 (s, 1H),
4.2.4. Methyl 6-amino-2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)
butanamido)hexanoate trifluoro acetic acid salt (7)
The compound 7 was synthesized by following the procedure
described for the compound 6 using 5 (2.00 g, 4.21 mmol) in DCM
(10 mL) and 50% TFA in DCM (15 mL).
8.16e8.14 (d, 1H, J ¼ 7.6 Hz), 8.07e8.05 (d, 1H, J ¼ 7.2 Hz), 7.77e7.73
(t, 1H, J ¼ 8.4 Hz), 7.59e7.57 (d, 1H, J ¼ 8.4 Hz), 7.46e7.42 (t, 1H,
J ¼ 7.2 Hz), 6.71 (s, 1H), 4.19e4.13 (m, 1H), 2.87e2.85 (m, 2H),
2.61e2.57 (t, 2H, J ¼ 7.4 Hz), 2.21e2.18 (t, 2H, J ¼ 7.4 Hz), 1.95e1.92
(m, 2H),1.64e1.49 (m, 2H),1.33 (s, 9H),1.32e1.30 (m, 2H),1.24e1.22
(m, 2H). 13C NMR (DMSO-D6, 100 MHz):
d 174.9, 171.5, 169.7, 162.3,
4.2.5. 6-(tert-Butoxycarbonylamino)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoic acid (8)
157.8, 149.2, 134.3, 128.3, 127.3, 126.1, 125.9, 80.4, 52.1, 40.3, 34.3,
34.0, 31.1, 29.7, 29.0, 23.2, 23.0.
To a stirred solution of 4 (0.20 g, 0.42 mmol) in methanol
(0.5 mL), water (0.5 mL) and THF (0.5 mL), LiOH (0.02 g,
0.84 mmol) was added. The reaction mixture was stirred for 24 h
at room temperature and the solvent was evaporated under
reduced pressure. The residue was dissolved in water and washed
with ethyl acetate. The aqueous layer was acidified with 1N HCl,
extracted with ethyl acetate, dried and evaporated under reduced
pressure to afford 8 as solid which was recrystallized from hexane
4.2.7. 6-Amino-2-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)
propanamido)hexanoic acid trifluoro acetic acid salt (10)
The compound 10 was synthesized by following the procedure
described for compound 6 using 8 (0.10 g, 0.22 mmol) in DCM
(0.5 mL) and 50% TFA in DCM (1 mL).
4.2.8. 6-Amino-2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)
butanamido)hexanoic acid trifluoro acetic acid salt (11)
The compound 11 was synthesized by following the procedure
described for compound 6 using 9 (0.10 g, 0.21 mmol) with 50% TFA
in DCM (1 mL).
and ethyl acetate. 1H NMR (DMSO-D6, 400 MHz):
d 12.12 (s, 1H),
12.01 (s, 1H), 8.29e8.28 (d, 1H, J ¼ 7.6 Hz), 8.06e8.04 (d, 1H,
J ¼ 8.0 Hz), 7.76e7.73 (t, 1H, J ¼ 7.4 Hz), 7.55e7.53 (d, 1H,
J ¼ 8.0 Hz), 7.45e7.41 (t, 1H, J ¼ 7.4 Hz), 6.71 (s, 1H), 4.21e4.16

G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
2535
4.2.9. General procedure for the synthesis of uriedo derivatives
13aec and 14aec
1H, J ¼ 7.4 Hz), 7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40 (t, 1H,
J ¼ 7.2 Hz), 6.91e6.89 (d, 1H, J ¼ 7.2 Hz), 6.79 (s, 3H), 4.21e4.19 (d,
1H, J ¼ 5.2 Hz), 3.79 (s, 3H), 3.56 (s, 3H), 2.99e2.81 (m, 2H),
2.80e2.71 (m, 2H), 2.70e2.58 (m, 2H), 1.66e1.57 (m, 2H), 1.36e1.29
d 173.2, 171.7, 162.1, 157.0,
155.6, 149.2, 134.7, 130.0, 127.2, 126.4, 126.2, 126.1, 121.2, 120.9,
118.3, 110.9, 56.1, 52.4, 52.2, 31.5, 31.3, 30.0, 29.7, 23.3.
To a solution of compound 6/7 (0.42 mmol) and DIEA (0.15 mL,
0.84 mmol) in dry THF (3 mL), the appropriate isocyanates: namely:
1-chloro-4-isocyanatobenzene, 1-isocyanato-4-methoxybenzene
and 1-fluoro-3-isocyanatobenzene (0.63 mmol) was added
respectively at 0 ꢁC. The reaction mixture was stirred for 8 h slowly
warming to room temperature. The solution was filtered and the
solvent was evaporated. The residue was purified by chromatog-
raphy (30% EtOAc-Hexane) over silica gel (100e200 mesh) to give
solid 13aec and 14aec.
(m, 4H). 13C NMR (DMSO-D6, 100 MHz):
4.2.15. Methyl 6-(3-(3-fluorophenyl)ureido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl) propanamido) hexanoate (13c)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 8.58 (s, 1H),
8.30e8.29 (d,1H, J ¼ 7.2 Hz), 8.05e8.04 (d, 1H, J ¼ 7.2 Hz), 7.76e7.72
(t, 1H, J ¼ 7.2 Hz), 7.54e7.52 (d, 1H, J ¼ 8.4 Hz), 7.42e7.39 (m, 2H),
7.21e7.15 (m, 1H), 6.98e6.96 (d, 1H, J ¼ 8.0 Hz), 6.65e6.61 (t, 1H,
J ¼ 7.2 Hz), 6.14 (s, 1H), 4.20e4.19 (d, 1H, J ¼ 5.2 Hz), 3.56 (s, 3H),
3.01e3.00 (d, 2H, J ¼ 6.0 Hz), 2.81e2.80 (d, 2H, J ¼ 7.2 Hz),
2.68e2.60 (m, 2H), 1.66e1.60 (m, 2H), 1.37e1.21 (m, 4H). 13C NMR
(DMSO-D6, 100 MHz): d 172.8, 171.3, 163.7, 156.6, 155.0, 148.8, 134.3,
130.2, 130.2, 126.8,126.0,125.7,120.9,113.3,107.3, 107.1,104.4,104.1,
52.0, 51.8, 31.1, 30.7, 29.6, 29.3, 22.8.
4.2.10. General procedure for the synthesis of thiouriedo derivatives
18aec and 19aec
To a solution of compound 6/7 (0.42 mmol) and DIEA (0.15 mL,
0.84 mmol) in dry THF (3 mL), the appropriate isothiocyanates:
namely: 4-fluoro-1-isothiocyanato-2-methylbenzene, 1-isothiocya-
nato-2-methylbenzene and 1-fluoro-3-isothiocyanatobenzene (0.63
mmol) was added respectively at 0 ꢁC. The reaction mixture was
stirredfor 8 h slowly warmingto room temperature. The solutionwas
filtered and the solvent was evaporated. The residue was purified by
chromatography (30% EtOAc-Hexane) over silica gel (100e200
mesh) to give solid 18aec and 19aec.
4.2.16. Methyl 6-(3-(4-chlorophenyl)ureido)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl) butanamido) hexanoate (14a)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 8.29e8.28 (d, 1H,
4.2.11. General procedure for the synthesis of acetamide and
sulphonamide derivatives 23, 24, 28 and 29
J ¼ 6.8 Hz), 8.05e8.03 (d,1H, J ¼ 8.0 Hz), 7.75e7.72 (t,1H, J ¼ 7.4 Hz),
7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40 (t, 1H, J ¼ 7.4 Hz), 7.33e7.31
(d, 2H, J ¼ 8.0 Hz), 7.22e7.20 (d, 2H, J ¼ 8.0 Hz), 6.28 (br, 1H), 5.90
(br,1H), 4.18 (br, 1H), 3.56 (s, 3H), 2.94e2.92 (d, 2H, J ¼ 5.2 Hz),
2.81e2.80 (d, 2H, J ¼ 6.8 Hz), 2.71e2.60 (m, 2H), 1.97e1.93 (m, 2H),
1.63e1.55 (m, 2H), 1.30e1.21 (m, 4H). 13C NMR (DMSO-D6,
To a stirred solution of 6/7 (0.42 mmol) in DCM (3 mL) were
added DIEA (0.15 mL, 0.84 mmol) and acetyl chloride/sulphonyl
chloride (0.42 mmol) at 0 ꢁC. After stirring at room temperature for
1 h, saturated NaHCO3 was added to the reaction mixture with
vigorous stirring. After stirring for 30 min, the reaction mixture was
then diluted with EtOAc and washed sequentially with brine, 1N
HCl, brine, saturated NaHCO3, and brine. The organic layer was
dried over anhydrous MgSO4. Removal of the volatiles in vacuo
provided the compounds 23, 24, 28 and 29 respectively.
100 MHz):
d 173.3, 171.5, 162.2, 155.8, 151.2, 149.0, 134.3, 129.9,
127.4, 126.4, 126.3, 126.2, 121.3, 120.7, 118.3, 110.8, 56.1, 52.3, 52.2,
34.4, 34.1, 31.0, 29.7, 23.3, 23.0.
4.2.17. Methyl 6-(3-(4-methoxyphenyl)ureido)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl) butanamido) hexanoate (14b)
4.2.12. General procedure for the synthesis of acids by hydrolysis 15
(aec), 16(aec); 20(aec), 21(aec); 25, 26; 30 and 31
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 8.17e8.15 (d, 1H,
J ¼ 7.2 Hz), 8.06e8.03 (m, 2H), 7.79 (s, 1H), 7.76e7.72 (t, 1H,
J ¼ 7.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.4 Hz), 7.45e7.41 (t, 1H, J ¼ 7.2 Hz),
6.92e6.90 (d, 1H, J ¼ 7.6 Hz), 6.84e6.77 (m, 3H), 4.19e4.15 (m, 1H),
3.79 (s, 3H), 3.59 (s, 3H), 3.03e3.02 (m, 2H), 2.60e2.56 (t, 2H,
J ¼ 7.6 Hz), 2.21e2.17 (t, 2H, J ¼ 7.6 Hz),1.95e1.91 (m, 2H), 1.68e1.53
To a stirred solution of 13(aec), 14(aec)/18(aec), 19(aec)/23,
24/28, 29 (0.42 mmol) in methanol (0.5 mL), water (0.5 mL) and
THF (0.5 mL), LiOH (0.02 g, 0.84 mmol) was added. The reaction
mixture was stirred for 24 h at room temperature and the solvent
was evaporated under reduced pressure. The residue was dissolved
in water and washed with ethyl acetate. The aqueous layer was
acidified with 1N HCl, extracted with ethyl acetate, dried and
evaporated under reduced pressure to afford 15(aec), 16(aec); 20
(aec), 21(aec); 25, 26; 30 and 31 respectively which was recrys-
tallized from hexane and ethyl acetate.
(m, 2H), 1.38e1.30 (m, 4H). 13C NMR (DMSO-D6, 100 MHz):
d 173.3,
172.4,162.2,157.4,155.6,149.3,134.7,130.0,127.3,126.4,126.1,121.3,
120.9, 118.3, 110.9, 56.1, 52.4, 52.2, 34.5, 34.2, 31.0, 29.8, 23.3, 23.1.
4.2.18. Methyl 6-(3-(3-fluorophenyl)ureido)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl) butanamido) hexanoate (14c)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 8.58 (s, 1H),
4.2.13. Methyl 6-(3-(4-chlorophenyl)ureido)-2-(3-(4-oxo-3,4-
8.17e8.15 (d, 1H, J ¼ 6.8 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz), 7.76e7.72
(t, 1H, J ¼ 8.1 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (m, 2H),
7.21e7.16 (q, 1H, J ¼ 7.8 Hz), 6.98e6.96 (d, 1H, J ¼ 8.0 Hz), 6.66e6.62
(t, 1H, J ¼ 8.4 Hz), 6.17e6.14 (t, 1H, J ¼ 5.4 Hz), 4.21e4.15 (m, 1H),
3.59 (s, 3H), 3.06e3.01 (m, 2H), 2.60e2.56 (t, 2H, J ¼ 7.6 Hz),
2.21e2.17 (t, 2H, J ¼ 7.6 Hz), 1.95e1.89 (m, 2H), 1.69e1.54 (m, 2H),
1.40e1.34 (m, 2H), 1.29e1.27 (m, 2H). 13C NMR (DMSO-D6,
100 MHz): d 172.9, 171.3, 163.8, 156.7, 149.9, 148.7, 134.3, 130.1, 130.1,
126.9, 126.0, 125.8, 120.9, 113.4, 107.4, 107.2, 104.4, 104.2, 52.0, 51.9,
34.4, 34.1, 29.9, 29.8, 23.2, 23.0.
dihydroquinazolin-2-yl) propanamido) hexanoate (13a)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 8.29e8.28 (d, 1H,
J ¼ 6.8 Hz), 8.05e8.03 (d,1H, J ¼ 8.0 Hz), 7.75e7.72 (t,1H, J ¼ 7.4 Hz),
7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40 (t, 1H, J ¼ 7.4 Hz), 7.33e7.31
(d, 2H, J ¼ 8.0 Hz), 7.22e7.20 (d, 2H, J ¼ 8.0 Hz), 6.28 (br, 1H), 5.90
(br,1H), 4.18 (br, 1H), 3.56 (s, 3H), 2.94e2.92 (d, 2H, J ¼ 5.2 Hz),
2.81e2.80 (d, 2H, J ¼ 6.8 Hz), 2.71e2.60 (m, 2H), 1.63e1.55 (m, 2H),
1.30e1.21 (m, 4H). 13C NMR (DMSO-D6, 100 MHz):
d
173.2, 171.7,
162.1, 160.0, 158.5, 149.2, 134.7, 131.4, 129.2, 128.6, 125.5, 127.2,
126.4, 126.1, 121.3, 52.3, 52.1, 42.6, 31.1, 31.1, 30.1, 30.0, 23.2.
4.2.19. 6-(3-(4-Chlorophenyl)ureido)-2-(3-(4-oxo-3,4-
4.2.14. Methyl 6-(3-(4-methoxyphenyl)ureido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoic acid (15a)
dihydroquinazolin-2-yl) propanamido)hexanoate (13b)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 11.90 (s, 1H),
1H NMR (DMSO-D6, 400 MHz):
d
12.10 (s, 1H), 8.30e8.28 (d, 1H,
8.29e8.28 (d, 1H, J ¼ 6.8 Hz), 8.05e8.03 (d, 1H, J ¼ 8.0 Hz),
J ¼ 6.4 Hz), 8.05e8.03 (d, 2H, J ¼ 5.7 Hz), 7.79 (s, 1H), 7.76e7.72 (t,
7.75e7.72 (t, 1H, J ¼ 7.4 Hz), 7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40

2536
G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
(t, 1H, J ¼ 7.4 Hz), 7.33e7.31 (d, 2H, J ¼ 8.0 Hz), 7.22e7.20 (d, 2H,
J ¼ 8.0 Hz), 6.28 (br,1H), 5.90 (br,1H), 4.18 (br,1H), 2.94e2.92 (d, 2H,
J ¼ 5.2 Hz), 2.81e2.80 (d, 2H, J ¼ 6.8 Hz), 2.71e2.60 (m, 2H),
1.63e1.55 (m, 2H), 1.30e1.21 (m, 4H). 13C NMR (DMSO-D6,
100 MHz): d 175.3, 171.8,162.2, 160.1,158.4, 149.2,134.5, 131.3, 129.1,
128.5, 128.4, 127.1, 126.3, 126.0, 121.2, 52.3, 42.8, 31.2, 31.2, 30.2,
30.1, 23.2.
(m, 1H), 3.06e3.01 (m, 2H), 2.60e2.56 (t, 2H, J ¼ 7.6 Hz), 2.21e2.17
(t, 2H, J ¼ 7.6 Hz), 1.95e1.89 (m, 2H), 1.69e1.54 (m, 2H), 1.40e1.34
(m, 2H), 1.29e1.27 (m, 2H). 13C NMR (DMSO-D6, 100 MHz):
d 175.3,
171.2, 163.7, 156.6, 150.0, 148.7, 134.2, 130.2, 130.2, 126.8, 126.1,
125.7, 120.8, 113.3, 107.5, 107.1, 104.3, 104.1, 52.0, 34.3, 34.0, 29.9,
29.7, 23.1, 22.9.
4.2.25. Methyl 6-(3-(4-fluoro-2-methylphenyl)thioureido)-2-(3-(4-
oxo-3,4-dihydroquinazolin-2-yl)propanamido) hexanoate (18a)
4.2.20. 6-(3-(4-Methoxyphenyl)ureido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoic acid (15b)
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 8.90 (s, 1H),
1H NMR (DMSO-D6, 400 MHz):
d
12.10 (s, 1H), 12.04 (s, 1H),
8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz), 7.76e7.72
(t, 1H, J ¼ 7.6 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t, 1H,
J ¼ 7.6 Hz), 7.41e7.36 (m, 1H), 7.16e7.12 (m, 1H), 7.07e7.04 (m, 1H),
6.98e6.94 (t, 1H, J ¼ 8.4 Hz), 4.17e4.16 (m, 1H), 3.59 (s, 3H),
3.41e3.36 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.21e2.18 (t, 2H,
J ¼ 7.6 Hz), 2.12 (s, 3H), 1.64e1.61 (m, 1H), 1.58e1.55 (m, 1H),
1.48e1.45 (m, 2H), 1.27e1.21 (m, 2H). 13C NMR (DMSO-D6,
8.30e8.28 (d, 1H, J ¼ 6.4 Hz), 8.05e8.03 (d, 2H, J ¼ 5.7 Hz), 7.79 (s,
1H), 7.76e7.72 (t, 1H, J ¼ 7.4 Hz), 7.54e7.52 (d, 1H, J ¼ 8.0 Hz),
7.44e7.40 (t, 1H, J ¼ 7.2 Hz), 6.91e6.89 (d, 1H, J ¼ 7.2 Hz), 6.79 (s,
3H), 4.21e4.19 (d, 1H, J ¼ 5.2 Hz), 3.79 (s, 3H), 2.99e2.81 (m, 2H),
2.80e2.71 (m, 2H), 2.70e2.58 (m, 2H), 1.66e1.57 (m, 2H), 1.36e1.29
(m, 4H). 13C NMR (DMSO-D6, 100 MHz):
d 175.0, 171.7, 162.0, 157.1,
155.5, 149.0, 134.8, 129.2, 127.1, 126.5, 126.3, 126.2, 121.0, 120.7,
118.4, 110.7, 56.2, 52.3, 31.4, 31.2, 29.9, 29.7, 23.3.
100 MHz): d 180.3, 173.1, 171.9, 162.0, 159.9, 157.2, 149.3, 141.7, 134.7,
130.4, 127.2, 126.4, 126.1, 121.2, 120.8, 118.3, 52.3, 52.1, 44.1, 31.4,
31.3, 29.9, 28.4, 23.3, 17.8.
4.2.21. 6-(3-(3-Fluorophenyl)ureido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoic acid (15c)
4.2.26. Methyl 2-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)
1H NMR (DMSO-D6, 400 MHz):
d
12.10 (s, 1H), 12.00 (s, 1H), 8.58
propanamido)-6-(3-o-tolylthioureido) hexanoate (18b)
(s, 1H), 8.30e8.29 (d, 1H, J ¼ 7.2 Hz), 8.05e8.04 (d, 1H, J ¼ 7.2 Hz),
7.76e7.72 (t, 1H, J ¼ 7.2 Hz), 7.54e7.52 (d, 1H, J ¼ 8.4 Hz), 7.42e7.39
(m, 2H), 7.21e7.15 (m, 1H), 6.98e6.96 (d, 1H, J ¼ 8.0 Hz), 6.65e6.61
(t, 1H, J ¼ 7.2 Hz), 6.14 (s, 1H), 4.20e4.19 (d, 1H, J ¼ 5.2 Hz),
3.01e3.00 (d, 2H, J ¼ 6.0 Hz), 2.81e2.80 (d, 2H, J ¼ 7.2 Hz),
2.68e2.60 (m, 2H), 1.66e1.60 (m, 2H), 1.37e1.21 (m, 4H). 13C NMR
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 8.94 (s, 1H),
8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz), 7.76e7.72
(t, 1H, J ¼ 8.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t, 1H,
J ¼ 7.2 Hz), 7.28e7.28 (m, 1H), 7.21e7.12 (m, 4H), 4.19e4.14 (m, 1H),
3.59 (s, 3H), 3.38e3.32 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz),
2.21e2.18 (t, 2H, J ¼ 6.8 Hz), 2.13 (s, 3H), 1.68e1.53 (m, 2H),
1.51e1.44 (m, 2H), 1.27e1.21 (m, 2H). 13C NMR (DMSO-D6,
(DMSO-D6, 100 MHz): d 174.9, 171.2, 163.9, 156.7, 149.9, 148.8, 134.2,
130.2, 130.2, 126.7, 126.0, 125.5, 120.8, 113.1, 107.4, 107.2, 104.4,
104.2, 52.0, 31.0, 30.6, 29.5, 29.2, 22.8.
100 MHz): d 180.1, 172.9, 171.8, 161.9, 160.0, 157.3, 149.4, 141.6, 134.8,
130.3, 127.3, 126.4, 126.0, 121.2, 120.9, 118.4, 52.3, 52.0, 44.0, 31.5,
31.3, 30.0, 28.4, 23.4, 18.0.
4.2.22. 6-(3-(4-Chlorophenyl)ureido)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl)butanamido) hexanoic acid (16a)
4.2.27. Methyl 6-(3-(3-fluorophenyl)thioureido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl) propanamido) hexanoate (18c)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 11.90 (s, 1H),
8.29e8.28 (d, 1H, J ¼ 6.8 Hz), 8.05e8.03 (d, 1H, J ¼ 8.0 Hz),
7.75e7.72 (t, 1H, J ¼ 7.4 Hz), 7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40
(t, 1H, J ¼ 7.4 Hz), 7.33e7.31 (d, 2H, J ¼ 8.0 Hz), 7.22e7.20 (d, 2H,
J ¼ 8.0 Hz), 6.28 (br,1H), 5.90 (br,1H), 4.18 (br,1H), 2.94e2.92 (d, 2H,
J ¼ 5.2 Hz), 2.81e2.80 (d, 2H, J ¼ 6.8 Hz), 2.71e2.60 (m, 2H),
1.97e1.93 (m, 2H), 1.63e1.55 (m, 2H), 1.30e1.21 (m, 4H). 13C NMR
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 9.54 (s, 1H),
8.31e8.30 (d, 1H, J ¼ 7.2 Hz), 8.05e8.04 (d, 1H, J ¼ 7.2 Hz), 7.85 (br,
1H), 7.76e7.72 (t,1H, J ¼ 7.2 Hz), 7.55e7.47 (m, 2H), 7.44e7.40 (t,1H,
J ¼ 7.2 Hz), 7.32e7.26 (q, 1H, J ¼ 7.6 Hz), 7.13e7.11 (d, 1H, J ¼ 7.6 Hz),
6.87e6.84 (t, 1H, J ¼ 8.0 Hz), 4.22e4.20 (m, 1H), 3.57 (s, 3H), 3.40
(br, 2H), 2.82e2.80 (m, 2H), 2.69e2.62 (m, 2H), 1.67e1.58 (m, 2H),
1.51e1.47 (m, 2H), 1.31e1.29 (m, 2H). 13C NMR (DMSO-D6,
(DMSO-D6, 100 MHz):
d 175.2, 171.3, 162.0, 155.7, 151.1, 149.1, 134.2,
129.8, 127.3, 126.4, 126.2, 126.1, 121.2, 120.6, 118.2, 110.7, 56.0, 52.3,
34.3, 34.1, 31.1, 29.8, 23.2, 23.1.
100 MHz): d 180.5, 173.2, 171.7, 162.1, 160.0, 157.3, 149.2, 141.8, 134.7,
130.5, 127.2, 126.4, 126.2, 121.3, 120.9, 118.4, 52.4, 52.2, 44.0, 31.5,
31.2, 30.0, 28.4, 23.3.
4.2.23. 6-(3-(4-Methoxyphenyl)ureido)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl)butanamido) hexanoic acid (16b)
4.2.28. Methyl 6-(3-(4-fluoro-2-methylphenyl)thioureido)-2-(4-(4-
oxo-3,4-dihydroquinazolin-2-yl)butanamido) hexanoate (19a)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 12.06 (s, 1H),
8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.03 (m, 2H), 7.79 (s, 1H),
7.76e7.72 (t, 1H, J ¼ 7.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.4 Hz), 7.45e7.41
(t, 1H, J ¼ 7.2 Hz), 6.92e6.90 (d, 1H, J ¼ 7.6 Hz), 6.84e6.77 (m, 3H),
4.19e4.15 (m, 1H), 3.79 (s, 3H), 3.03e3.02 (m, 2H), 2.60e2.56 (t, 2H,
J ¼ 7.6 Hz), 2.21e2.17 (t, 2H, J ¼ 7.6 Hz), 1.95e1.91 (m, 2H), 1.68e1.53
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 8.90 (s, 1H),
8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz), 7.76e7.72
(t, 1H, J ¼ 7.6 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t, 1H,
J ¼ 7.6 Hz), 7.41e7.36 (m, 1H), 7.16e7.12 (m, 1H), 7.07e7.04 (m, 1H),
6.98e6.94 (t, 1H, J ¼ 8.4 Hz), 4.17e4.16 (m, 1H), 3.59 (s, 3H),
3.41e3.36 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.21e2.18 (t, 2H,
J ¼ 7.6 Hz), 2.12 (s, 3H), 1.97e1.91 (m, 2H), 1.64e1.61 (m, 1H),
1.58e1.55 (m, 1H), 1.48e1.45 (m, 2H), 1.27e1.21 (m, 2H). 13C NMR
(m, 2H), 1.38e1.30 (m, 4H). 13C NMR (DMSO-D6, 100 MHz):
d 174.8,
172.3, 162.3, 157.3, 155.5, 149.2, 134.6, 129.9, 127.3, 126.4, 126.0, 121.3,
121.2, 120.8, 118.2, 110.8, 56.1, 52.3, 34.4, 34.1, 31.0, 29.7, 23.2, 23.0.
(DMSO-D6, 100 MHz): d 180.4, 173.3, 172.4, 162.2, 159.6, 157.4, 149.3,
4.2.24. 6-(3-(3-Fluorophenyl)ureido)-2-(4-(4-oxo-3,4-
141.8, 134.7, 130.3, 127.3, 126.4, 126.1, 121.3, 120.8, 118.8, 110.9, 52.4,
52.2, 43.9, 34.5, 34.2, 31.1, 28.7, 23.3, 23.1, 18.1.
dihydroquinazolin-2-yl)butanamido) hexanoic acid (16c)
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 11.80 (s, 1H), 8.58
(s, 1H), 8.17e8.15 (d, 1H, J ¼ 6.8 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz),
7.76e7.72 (t, 1H, J ¼ 8.1 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(m, 2H), 7.21e7.16 (q, 1H, J ¼ 7.8 Hz), 6.98e6.96 (d, 1H, J ¼ 8.0 Hz),
6.66e6.62 (t, 1H, J ¼ 8.4 Hz), 6.17e6.14 (t, 1H, J ¼ 5.4 Hz), 4.21e4.15
4.2.29. Methyl 2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)
butanamido)-6-(3-o-tolylthioureido) hexanoate (19b)
1H NMR (DMSO-D6, 400 MHz):
d
12.11 (s, 1H), 8.94 (s, 1H),
8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz), 7.76e7.72

G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
2537
Fig. 1. Diagramatic representation of antibacterial activity of the compounds against B. substilis.
(t, 1H, J ¼ 8.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t, 1H,
J ¼ 7.2 Hz), 7.28e7.28 (m, 1H), 7.21e7.12 (m, 4H), 4.19e4.14 (m, 1H),
3.59 (s, 3H), 3.38e3.32 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz),
2.21e2.18 (t, 2H, J ¼ 6.8 Hz), 2.13 (s, 3H), 1.97e1.90 (m, 2H),
1.68e1.53 (m, 2H), 1.51e1.44 (m, 2H), 1.27e1.21 (m, 2H). 13C NMR
(m, 1H), 6.98e6.94 (t, 1H, J ¼ 8.4 Hz), 4.17e4.16 (m, 1H), 3.41e3.36
(m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.21e2.18 (t, 2H, J ¼ 7.6 Hz),
2.12 (s, 3H),1.64e1.61 (m,1H), 1.58e1.55 (m, 1H),1.48e1.45 (m, 2H),
1.27e1.21 (m, 2H). 13C NMR (DMSO-D6, 100 MHz):
d 180.3, 175.2,
171.8, 162.0, 159.8, 157.1, 149.4, 141.8, 134.6, 130.5, 127.1, 126.4, 126.1,
121.1, 120.7, 118.2, 52.4, 44.0, 31.3, 31.1, 30.0, 28.3, 23.2, 17.9.
(DMSO-D6, 100 MHz): d 180.3, 173.2, 172.4, 162.1, 159.6, 157.0, 149.2,
141.7, 134.6, 130.0, 127.5, 126.3, 126.0, 121.1, 120.9, 118.5, 110.7, 52.5,
52.2, 43.9, 34.3, 34.2, 31.1, 28.6, 23.2, 23.0, 17.7.
4.2.32. 2-(3-(4-Oxo-3,4-dihydroquinazolin-2-yl)propanamido)-6-
(3-o-tolylthioureido)hexanoic acid (20b)
4.2.30. Methyl 6-(3-(3-fluorophenyl)thioureido)-2-(4-(4-oxo-3,4-
dihydroquinazolin-2-yl) butanamido) hexanoate (19c)
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 12.01 (s, 1H), 8.94
(s, 1H), 8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz),
7.76e7.72 (t, 1H, J ¼ 8.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(t, 1H, J ¼ 7.2 Hz), 7.28e7.28 (m, 1H), 7.21e7.12 (m, 4H), 4.19e4.14
(m, 1H), 3.38e3.32 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.21e2.18
(t, 2H, J ¼ 6.8 Hz), 2.13 (s, 3H), 1.68e1.53 (m, 2H), 1.51e1.44 (m, 2H),
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 9.54 (s, 1H),
8.18e8.17 (d, 1H, J ¼ 6.8 Hz), 8.06e8.04 (d, 1H, J ¼ 7.2 Hz), 7.86 (br,
1H), 7.76e7.73 (t, 1H, J ¼ 7.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.4 Hz),
7.50e7.41 (m, 2H), 7.32e7.26 (q, 1H, J ¼ 8.2 Hz), 7.12e7.10 (d, 1H,
J ¼ 7.6 Hz), 6.87e6.84 (t, 1H, J ¼ 7.2 Hz), 4.22e4.16 (m, 1H), 3.60 (s,
3H), 3.41 (br, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.22e2.18 (t, 2H,
J ¼ 7.6 Hz), 1.97e1.90 (m, 2H), 1.68e1.54 (m, 2H), 1.52e1.47 (m, 2H),
1.27e1.21 (m, 2H). 13C NMR (DMSO-D6, 100 MHz):
d 180.1, 174.8,
171.7, 161.8, 159.9, 157.4, 149.3, 141.5, 134.9, 130.2, 127.2, 126.3, 126.0,
121.1, 120.8, 118.5, 52.1, 44.3, 31.4, 31.0, 30.0, 28.3, 23.3, 17.9.
1.31e1.29 (m, 2H). 13C NMR (DMSO-D6, 100 MHz):
d 180.0, 173.3,
172.3,162.0,159.7,157.2,149.2,141.6,139.5,129.9,127.4,126.3,121.2,
120.7, 118.2, 110.9, 52.4, 52.3, 43.8, 34.2, 34.1, 31.0, 28.5, 23.1, 22.9.
4.2.33. 6-(3-(3-Fluorophenyl)thioureido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoic acid (20c)
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 12.01 (s, 1H), 9.54
4.2.31. 6-(3-(4-Fluoro-2-methylphenyl)thioureido)-2-(3-(4-oxo-
(s, 1H), 8.31e8.30 (d, 1H, J ¼ 7.2 Hz), 8.05e8.04 (d, 1H, J ¼ 7.2 Hz),
7.85 (br, 1H), 7.76e7.72 (t, 1H, J ¼ 7.2 Hz), 7.55e7.47 (m, 2H),
7.44e7.40 (t, 1H, J ¼ 7.2 Hz), 7.32e7.26 (q, 1H, J ¼ 7.6 Hz), 7.13e7.11
(d, 1H, J ¼ 7.6 Hz), 6.87e6.84 (t, 1H, J ¼ 8.0 Hz), 4.22e4.20 (m, 1H),
3.40 (br, 2H), 2.82e2.80 (m, 2H), 2.69e2.62 (m, 2H), 1.67e1.58 (m,
2H), 1.51e1.47 (m, 2H), 1.31e1.29 (m, 2H). 13C NMR (DMSO-D6,
3,4-dihydroquinazolin-2-yl) propanamido)hexanoic acid (20a)
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 11.91 (s, 1H), 8.90
(s, 1H), 8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz),
7.76e7.72 (t, 1H, J ¼ 7.6 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(t, 1H, J ¼ 7.6 Hz), 7.41e7.36 (m, 1H), 7.16e7.12 (m, 1H), 7.07e7.04
Fig. 2. Diagramatic representation of antibacterial activity of the compounds against E. coli.

2538
G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
Fig. 3. Diagramatic representation of antibacterial activity of the compounds against P. fluorescens.
100 MHz):
d
180.5, 173.2, 171.6, 162.0, 159.9,157.3,149.1,141.6, 134.8,
100 MHz): d 180.2, 175.1, 172.4, 162.1, 159.8, 157.0, 149.1, 141.6, 134.5,
130.6, 127.3, 126.4, 126.1, 121.3, 120.8, 118.6, 52.3, 44.1, 31.6, 31.1,
30.2, 28.3, 23.2.
129.9, 127.4, 126.4, 126.1, 121.0, 120.8, 118.4, 110.6, 52.4, 44.2, 34.2,
34.1, 31.3, 28.9, 23.1, 22.9, 18.0.
4.2.34. 6-(3-(4-Fluoro-2-methylphenyl)thioureido)-2-(4-(4-oxo-
4.2.36. 6-(3-(3-Fluorophenyl)thioureido)-2-(4-(4-oxo-3,4-
3,4-dihydroquinazolin-2-yl) butanamido)hexanoic acid (21a)
dihydroquinazolin-2-yl)butanamido) hexanoic acid (21c)
1H NMR (DMSO-D6, 400 MHz):
d
12.11 (s, 1H), 12.01 (s, 1H), 8.90
1H NMR (DMSO-D6, 400 MHz):
d 12.10 (s, 1H), 12.00 (s, 1H), 9.54
(s, 1H), 8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz),
7.76e7.72 (t, 1H, J ¼ 7.6 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(t, 1H, J ¼ 7.6 Hz), 7.41e7.36 (m, 1H), 7.16e7.12 (m, 1H), 7.07e7.04
(m, 1H), 6.98e6.94 (t, 1H, J ¼ 8.4 Hz), 4.17e4.16 (m, 1H), 3.41e3.36
(m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.21e2.18 (t, 2H, J ¼ 7.6 Hz),
2.12 (s, 3H), 1.97e1.91 (m, 2H), 1.64e1.61 (m, 1H), 1.58e1.55 (m, 1H),
1.48e1.45 (m, 2H), 1.27e1.21 (m, 2H). 13C NMR (DMSO-D6,
(s, 1H), 8.18e8.17 (d, 1H, J ¼ 6.8 Hz), 8.06e8.04 (d, 1H, J ¼ 7.2 Hz),
7.86 (br, 1H), 7.76e7.73 (t, 1H, J ¼ 7.2 Hz), 7.58e7.56 (d, 1H,
J ¼ 8.4 Hz), 7.50e7.41 (m, 2H), 7.32e7.26 (q, 1H, J ¼ 8.2 Hz),
7.12e7.10 (d, 1H, J ¼ 7.6 Hz), 6.87e6.84 (t, 1H, J ¼ 7.2 Hz), 4.22e4.16
(m, 1H), 3.41 (br, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.22e2.18 (t, 2H,
J ¼ 7.6 Hz), 1.97e1.90 (m, 2H), 1.68e1.54 (m, 2H), 1.52e1.47 (m, 2H),
1.31e1.29 (m, 2H). 13C NMR (DMSO-D6, 100 MHz):
d 180.1, 175.5,
100 MHz):
d
180.6, 175.4, 172.3, 162.0, 159.8, 157.3, 149.2, 141.7,
172.2, 161.9, 159.3, 157.0, 149.1, 141.5, 139.7, 130.0, 127.3, 126.2, 126.2,
121.4, 120.6, 118.4, 110.7, 52.3, 43.5, 34.1, 34.0, 31.3, 28.1, 23.0, 22.6.
134.5, 130.2, 127.2, 126.1, 126.0, 121.5, 120.9, 118.5, 110.2, 52.3, 43.6,
34.3, 34.0, 31.6, 28.5, 23.2, 23.0, 17.8.
4.2.37. Methyl 6-acetamido-2-(3-(4-oxo-3,4-dihydroquinazolin-2-
4.2.35. 2-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)butanamido)-6-
yl)propanamido)hexanoate (23)
(3-o-tolylthioureido)hexanoic acid (21b)
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 9.34 (s, 1H),
1H NMR (DMSO-D6, 400 MHz):
d
12.11 (s, 1H), 11.81 (s, 1H), 8.94
8.30e8.28 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 6.8 Hz), 7.76e7.72
(t, 1H, J ¼ 7.8 Hz), 7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40 (t, 1H,
J ¼ 7.6 Hz), 4.20e4.16 (m, 1H), 3.57 (s, 3H), 3.13e3.08 (q, 2H,
J ¼ 6.2 Hz), 2.83e2.80 (t, 2H, J ¼ 6.8 Hz), 2.68e2.62 (q, 2H, J ¼ 8.0 Hz),
2.06 (s, 3H),1.67e1.54 (m, 2H),1.31e1.21 (m, 4H).13C NMR (DMSO-D6,
(s, 1H), 8.17e8.15 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz),
7.76e7.72 (t, 1H, J ¼ 8.2 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(t, 1H, J ¼ 7.2 Hz), 7.28e7.28 (m, 1H), 7.21e7.12 (m, 4H), 4.19e4.14
(m, 1H), 3.38e3.32 (m, 2H), 2.61e2.57 (t, 2H, J ¼ 7.2 Hz), 2.21e2.18
(t, 2H, J ¼ 6.8 Hz), 2.13 (s, 3H), 1.97e1.90 (m, 2H), 1.68e1.53 (m, 2H),
1.51e1.44 (m, 2H), 1.27e1.21 (m, 2H). 13C NMR (DMSO-D6,
100 MHz):
d 173.3, 171.6, 171.2, 162.4, 158.4, 149.1, 134.5, 128.5, 127.4,
126.4, 126.2, 52.3, 52.0, 40.4, 31.3, 31.2, 30.2, 30.0, 23.9, 23.2.
Fig. 4. Diagramatic representation of antibacterial activity of the compounds against X. campestris pvs.

G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
2539
Fig. 5. Diagramatic representation of antibacterial activity of the compounds against X. oryzae.
4.2.38. Methyl 6-acetamido-2-(4-(4-oxo-3,4-dihydroquinazolin-2-
4.2.42. Methyl 6-(methylsulfonamido)-2-(4-(4-oxo-3,4-
yl)butanamido)hexanoate (24)
dihydroquinazolin-2-yl)butanamido) hexanoate (29)
1H NMR (DMSO-D6, 400 MHz):
d
12.10 (s, 1H), 9.34 (s, 1H),
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 9.34 (s, 1H),
8.17e8.14 (t, 1H, J ¼ 7.8 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz), 7.76e7.73
(t, 1H, J ¼ 7.0 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t, 1H,
J ¼ 7.4 Hz), 4.18e4.15 (m, 1H), 3.59 (s, 3H), 3.56e3.51 (m, 2H),
2.61e2.57 (t, 2H, J ¼ 7.4 Hz), 2.28 (s, 3H), 2.24e2.19 (t, 2H,
J ¼ 10.0 Hz), 1.97e1.91 (m, 2H), 1.67e1.53 (m, 2H), 1.27e1.21 (m,
8.17e8.15 (d, 1H, J ¼ 7.6 Hz), 8.06e8.04 (d, 1H, J ¼ 7.2 Hz), 7.77e7.73
(t, 1H, J ¼ 8.0 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41 (t, 1H,
J ¼ 7.6 Hz), 4.21e4.19 (m, 1H), 3.59 (s, 3H), 3.14e3.12 (m, 2H),
2.61e2.57 (t, 2H, J ¼ 7.4 Hz), 2.48 (s, 3H), 2.21e2.17 (t, 2H,
J ¼ 7.6 Hz), 1.95e1.91 (m, 2H), 1.69e1.54 (m, 2H), 1.29e1.24 (m, 4H).
4H). 13C NMR (DMSO-D6,100 MHz):
d
173.1,171.5,171.0,162.3,158.3,
13C NMR (DMSO-D6, 100 MHz):
d 173.4, 171.8, 171.2, 162.6, 158.5,
149.0, 134.5, 128.5, 127.5, 126.4, 126.1, 52.2, 51.9, 40.5, 34.4, 34.3,
31.2, 29.7, 23.2, 23.1, 22.8.
149.1, 134.4, 128.2, 127.6, 126.3, 126.3, 52.4, 51.5, 44.6, 40.7, 34.6,
34.5, 31.1, 29.8, 23.3, 22.6.
4.2.39. 6-Acetamido-2-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)
4.2.43. 6-(Methylsulfonamido)-2-(3-(4-oxo-3,4-
propanamido)hexanoic acid (25)
dihydroquinazolin-2-yl)propanamido)hexanoic acid (30)
1H NMR (DMSO-D6, 400 MHz):
d
12.11 (s, 1H), 11.91 (s, 1H), 9.34
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 11.91 (s, 1H), 9.33
(s, 1H), 8.30e8.28 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 6.8 Hz),
7.76e7.72 (t, 1H, J ¼ 7.8 Hz), 7.54e7.52 (d, 1H, J ¼ 8.0 Hz), 7.44e7.40
(t, 1H, J ¼ 7.6 Hz), 4.20e4.16 (m, 1H), 3.13e3.08 (q, 2H, J ¼ 6.2 Hz),
2.83e2.80 (t, 2H, J ¼ 6.8 Hz), 2.68e2.62 (q, 2H, J ¼ 8.0 Hz), 2.06 (s,
3H), 1.67e1.54 (m, 2H), 1.31e1.21 (m, 4H). 13C NMR (DMSO-D6,
(s, 1H), 8.30e8.28 (d, 1H, J ¼ 7.2 Hz), 8.06e8.04 (d, 1H, J ¼ 6.8 Hz),
7.76e7.72 (t, 1H, J ¼ 8.2 Hz), 7.54e7.52 (d, 1H, J ¼ 8.4 Hz), 7.44e7.41
(t, 1H, J ¼ 7.2 Hz), 4.22e4.16 (m, 1H), 3.13e3.08 (q, 2H, J ¼ 6.4 Hz),
2.83e2.80 (t, 2H, J ¼ 6.8 Hz), 2.68e2.62 (q, 2H, J ¼ 7.8 Hz), 2.47 (s,
3H), 1.67e1.54 (m, 2H), 1.33e1.21 (m, 4H). 13C NMR (DMSO-D6,
100 MHz):
d
175.3, 171.5, 171.0, 162.3, 158.4, 149.0, 134.5, 128.6,
100 MHz): d 175.3, 171.4, 170.8, 162.2, 157.4, 149.3, 134.7, 128.3,
127.4, 126.3, 126.1, 52.4, 40.5, 31.4, 31.3, 30.2, 29.9, 23.9, 23.3.
127.5, 126.2, 126.3, 52.3, 44.4, 40.3, 31.3, 30.2, 30.0, 23.7.
4.2.40. 6-Acetamido-2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)
4.2.44. 6-(Methylsulfonamido)-2-(4-(4-oxo-3,4-
butanamido)hexanoic acid (26)
dihydroquinazolin-2-yl)butanamido)hexanoic acid (31)
1H NMR (DMSO-D6, 400 MHz):
d
12.10 (s, 1H), 11.90 (s, 1H), 9.34
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 12.01 (s, 1H), 9.34
(s, 1H), 8.17e8.14 (t, 1H, J ¼ 7.8 Hz), 8.06e8.04 (d, 1H, J ¼ 7.6 Hz),
7.76e7.73 (t, 1H, J ¼ 7.0 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(t, 1H, J ¼ 7.4 Hz), 4.18e4.15 (m, 1H), 3.56e3.51 (m, 2H), 2.61e2.57
(t, 2H, J ¼ 7.4 Hz), 2.28 (s, 3H), 2.24e2.19 (t, 2H, J ¼ 10.0 Hz),
1.97e1.91 (m, 2H), 1.67e1.53 (m, 2H), 1.27e1.21 (m, 4H). 13C NMR
(s, 1H), 8.17e8.15 (d, 1H, J ¼ 7.6 Hz), 8.06e8.04 (d, 1H, J ¼ 7.2 Hz),
7.77e7.73 (t, 1H, J ¼ 8.0 Hz), 7.58e7.56 (d, 1H, J ¼ 8.0 Hz), 7.45e7.41
(t,1H, J ¼ 7.6 Hz), 4.21e4.19 (m,1H), 3.14e3.12 (m, 2H), 2.61e2.57 (t,
2H, J ¼ 7.4 Hz), 2.48 (s, 3H), 2.21e2.17 (t, 2H, J ¼ 7.6 Hz), 1.95e1.91
(m, 2H), 1.69e1.54 (m, 2H), 1.29e1.24 (m, 4H). 13C NMR (DMSO-D6,
(DMSO-D6, 100 MHz):
d
175.0, 171.5, 169.9, 162.4, 158.3, 149.1, 134.6,
100 MHz): d 175.1, 171.6, 171.0, 162.5, 158.4, 149.0, 134.3, 128.1, 127.4,
128.3, 127.4, 126.4, 126.3, 52.4, 41.1, 34.8, 34.3, 31.3, 29.8, 23.3, 23.1,
22.6.
126.2, 126.2, 52.2, 44.8, 40.5, 34.5, 34.4, 31.1, 29.8, 23.2, 22.5.
4.3. Antibacterial activity
4.2.41. Methyl 6-(methylsulfonamido)-2-(3-(4-oxo-3,4-
dihydroquinazolin-2-yl)propanamido) hexanoate (28)
In vitro antibacterial assay was performed against B. substilis
(Fig. 1), E. coli (Fig. 2), P. fluorescens (Fig. 3), X. campestris pvs. (Fig. 4)
and X. oryzae (Fig. 5) by using the disc diffusion method [23]. The
bacterial strains were maintained on LB agar medium at 28 ꢁC. The
bacteria were grown in LB broth and centrifuged at 10,000 rpm for
5 min. The pellet was dissolved in double distilled water and used
to inoculate the plates. The paper discs containing streptomycin
and tetracycline were used as positive control and DMSO as
1H NMR (DMSO-D6, 400 MHz):
d 12.11 (s, 1H), 9.33 (s, 1H),
8.30e8.28 (d,1H, J ¼ 7.2 Hz), 8.06e8.04 (d,1H, J ¼ 6.8 Hz), 7.76e7.72
(t, 1H, J ¼ 8.2 Hz), 7.54e7.52 (d, 1H, J ¼ 8.4 Hz), 7.44e7.41 (t, 1H,
J ¼ 7.2 Hz), 4.22e4.16 (m, 1H), 3.56 (s, 3H), 3.13e3.08 (q, 2H,
J ¼ 6.4 Hz), 2.83e2.80 (t, 2H, J ¼ 6.8 Hz), 2.68e2.62 (q, 2H,
J ¼ 7.8 Hz), 2.47 (s, 3H), 1.67e1.54 (m, 2H), 1.33e1.21 (m, 4H). 13C
NMR (DMSO-D6, 100 MHz):
d 173.5, 171.6, 171.0, 162.3, 158.5, 149.4,
134.5,128.3,127.5,126.4,126.3, 52.4, 51.8, 44.3, 40.5, 31.4, 30.3, 30.2,
23.8.
a negative control. Each disc contained 10
mg of standard drugs and
10 g of synthesized compounds. The plates were maintained at
m

2540
G.P. Suresha et al. / European Journal of Medicinal Chemistry 46 (2011) 2530e2540
[11] J. Fournier, C. Bruneau, H. Dixneuf, S. Lécolier, J. Org. Chem. 56 (1991)
4
ꢁC for 2 h to allow the diffusion of drugs and then incubated at
4456e4458.
28 ꢁC. All the compounds were tested in triplicate and inhibition
zones were measured in mm after 24 h of incubation.
[12] G. Groszek, Org. Process Res. Dev. 6 (2002) 759e761.
[13] J.C. Emerson, L.H. Steimel, U.S. Patent 11/333155 (2007).
[14] A. Floersheimer, P. Furet, P.W. Manley, G. Bold, E. Boss, V. Guagnano,
A. Vaupel, European Patent 20030755147 (2005).
[15] S. Igarashi, M. Futagawa, N. Tanaka, Y. Kawamura, K. Morimoto, Japanese
Patent 000855 (1998).
Acknowledgements
[16] K.M. Khan, S. Saeed, M. Ali, M. Gohar, J. Zahid, A. Khan, S. Perveen,
M.I. Choudhary, Bioorg. Med. Chem. 17 (2009) 2447e2451.
[17] S. Young, J. Psychiatry, Neurosci 16 (1991) 241e246.
[18] K.N. Shivakumara, K.C. Prakasha, G.P. Suresha, R. Suhas, D.C. Gowda,
Myscience II 2 (2007) 100e106.
One of the authors RS gratefully acknowledges Lady Tata
Memorial Trust, Mumbai for the award of Junior Research
Scholarship.
[19] R. Suhas, S. Chandrashekar, D.C. Gowda, Eur. J. Med. Chem. 46 (2011)
704e711.
References
[20] B.M. Santhosh, P.A. Narasimha, J. Org. Chem. 66 (2001) 9038e9040.
[21] A. Wohlrab, R. Lamer, M.S. VanNieuwenhze, J. Am, Chem. Soc. 129 (2007)
4175e4177.
[22] K. Takahashi, M. Ikura, H. Habashita, M. Nishizaki, T. Sugiura, S. Yamamoto,
S. Nakatani, K. Ogawa, H. Ohno, H. Nakai, M. Toda, Bioorg. Med. Chem. 13
(2005) 4527e4543.
[1] M.L. Cohen, Science 257 (1992) 1050e1055.
[2] G.P. Suresha, K.C. Prakasha, K.N. Shivakumara, Wethroe Kapfo, D.C. Gowda,
Int. J. Pept. Res. Ther. 15 (2009) 25e30.
[3] V. Alagarsamy, V. Raja Solomon, G. Vanikavitha, V. Paluchamy,
S. Amuthalakshmi, M. Ravi Chandran, A. Arnold Sujin, A. Thangathirupathy,
R. Revathi, Biol. Pharm. Bull. 25 (2002) 1432e1435.
[4] V. Alagarsamy, A. Thangathirupathy, S.C. Mandal, S. Rajasekaran,
S. Vijayakumar, R. Revathi, J. Anburaj, S. Arunkumar, S. Rajesh, Ind. J. Pharm.
Sci. 68 (2006) 108e111.
[5] V. Murgan, C.C. Thomas, G.V.S. Rama Sarma, E.P. Kumar, Ind. J. Pharm. Sci. 65
(2003) 386e389.
[6] P. Nandy, M.T. Vishalakshi, A.R. Bhat, Ind. J. Heterocycl. Chem. 15 (2006)
293e294.
[7] H. Chabriat, J.E. Joire, J. Danchot, P. Grippon, M.G. Bousser, Cephalalgia 14
(1994) 297e300.
[23] S. Lemriss, B. Marquet, H. Ginestet, L. Lefeuvre, A. Fassouane, P. Boiron,
J. Mycol. Med. 13 (2003) 189e192.
[24] R. Tokuyama, Y. Takahashi, Y. Tomita, T. Suzuki, T. Yoshida, N. Iwasaki,
N. Kado, E. Okezaki, O. Nagata, Chem. Pharm. Bull. 49 (2001) 347e352.
[25] R. Tokuyama, Y. Takahashi, Y. Tomita, M. Tsubouchi, T. Yoshida, N. Iwasaki,
N. Kado, E. Okezaki, O. Nagata, Chem. Pharm. Bull. 49 (2001) 353e360.
[26] R. Tokuyama, Y. Takahashi, Y. Tomita, M. Tsubouchi, N. Iwasaki, N. Kado,
E. Okezaki, O. Nagata, Chem. Pharm. Bull. 49 (2001) 361e367.
[27] B.S. Holla, M. Mahalinga, M.S. Karthikeyan, P.M. Akberali, N.S. Shetty, Bioorg.
Med. Chem. 14 (2006) 2040e2047.
[28] B.B. Lohray, V.B. Lohary, B.K. Srivastava, P.B. Kapadnis, P. Pandya, Bioorg. Med.
Chem. 12 (2004) 4557e4564.
[29] G.P. Suresha, K.C. Prakasha, Wethroe Kapfo, D.C. Gowda, E. J. Chem. 7 (2010)
449e456.
[8] J.D. Symanski, L.S. Gettes, Drugs 46 (1993) 219e248.
[9] J. Hill, H. Bird, G. Fenn, C. Lee, M. Woodward, V. Wright, J. Clin. Pharm. Ther.
15 (1990) 205e211.
[10] E. Wright, Gen. Dentistry 42 (1994) 40.