Synthesis of uriedo and thiouriedo derivatives of peptide conjugated heterocycles - A new class of promising antimicrobials

Article abstract of DOI:10.1016/j.ejmech.2011.12.012

Forty five new derivatives of ureas and thioureas were synthesized by the reaction of peptide conjugated heterocycles with isocyanates and isothiocyanates respectively. All the compounds have been characterized by IR, ¹H NMR, mass and elemental

Full text of DOI:10.1016/j.ejmech.2011.12.012

European Journal of Medicinal Chemistry 48 (2012) 179e191
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of uriedo and thiouriedo derivatives of peptide conjugated
heterocycles e A new class of promising antimicrobials
*
R. Suhas, S. Chandrashekar, D. Channe Gowda
Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Forty five new derivatives of ureas and thioureas were synthesized by the reaction of peptide conjugated
heterocycles with isocyanates and isothiocyanates respectively. All the compounds have been charac-
terized by IR, 1H NMR, mass and elemental analysis. The compounds were evaluated for their ability to
inhibit the growth of a panel of microorganisms and all the synthesized compounds displayed an
excellent antimicrobial activity. From structureeactivity relationship studies, it was apparent that thio-
ureas infact is slightly more active than ureas. Also, substituents on the phenyl ring of the title
compounds play a key role in the activity. Further, compound 40 is nearly twenty times more potent than
the standard used. These results present a platform for the further studies in this line.
Received 16 June 2011
Received in revised form
6 December 2011
Accepted 7 December 2011
Available online 14 December 2011
Keywords:
Synthesis
Derivatives of conjugates
Uriedo and thiouriedo
Potent antimicrobials
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
likeliness/structural diversity of amino acid residues with the bio-
logical system, currently there is huge tendency of conjugating
The increasing incidence of infection caused by the rapid
development of bacterial resistance to most of the known antibi-
otics is a serious health problem [1]. While many factors may be
responsible for mutations in microbial genomes, it has been widely
demonstrated that the incorrect use of antibiotics can greatly
increase the development of resistant genotypes [2]. As multidrug-
resistant bacterial strains proliferate, the necessity for effective
therapy has stimulated research into the design and synthesis of
novel antimicrobial molecules.
Peptides are among the most versatile bioactive molecules e.g.
many peptide hormones and shorter peptides analogous exert their
action by binding to membrane receptors [3]. Peptides and their
derivatives exhibit a broad spectrum of biological activities such as
antimicrobial [4], antiviral, and anticancer activities [5]. These
novel compounds open up new perspectives in drug design by
providing an entire range of highly specific and non-toxic phar-
maceuticals. With growing application on their synthesis and
bioactivity, chemists and biologists in recent years have directed
considerable attention on the research of peptide-based derivatives
[6,7]. Taking the advantage of low toxicity, biocompatibility and
amino acid/peptide residues with small bioactive heterocyclic
motifs in the field of biomedical research [8].
Urea derivatives have been used for the treatment of a wide
range of solid tumours [9,10]. Urea-based prodrugs have been re-
ported as candidates for melanocyte-directed enzyme prodrug
therapy (MDEPT), in which they release the drug upon exposure to
tyrosinase [11]. Some related urea derivatives also have been re-
ported as protein tyrosine kinases (PTKs) inhibitors, and have
become an important class of potential anticancer drugs [12]. The
urea and the thiourea derivatives have also been used for brain
cancer treatment and as potent inhibitors of human DNA-
topoisomerase II [13]. Moreover, other properties were attributed
to urea derivatives such as HIV-1 protease and cholesterol acyl-
transferase (ACAT) inhibitory activities. They are also promising
therapeutic agents for hypercholesteromia and atherosclerosis
[14,15]. Urea/thiourea derivatives display a wide range of biological
activities including antibacterial, antifungal, antitubercular, anti-
thyroid, antihelmintic, rodenticidal, insecticidal, herbicidal, and
plant growth regulator properties [16e21]. For these reasons, the
synthesis of urea and their functionalized derivatives is of high
interest.
Thus, due to the important properties presented by urea and
thiourea derivatives involving particularly antimicrobial activity,
and in continuation of our programme on development of novel
antimicrobial agents [22e26], in this work we report the synthesis
Abbreviations: Boc, t-Butoxycarbonyl; NMM, N-Methyl morpholine; TFA, Tri-
fluoroacetic acid.
* Corresponding author. Tel.: þ91 821 2419664.
E-mail address: dchannegowda@yahoo.co.in (D.C. Gowda).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.12.012

180
R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
Table 1
of ureas and thioureas of elastin-based peptide conjugated
heterocycles and their activity against various strains of human
pathogens.
Physical and mass data of the synthesized compounds.
Entry
Rfa
Rfb
Yield
(%)
M.P. (ꢂC)
Mol. For.
Mass
(MþþNa)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
40
41
42
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
73
74
75
0.54
0.34
0.33
0.39
0.41
0.41
0.32
0.35
0.31
0.33
0.34
0.40
0.50
0.35
0.34
0.42
0.40
0.40
0.31
0.37
0.34
0.35
0.38
0.42
0.42
0.38
0.43
0.51
0.36
0.44
0.40
0.37
0.39
0.52
0.39
0.39
0.42
0.42
0.36
0.40
0.40
0.38
0.41
0.40
0.40
0.61
0.41
0.45
0.52
0.48
0.50
0.50
0.50
0.47
0.51
0.46
0.50
0.58
0.43
0.46
0.48
0.49
0.51
0.48
0.52
0.49
0.49
0.47
0.54
0.52
0.50
0.54
0.58
0.43
0.51
0.50
0.50
0.51
0.60
0.53
0.50
0.52
0.52
0.49
0.51
0.52
0.50
0.52
0.53
0.52
87.4
87.7
90.6
91.4
92.3
91.8
91.3
85.9
92.8
88.5
90.8
93.0
91.3
91.5
90.3
88.6
90.6
92.3
89.0
91.5
92.5
87.6
86.4
94.8
90.2
91.8
86.3
92.2
87.6
89.5
92.7
93.3
87.9
93.4
89.1
90.0
86.3
91.7
88.7
88.1
94.1
91.7
88.4
86.5
88.8
155e157
90e92
96e98
66e69
109e111
62e65
175e178
180e182
130e132
110e112
85e87
80e83
Gum
110e112
55e57
94e96
140e142
65e68
195e197
109e111
80e82
80e82
105e107
67e70
125e127
133e135
166e168
107e109
163e164
209e211
127e129
135e137
98e100
109e111
89e91
111e112
159e162
80e82
159e161
144e146
110e112
129e130
111e113
122e124
141e143
C
30H27F2N5O3
566.5128
734.6298
730.2593
738.4692
754.6092
750.1095
789.7337
805.2267
801.7054
885.5691
901.3265
897.7008
582.5493
750.4167
746.4637
754.3367
770.0956
766.6413
805.5963
821.2460
817.4638
901.9367
917.4269
913.7763
*
2. Results and discussion
C35H43ClFN7O6
C36H46FN7O7
C37H39F2N7O6
2.1. Chemistry
C37H39ClFN7O6
C38H42FN7O7
C38H48F2N8O7
C38H48ClFN8O7
C39H51FN8O8
C46H48F2N8O7
C46H48ClFN8O7
C47H51FN8O8
The uriedo and thiouriedo derivatives were synthesized by
reacting peptide conjugated heterocycles with isocyanates and
isothiocyanates respectively using NMM as base. All the derivatives
were obtained in high yields. The evidence for the formation of
compounds was obtained from IR, 1H NMR, mass and elemental
analysis. IR spectrum of the ureas and thioureas exhibited peaks at
w1640 cmꢀ1 (C]O) and w2040 cmꢀ1 (C]S) respectively along
with
w3280 cmꢀ1 for NH. 1H NMR spectra showed singlet for one
proton (NH) at w8.10, multiplet for NH at w8.01 for urea
derivatives. On the other hand, singlet at w8.9 (NH) and multiplet
at w8.11 (NH) for thiourea derivatives. Further, all the other peaks
n
C30H27F2N5O2S
n
C35H43ClFN7O5S
C36H46FN7O6S
C37H39F2N7O5S
C37H39ClFN7O5S
C38H42FN7O6S
C38H48F2N8O6S
C38H48ClFN8O6S
n
d
d
d
d
are exactly matching the structure. Also % of each element (C, H, N
and S) of the synthesized compounds was confirmed by elemental
analysis and the values are found to be within ꢁ0.4% of the calcu-
lated ones. The physical and mass data of the derivatives are pre-
sented in Table 1.
C
39H51FN8O7S
C46H48F2N8O6S
C46H48ClFN8O6S
C47H51FN8O7S
C159H211FN32O35
C159H211ClFN32O35
C160H214FN32O36
C28H26Cl2FN5O2
C
C35H43ClFN7O6
C36H46FN7O7
C36H47Cl2FN8O6
C44H47Cl2FN8O6
C28H26Cl2FN5OS
C35H42Cl3N7O4S
C34H45Cl2N7O5S
C35H43ClFN7O5S
C36H46FN7O6S
C36H47Cl3N8O5S
C37H50Cl2N8O6S
C44H47Cl3N8O5S
C45H50Cl2N8O6S
C157H211Cl2FN33O35
C
S
*
*
S
2.2. Biology
576.3267
728.4168
734.2005
730.3691
799.8792
895.6374
592.3691
740.0254
756.6934
750.0951
746.5593
831.4467
824.7265
927.6314
923.4496
*
33H42Cl2FN7O5
The synthesized ureas and thioureas were evaluated for their
ability to inhibit the growth of different strains of human pathogens
of both gram negative organisms like Escherichia coli and Xantho-
monas oryzae and gram positive bacteria namely Klebsiella pneu-
moniae and Coagulase positive staphylococcus and antifungal studies
against Aspergillus niger, Aspergillus flavus and Fusarium oxysporum.
The results obtained as zone of inhibition (mm) and minimum
inhibitory concentration (mg/mL) are presented in Tables 2 and 3
respectively. Amoxicillin and bavistin served as standard drugs
for antibacterial and antifungal studies respectively.
In our earlier article [24,25], we discussed the synthesis and
biological activity of amino acid/peptide conjugated heterocycles.
Also, in another article [26], our group aimed at the synthesis of
ureas/thioureas of lysine-quinazolinone conjugates. Prompted by
the results obtained in these studies, the present work involved the
synthesis and antimicrobial screening of a series of urea/thiourea
derivatives of peptide conjugated 6-fluoro-3-(4-piperidinyl)-1,2-
benzisoxazole (Heterocycle 1) and 1-(2,3-dichlorophenyl)pipera-
zine (Heterocycle 2).
Among the derivatives synthesized, compounds containing
thiourea group (23e34, 59e67, 41e42 and 74e75) have exhibited
enhanced activity compared to urea derivatives (11e22, 53e58, 40
and 73). This would be due to the electronegativity and larger size
of S which could alter the binding affinity of thioureas in the
interacting site/s. This is supported by the earlier works [26,28].
Also, S and O atoms in the molecules are likely to act as hydrogen
bond acceptors [28]. Due to these reasons, the synthesized ureas
and thioureas might have exerted highly potent activity.
The results of the derivatives appeared to be related to the
nature of the substituent group on the phenyl ring of ureas/thio-
ureas. The compounds with electron withdrawing groups were
more active with low MIC values. However, electron donating
group did not present significant results as the latter did. In addi-
tion, it should be noted that the fluoro containing molecules are
better than Cl, while the methoxy is comparable. This may be due to
electronic effects [26,29]. This trend was observed in all the
compounds used herein whether they were ureas or thioureas.
157H211Cl3N33O35
S
S
*
*
C158H214Cl2N33O36
*Confirmed by elemental analysis.
This reveals that substituent on the aromatic ring has an impact on
the activity.
Among the derivatives of two heterocycles 1 and 2, compounds
containing piperidine nucleus (11e34, 40e42) have shown slight
enhancement in the activity over the piperazine analogues (53e67,
73e75). The reason could be more lipophilic nature of piperidine
moiety [30] along with the presence of benzisoxazole and fluoro
groups. Whereas in piperazine, it contains only Cl groups attached
to phenyl ring. This clearly demonstrates the importance of lip-
ophilicity for the antimicrobial activity.
Further, it has been reported in our earlier papers that [23e25]
as the length and hydrophobicity of the peptide chain increases,
activity also increases. This trend has been observed in the current
investigation also.
Based on the primary growth inhibition activity, compounds
that showed potent effects were selected to determine the
minimum inhibitory inhibition (MIC). As a result, the derivatives of
peptide conjugates have exhibited very high activity compared to
peptide conjugates devoid of ureas/thioureas [24,25]. Particularly it
is interesting to note that derivatives of tricosamer conjugates
(40e42 and 73e75) have inhibited the growth of fungal species at

R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
181
Table 2
Inhibitory zone (diameter) mm of the synthesized derivatives against tested bacterial and fungal strains by agar well diffusion method.
Entry
Antibacterial activity
Antifungal activity
Zone of inhibitiona (mm) ꢁ SD (n ¼ 3)
E. coli
X. oryzae
K. pneumoniae
C. positive staphylococcus
A. niger
A. flavus
F. oxysporum
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
40
41
42
53
54
55
56
57
11 ꢁ 0.40
26 ꢁ 0.26
22 ꢁ 0.40
31 ꢁ 0.36
28 ꢁ 0.51
26 ꢁ 0.55
34 ꢁ 0.25
30 ꢁ 0.55
26 ꢁ 0.40
39 ꢁ 0.41
34 ꢁ 0.35
30 ꢁ 0.37
13 ꢁ 0.32
28 ꢁ 0.56
24 ꢁ 0.56
32 ꢁ 0.41
30 ꢁ 0.45
24 ꢁ 0.43
35 ꢁ 0.40
31 ꢁ 0.32
28 ꢁ 0.56
41 ꢁ 0.30
35 ꢁ 0.10
31 ꢁ 0.26
24 ꢁ 0.30
21 ꢁ 0.30
17 ꢁ 0.30
09 ꢁ 0.35
29 ꢁ 0.40
27 ꢁ 0.60
25 ꢁ 0.40
33 ꢁ 0.49
37 ꢁ 0.40
10 ꢁ 0.45
27 ꢁ 0.45
23 ꢁ 0.30
29 ꢁ 0.45
23 ꢁ 0.32
29 ꢁ 0.61
27 ꢁ 0.11
32 ꢁ 0.43
29 ꢁ 0.47
22 ꢁ 0.50
19 ꢁ 0.50
15 ꢁ 0.32
12 ꢁ 0.57
e
11 ꢁ 0.35
22 ꢁ 0.35
17 ꢁ 0.30
29 ꢁ 0.40
25 ꢁ 0.45
24 ꢁ 0.40
35 ꢁ 0.50
26 ꢁ 0.52
33 ꢁ 0.15
40 ꢁ 0.25
35 ꢁ 0.51
30 ꢁ 0.41
12 ꢁ 0.35
25 ꢁ 0.32
20 ꢁ 0.36
30 ꢁ 0.30
27 ꢁ 0.36
22 ꢁ 0.35
36 ꢁ 0.17
32 ꢁ 0.20
28 ꢁ 0.23
41 ꢁ 0.34
36 ꢁ 0.50
31 ꢁ 0.55
21 ꢁ 0.45
17 ꢁ 0.26
14 ꢁ 0.51
09 ꢁ 0.30
26 ꢁ 0.25
24 ꢁ 0.28
23 ꢁ 0.15
34 ꢁ 0.52
38 ꢁ 0.15
10 ꢁ 0.41
24 ꢁ 0.30
19 ꢁ 0.41
26 ꢁ 0.41
21 ꢁ 0.36
31 ꢁ 0.35
26 ꢁ 0.52
33 ꢁ 0.51
28 ꢁ 0.47
19 ꢁ 0.47
16 ꢁ 0.32
13 ꢁ 0.37
09 ꢁ 0.26
e
08 ꢁ 0.05
18 ꢁ 0.37
16 ꢁ 0.36
27 ꢁ 0.23
23 ꢁ 0.26
19 ꢁ 0.34
33 ꢁ 0.20
29 ꢁ 0.28
27 ꢁ 0.45
36 ꢁ 0.32
33 ꢁ 0.20
30 ꢁ 0.32
09 ꢁ 0.26
21 ꢁ 0.30
14 ꢁ 0.20
28 ꢁ 0.20
26 ꢁ 0.23
21 ꢁ 0.41
35 ꢁ 0.55
30 ꢁ 0.25
26 ꢁ 0.26
37 ꢁ 0.36
34 ꢁ 0.37
31 ꢁ 0.37
22 ꢁ 0.36
19 ꢁ 0.26
16 ꢁ 0.05
10 ꢁ 0.20
23 ꢁ 0.20
22 ꢁ 0.17
18 ꢁ 0.20
32 ꢁ 0.37
35 ꢁ 0.30
11 ꢁ 0.35
20 ꢁ 0.47
13 ꢁ 0.17
25 ꢁ 0.20
20 ꢁ 0.43
24 ꢁ 0.45
22 ꢁ 0.36
32 ꢁ 0.20
29 ꢁ 0.32
21 ꢁ 0.28
18 ꢁ 0.20
15 ꢁ 0.25
08 ꢁ 0.26
e
08 ꢁ 0.20
19 ꢁ 0.30
14 ꢁ 0.20
25 ꢁ 0.40
21 ꢁ 0.50
17 ꢁ 0.41
30 ꢁ 0.32
27 ꢁ 0.32
23 ꢁ 0.25
34 ꢁ 0.37
31 ꢁ 0.30
28 ꢁ 0.40
09 ꢁ 0.26
21 ꢁ 0.21
16 ꢁ 0.25
26 ꢁ 0.25
24 ꢁ 0.30
19 ꢁ 0.36
31 ꢁ 0.47
28 ꢁ 0.15
24 ꢁ 0.30
36 ꢁ 0.32
32 ꢁ 0.25
29 ꢁ 0.43
22 ꢁ 0.30
17 ꢁ 0.36
15 ꢁ 0.30
11 ꢁ 0.30
24 ꢁ 0.15
20 ꢁ 0.32
16 ꢁ 0.06
29 ꢁ 0.36
33 ꢁ 0.31
12 ꢁ 0.20
22 ꢁ 0.35
18 ꢁ 0.11
23 ꢁ 0.25
18 ꢁ 0.34
26 ꢁ 0.25
22 ꢁ 0.35
30 ꢁ 0.20
26 ꢁ 0.23
20 ꢁ 0.49
16 ꢁ 0.41
14 ꢁ 0.17
08 ꢁ 0.25
e
12 ꢁ 0.11
27 ꢁ 0.49
23 ꢁ 0.37
34 ꢁ 0.36
31 ꢁ 0.36
27 ꢁ 0.36
36 ꢁ 0.10
33 ꢁ 0.38
30 ꢁ 0.10
40 ꢁ 0.30
38 ꢁ 0.23
35 ꢁ 0.51
13 ꢁ 0.45
29 ꢁ 0.52
26 ꢁ 0.28
35 ꢁ 0.26
33 ꢁ 0.49
28 ꢁ 0.46
37 ꢁ 0.31
34 ꢁ 0.57
31 ꢁ 0.32
41 ꢁ 0.41
39 ꢁ 0.35
36 ꢁ 0.45
46 ꢁ 0.35
45 ꢁ 0.21
43 ꢁ 0.25
10 ꢁ 0.36
32 ꢁ 0.40
30 ꢁ 0.17
26 ꢁ 0.36
35 ꢁ 0.06
39 ꢁ 0.43
11 ꢁ 0.46
28 ꢁ 0.41
25 ꢁ 0.40
32 ꢁ 0.28
29 ꢁ 0.23
32 ꢁ 0.42
29 ꢁ 0.29
34 ꢁ 0.15
32 ꢁ 0.30
48 ꢁ 0.26
44 ꢁ 0.20
42 ꢁ 0.43
e
09 ꢁ 0.28
24 ꢁ 0.10
19 ꢁ 0.32
29 ꢁ 0.23
26 ꢁ 0.32
20 ꢁ 0.36
32 ꢁ 0.25
29 ꢁ 0.49
27 ꢁ 0.26
35 ꢁ 0.34
31 ꢁ 0.52
29 ꢁ 0.21
10 ꢁ 0.20
27 ꢁ 0.36
22 ꢁ 0.32
30 ꢁ 0.25
29 ꢁ 0.21
23 ꢁ 0.26
33 ꢁ 0.20
30 ꢁ 0.25
26 ꢁ 0.49
36 ꢁ 0.15
32 ꢁ 0.30
30 ꢁ 0.15
43 ꢁ 0.44
40 ꢁ 0.34
38 ꢁ 0.23
11 ꢁ 0.30
28 ꢁ 0.30
25 ꢁ 0.36
19 ꢁ 0.32
31 ꢁ 0.31
34 ꢁ 0.35
12 ꢁ 0.40
26 ꢁ 0.49
21 ꢁ 0.32
28 ꢁ 0.06
22 ꢁ 0.40
24 ꢁ 0.26
23 ꢁ 0.32
30 ꢁ 1.00
28 ꢁ 0.42
42 ꢁ 0.41
39 ꢁ 0.32
37 ꢁ 0.43
e
08 ꢁ 0.32
26 ꢁ 0.26
21 ꢁ 0.23
31 ꢁ 0.40
28 ꢁ 0.35
23 ꢁ 0.30
33 ꢁ 0.06
32 ꢁ 0.34
27 ꢁ 0.41
39 ꢁ 0.11
35 ꢁ 0.42
32 ꢁ 0.44
07 ꢁ 0.26
29 ꢁ 0.36
24 ꢁ 0.35
32 ꢁ 0.32
31 ꢁ 0.25
25 ꢁ 0.25
35 ꢁ 0.26
31 ꢁ 0.46
26 ꢁ 0.58
40 ꢁ 0.30
36 ꢁ 0.37
33 ꢁ 0.35
44 ꢁ 0.40
41 ꢁ 0.35
39 ꢁ 0.40
07 ꢁ 0.20
30 ꢁ 0.32
27 ꢁ 0.45
22 ꢁ 0.32
32 ꢁ 0.15
34 ꢁ 0.35
06 ꢁ 0.11
28 ꢁ 0.34
23 ꢁ 0.40
30 ꢁ 0.36
24 ꢁ 0.47
29 ꢁ 0.36
24 ꢁ 0.25
31 ꢁ 0.75
29 ꢁ 0.23
43 ꢁ 0.25
40 ꢁ 0.31
38 ꢁ 0.17
e
58
59
60
61
62
63
64
65
66
67
73
74
75
Amoxicillin
Bavistin
12 ꢁ 0.31
09 ꢁ 0.26
10 ꢁ 0.20
a
Values are mean of three determinations, the ranges of which are <5% of the mean in all cases.
a concentration of 1e3
than the standard antibiotic used.
m
g/mL which is nearly 10e25 fold greater
nearly 20e25 fold greater activity than the standard used in the
assay. Thus, the present findings provide new opportunity for the
development of novel antimicrobials to overcome the ever-
increasing problem of drug resistance.
3. Conclusion
In conclusion, we prepared a series of urea and thiourea deriv-
atives of peptide conjugated heterocycles and evaluated their
inhibitory activities on the growth of pathogenic bacteria and fungi.
These have exhibited highly promising activity. Introduction of S in
place of O in the ureas has led to enhanced results. Presence of
electron withdrawing substituents particularly F is found to be
essential for potent activity compared to electron donating group.
Among the analogues of two heterocyclic conjugates, piperidine
nucleus bearing compounds have shown more activity compared to
piperazine moiety containing derivatives. The most striking feature
of this study is that F and Cl containing urea/thiourea derivatives of
4. Experimental
4.1. Materials
All the amino acids used except glycine were of L-configuration
unless otherwise mentioned. TFA was purchased from Advanced
Chem. Tech. (Louisville, Kentucky, USA). NMM and phenyl-
isocyanate/isothiocyanate were purchased from Sigma Chemical
Co. (St. Louis, MO). All solvents and reagents used for the synthesis
were of analytical grade. All the chemicals and reagents used for
antimicrobial studies were of bacteriological grade unless other-
wise indicated. Nutrient broth and nutrient agar were purchased
tricosamer conjugates 40 (1.25 mg/mL) and 41 (1.75 mg/mL) have

182
R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
Table 3
Minimum inhibitory concentration (MIC) in
m
g/mL of the synthesized derivatives against tested bacterial and fungal strains by microdilution method.
Entry
Antibacterial activity Antifungal activity
Minimum inhibitory concentration (MIC) in m
g/mLa
E. coli
X. oryzae
K. pneumoniae
C. positive staphylococcus
A. niger
A. flavus
F. oxysporum
14
12
09
09
11
09
13
14
17
18
20
21
26
29
30
32
33
40
41
42
7.75
9.25
5.00
6.25
11.50
7.25
8.75
4.75
6.00
e
6.75
8.50
5.00
6.50
8.50
6.25
8.00
4.75
6.25
e
5.25
6.75
3.25
4.75
8.25
5.00
6.50
3.00
4.50
e
6.75
8.75
4.25
6.00
10.25
6.25
8.00
4.00
5.75
e
5.00
6.50
3.25
4.75
8.50
4.75
6.00
3.00
4.50
1.25
1.75
2.00
11
5.75
7.50
4.75
6.25
12.25
5.50
6.75
4.50
6.00
1.25
1.75
2.00
14
7.00
8.50
4.25
6.00
13.25
6.75
8.00
4.00
5.75
1.50
2.50
2.00
15
e
e
e
e
e
e
e
e
54
13
10
10
12
57
58
64
66
73
74
75
8.25
5.50
9.50
6.75
e
7.25
5.75
8.75
6.75
e
6.00
4.00
7.00
5.00
e
7.25
5.00
9.00
6.25
e
5.50
4.00
6.75
5.00
2.00
2.50
2.75
e
6.25
5.25
7.75
6.50
1.75
2.50
2.75
e
7.50
5.00
8.75
6.25
2.00
3.00
3.25
e
e
e
e
e
e
e
e
e
Amoxicillin
Bavistin
24
e
19
e
20
e
23
e
22
26
25
‘e’ ¼ not determined.
a
Values are median of three determinations.
from Hi-media chemicals (Mumbai, India). The pathogens used for
the microbial studies were obtained from a local hospital. The
progress of the reaction was monitored by TLC using silica gel
coated on glass plates with the solvent system comprising chloro-
form/methanol/acetic acid in the ratio 95:5:3 (Raf )/90:10:3 (Rfb)
throughout the study and the compounds on TLC plates were
detected by iodine vapours. Melting points were determined on
a Thomas Hoover melting point apparatus and are uncorrected. FT-
IR was performed in Jasco Spectrometer. 1H NMR spectra were
obtained on VARIAN 400 MHz instrument using CDCl3 and the
was concentrated at high vacuum to get TFA$H-Xaa-Heterocycle 1/2
(6e10/36/48e52/69) which was then triturated with dry ether,
filtered, washed with ether and dried under vacuum (Yield: 100%).
4.4. General procedure for the synthesis of uriedo derivatives
(11e22, 53e58, 37 and 70)
To a solution of TFA$H-Xaa-Heterocycle 1/2 (0.001 mol) in DMF
(10 mL/g of compound), cooled to 0 ꢂC was added NMM (0.219 mL,
0.002 mol). To this solution respective isocyanate like 2F-phenyl
isocyanate, 4Cl-phenyl isocyanate and 4OMe-phenyl isocyanate
(0.0012 mol) was added dropwise maintaining the temperature at
chemical shifts are reported as parts per million (d ppm) using TMS
as an internal standard. Electrospray ionization mass spectrometry
(ESI-MS) was performed on a Bruker electrospray mass spectrom-
eter. Elemental analysis was performed by using VARIO EL III Ele-
mentar and the values are within ꢁ0.4% of the calculated ones.
0
ꢂC. The reaction mixture was stirred for 8 h slowly warming to
room temperature. DMF was evaporated under high vacuum and
the residue was poured into about 20 mL ice-cold 90% saturated
KHCO3 solution and stirred for 15 min. The precipitated compound
was extracted with ethyl acetate and washed sequentially with 5%
NaHCO3 solution (2 ꢃ 20 mL), water (2 ꢃ 20 mL), 0.1 N HCl
(2 ꢃ 20 mL) followed by brine solution. The organic layer was dried
over anhydrous sodium sulphate. The solvent was removed under
reduced pressure, triturated with hexane and dried under vacuum.
4.2. Synthesis
All the amino acid/peptide conjugates were prepared according
to the procedure described in our earlier reports [24,25]. The g-
carboxyl group of Glu was protected by cyclohexyl ester and
removed by treatment with polymer supported HCOOꢀNH3þ, 10%
PdeC [27]. The Boc group was used for temporary Na protection and
its removal was achieved with TFA. These were converted into urea
and thiourea derivatives of the conjugates by reacting with isocy-
anates and isothiocyanates respectively in presence of NMM as
a base. The procedure followed for the synthesis of derivatives of
heterocycle 1 conjugates are presented in Scheme 1 and 2 where as
that of the derivatives of heterocycle 2 conjugates are given in
Scheme 3 and 4 respectively.
4.5. General procedure for the synthesis of thiouriedo derivatives
(23e34, 59e67, 38e39 and 71e72)
To a solution of TFA$H-Xaa-Heterocycle 1/2 (0.001 mol) in DMF
(10 mL/g of compound), cooled to 0 ꢂC was added NMM (0.219 mL,
0.002 mol). To this solution respective isothiocyanates like
2F-phenyl isothiocyanate, 4Cl-phenyl isothiocyanate and 4OMe-
phenyl isothiocyanate (0.0012 mol) was added dropwise main-
taining the temperature at 0 ꢂC. The reaction mixture was stirred
for 8 h slowly warming to room temperature. DMF was evaporated
under high vacuum and the residue was poured into about 20 mL
ice-cold 90% saturated KHCO3 solution and stirred for 15 min. The
precipitated compound was extracted with ethyl acetate and
washed sequentially with 5% NaHCO3 solution (2 ꢃ 20 mL), water
4.3. General procedure for the deblocking of conjugated compounds
100 mg of Boc-Xaa-Heterocycle 1/2 (1e5/35/43e47/68) was
stirred with 1.0 mL of TFA for 1 h at room temperature. After the
completion of the reaction monitored by TLC, the reaction mixture

R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
183
Scheme 1. Schematic representation of the synthesis of uriedo/thiouriedo derivatives of amino acid/peptides conjugated heterocycle 1. Reagents and conditions: (a) TFA, 40 min, rt
(b) ReN]C]O, NMM/DMF, 8 h, 0 ꢂC to rt (c) ReN]C]S, NMM/DMF, 8 h, 0 ꢂC to rt where Xaa ¼ Trp, GGIP, GGFP, GVGVP, GFGFP; R ¼ 2F, 4Cl, 4OMe.
(2 ꢃ 20 mL), 0.1 N HCl (2 ꢃ 20 mL) followed by brine solution. The
organic layer was dried over anhydrous sodium sulphate. The
solvent was removed under reduced pressure, triturated with
hexane and dried under vacuum.
4.6.2. 4Cl-Urea derivative of G1G2I3P4-Heterocycle 1 (12)
IR nmax (nujol): 1644 (CO), 3324 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.15 (1H, s, NH), 7.94 (1H, m, NH), 7.05e7.88 (4H, m,
ArH); eNH ¼ 8.05e8.14 (2H, m); Gly1 ¼ 3.90 (2H, s, eaCH);
Gly2 ¼ 4.18 (2H, s, eaCH); Ile3 ¼ 0.89e1.04 (6H, m, e(CH3)2), 1.44
(2H, m, egCH2), 2.14 (1H, m, ebCH), 4.68 (1H, m, eaCH);
Pro4
¼
1.93e3.60 (6H, m, eCH2), 4.61 (1H, m, eaCH);
4.6. Deprotection of OcHx of Glu of the derivatives
Heterocycle ¼ 1.84,1.95 (4H, m, eCH2), 2.87 (1H, m, eCH), 3.65 (4H,
m, eCH2), 7.05e7.88 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 59.02, H ¼ 6.09, N ¼ 13.77, Found C ¼ 59.05, H ¼ 6.11, N ¼ 13.74.
To a solution of the derivatives 37e39 and 70e72 (0.001 mol) in
methanol (10 mL/g of compound), 10% PdeC (100 mg) and polymer
supported formate (1 g) were added and the mixture was stirred at
room temperature for 8 h. After completion of the reaction moni-
tored by TLC, catalyst and the polymer were filtered, washed with
methanol. The solvent was evaporated under reduced pressure and
the product was taken into CHCl3, washed with saturated NaCl and
the solvent was dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and triturated with ether and
dried to get side chain deprotected derivatives 40e42 and 73e75
respectively.
4.6.3. 4OMe-Urea derivative of G1G2I3P4-Heterocycle 1 (13)
IR nmax (nujol): 1615 (CO), 3312 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.10 (1H, s, NH), 7.90 (1H, m, NH), 7.00e7.81 (4H, m,
ArH), 3.60 (3H, s, OMe); eNH ¼ 8.01e8.08 (2H, m); Gly1 ¼ 3.94 (2H,
s, eaCH); Gly2 ¼ 4.20 (2H, s, eaCH); Ile3 ¼ 0.92e1.01 (6H, m,
e(CH3)2), 1.47 (2H, m, egCH2), 2.18 (1H, m, ebCH), 4.69 (1H, m,
eaCH); Pro4 ¼ 1.89e3.58 (6H, m, eCH2), 4.64 (1H, m, eaCH);
Heterocycle ¼ 1.88,1.97 (4H, m, eCH2), 2.81 (1H, m, eCH), 3.68 (4H,
m, eCH2), 7.00e7.81 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 61.09, H ¼ 6.55, N ¼ 13.85, Found C ¼ 61.04, H ¼ 6.52, N ¼ 13.44.
4.6.1. 2F-Urea derivative of Trp-Heterocycle 1 (11)
IR nmax (nujol): 1604 (CO), 3305 (NH); 1H NMR data (CDCl3,
4.6.4. 2F-Urea derivative of G1G2F3P4-Heterocycle 1 (14)
d
ppm): Urea ¼ 8.22 (1H, s, NH), 8.13 (1H, m, NH), 7.06e7.85 (4H, m,
IR nmax (nujol): 1629 (CO), 3278 (NH); 1H NMR data (CDCl3,
ArH); Trp ¼ 3.57e3.73 (2H, d, ebCH2), 4.65 (1H, t, eaCH), 6.99 (1H, s,
eCH of indole), 7.06e7.85 (4H, m, ArH), Exchanged (eNH of indole);
Heterocycle ¼ 1.93e1.96 (4H, m, eCH2), 2.97 (1H, m, eCH),
3.80e3.87 (4H, m, eCH2), 7.06e7.85 (3H, m, ArH); Elemental
Analysis: Calc. C ¼ 66.29, H ¼ 5.01, N ¼ 12.88, Found C ¼ 66.25,
H ¼ 5.04, N ¼ 12.86.
d
ppm): Urea ¼ 8.05 (1H, s, NH), 7.69 (1H, m, NH), 6.95e7.97 (4H, m,
ArH); eNH ¼ 8.10e8.53 (2H, s); Gly1 ¼ 3.82 (2H, s, eaCH);
Gly2 ¼ 4.07 (2H, s, eaCH); Phe3 ¼ 3.60, 3.71 (2H, d, ebCH2), 4.95 (1H,
t, eaCH); 6.95e7.97 (5H, m, ArH); Pro4 ¼ 2.00e3.95 (6H, m, eCH2),
4.65 (1H, m, eaCH); Heterocycle ¼ 1.90e1.97 (4H, m, eCH2), 2.93
Scheme 2. Schematic representation of the synthesis of uriedo/thiouriedo derivatives of tricosamer conjugated heterocycle 1. Reagents and conditions: (a) TFA, 40 min, rt
(b) 2FePheN]C]O, NMM/DMF, 8 h, 0 ꢂC to rt (c) ReN]C]S, NMM/DMF, 8 h, 0 ꢂC to rt (d) Polymer supported HCOOꢀNHþ3 /10% PdeC; R ¼ Cl, OMe where Xaa ¼ GE(OcHx)GFP
GVGVP GVGVP GVGVP GFGFP GFGFP, Ybb ¼ GEGFP GVGVP GVGVP GVGVP GFGFP GFGFP.

184
R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
Scheme 3. Schematic representation of the synthesis of uriedo/thiouriedo derivatives of amino acid/peptides conjugated heterocycle 2. Reagents and conditions: (a) TFA, 40 min, rt
(b) ReN]C]O, NMM/DMF, 8 h, 0 ꢂC to rt (c) ReN]C]S, NMM/DMF, 8 h, 0 ꢂC to rt where Xaa ¼ Trp, GGIP, GGFP, GVGVP, GFGFP; R ¼ 2F, 4Cl, 4OMe.
(1H, m, eCH), 3.50, 3.56 (4H, m, eCH2), 6.95e7.97 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 62.09, H ¼ 5.49, N ¼ 13.70, Found
C ¼ 61.94, H ¼ 5.40, N ¼ 13.65.
ArH); eNH ¼ 8.02e8.05 (3H, s); Gly1 ¼ 3.84 (2H, s, eaCH);
Val2 ¼ 0.97 (6H, m, e(CH3)2), 2.79 (1H, m, ebCH), 4.70 (1H, s,
eaCH); Gly3 ¼ 4.10 (2H, s, eaCH); Val4 ¼ 0.99 (6H, m, e(CH3)2), 2.93
(1H, m, ebCH), 4.90 (1H, s, eaCH); Pro5 ¼ 2.15e3.46 (6H, m, eCH2),
4.32 (1H, m, eaCH); Heterocycle ¼ 1.92e2.09 (4H, m, eCH2), 2.81
(1H, m, eCH), 3.62, 3.73 (4H, m, eCH2), 6.77e7.68 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 59.52, H ¼ 6.31, N ¼ 14.61, Found
C ¼ 59.52, H ¼ 6.29, N ¼ 14.63.
4.6.5. 4Cl-Urea derivative of G1G2F3P4-Heterocycle 1 (15)
IR nmax (nujol): 1636 (CO), 3294 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.00 (1H, s, NH), 7.73 (1H, m, NH), 6.90e7.92 (4H, m,
ArH); eNH ¼ 8.09e8.49 (2H, s); Gly1 ¼ 3.86 (2H, s, eaCH);
Gly2 ¼ 4.11 (2H, s, eaCH); Phe3 ¼ 3.58, 3.69 (2H, d, ebCH2), 4.92 (1H,
t, eaCH); 6.90e7.92 (5H, m, ArH); Pro4 ¼ 2.06e3.91 (6H, m, eCH2),
4.63 (1H, m, eaCH); Heterocycle ¼ 1.94e2.00 (4H, m, eCH2), 2.92
(1H, m, eCH), 3.48, 3.59 (4H, m, eCH2), 6.90e7.92 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 60.69, H ¼ 5.37, N ¼ 13.39, Found
C ¼ 60.72, H ¼ 5.30, N ¼ 13.36.
4.6.8. 4Cl-Urea derivative of G1V2G3V4P5-Heterocycle 1 (18)
IR nmax (nujol): 1654 (CO), 3301 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.06 (1H, s, NH), 7.57 (1H, m, NH), 6.82e7.77 (4H, m,
ArH); eNH ¼ 8.00e8.06 (3H, s); Gly1 ¼ 3.82 (2H, s, eaCH);
Val2 ¼ 0.98 (6H, m, e(CH3)2), 2.69 (1H, m, ebCH), 4.75 (1H, s,
eaCH); Gly3 ¼ 4.13 (2H, s, eaCH); Val4 ¼ 0.97 (6H, m, e(CH3)2), 2.96
(1H, m, ebCH), 4.95 (1H, s, eaCH); Pro5 ¼ 2.10e3.44 (6H, m, eCH2),
4.30 (1H, m, eaCH); Heterocycle ¼ 1.90e2.10 (4H, m, eCH2), 2.85
(1H, m, eCH), 3.60, 3.74 (4H, m, eCH2), 6.82e7.77 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 58.27, H ¼ 6.18, N ¼ 14.31, Found
C ¼ 58.25, H ¼ 6.15, N ¼ 14.33.
4.6.6. 4OMe-Urea derivative of G1G2F3P4-Heterocycle 1 (16)
IR nmax (nujol): 1638 (CO), 3304 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.03 (1H, s, NH), 7.79 (1H, m, NH), 6.94e7.99 (4H, m,
ArH), 3.66 (3H, s, OMe); eNH ¼ 8.14e8.44 (2H, s); Gly1 ¼ 3.90 (2H,
s, eaCH); Gly2 ¼ 4.14 (2H, s, eaCH); Phe3 ¼ 3.49, 3.60 (2H, d, ebCH2),
4.90 (1H, t, eaCH); 6.92e7.94 (5H, m, ArH); Pro4 ¼ 2.01e3.94 (6H,
m, eCH2), 4.64 (1H, m, eaCH); Heterocycle ¼ 1.96e2.04 (4H, m,
eCH2), 2.95 (1H, m, eCH), 3.42, 3.56 (4H, m, eCH2), 6.94e7.99 (3H,
m, ArH); Elemental Analysis: Calc. C ¼ 62.71, H ¼ 5.82, N ¼ 13.47,
Found C ¼ 62.75, H ¼ 5.80, N ¼ 13.51.
4.6.9. 4OMe-Urea derivative of G1V2G3V4P5-Heterocycle 1 (19)
IR nmax (nujol): 1624 (CO), 3299 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.02 (1H, s, NH), 7.68 (1H, m, NH), 6.75e7.66 (4H, m,
ArH), 3.69 (3H, s, OMe); eNH ¼ 8.02 (3H, s); Gly1 ¼ 3.87 (2H, s,
eaCH); Val2 ¼ 1.07 (6H, m, e(CH3)2), 2.86 (1H, m, ebCH), 4.63 (1H, s,
eaCH); Gly3 ¼ 4.08 (2H, s, eaCH); Val4 ¼ 1.09 (6H, m, e(CH3)2), 2.96
(1H, m, ebCH), 4.88 (1H, s, eaCH); Pro5 ¼ 2.14e3.42 (6H, m, eCH2),
4.31 (1H, m, eaCH); Heterocycle ¼ 1.97e2.07 (4H, m, eCH2), 2.86
4.6.7. 2F-Urea derivative of G1V2G3V4P5-Heterocycle 1 (17)
IR nmax (nujol): 1698 (CO), 3300 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.07 (1H, s, NH), 7.59 (1H, m, NH), 6.77e7.68 (4H, m,
Scheme 4. Schematic representation of the synthesis of uriedo/thiouriedo derivatives of tricosamer conjugated heterocycle 2. Reagents and conditions: (a) TFA, 40 min, rt
(b) 2FePheN]C]O, NMM/THF, 8 h, 0 ꢂC to rt (c) ReN]C]S, NMM/THF, 8 h, 0 ꢂC to rt (d) Polymer supported HCOOꢀNHþ3 /10% PdeC; R ¼ Cl, OMe where Xaa ¼ GE(OcHx)GFP
GVGVP GVGFP GFGFP GVGVP GVGFP; Ybb ¼ GEGFP GVGVP GVGFP GFGFP GVGVP GVGFP.

R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
185
(1H, m, eCH), 3.65, 3.75 (4H, m, eCH2), 6.75e7.66 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 60.14, H ¼ 6.60, N ¼ 14.39, Found
C ¼ 60.17, H ¼ 6.57, N ¼ 14.37.
4.6.15. 4OMe-Thiourea derivative of G1G2I3P4-Heterocycle 1 (25)
IR nmax (nujol): 1605 (CO), 2125 (CS), 3286 (NH); 1H NMR data
(CDCl3,
ppm): Thiourea ¼ 8.79 (1H, s, NH), 8.02 (1H, m, NH),
d
7.10e7.90 (4H, m, ArH), 3.65 (3H, s, OMe); eNH ¼ 8.04e8.14 (2H,
m); Gly1 ¼ 3.90 (2H, s, eaCH); Gly2 ¼ 4.24 (2H, s, eaCH);
Ile3 ¼ 0.95e1.07 (6H, m, e(CH3)2), 1.49 (2H, m, egCH2), 2.20 (1H, m,
ebCH), 4.72 (1H, m, eaCH); Pro4 ¼ 1.92e3.62 (6H, m, eCH2), 4.70
(1H, m, eaCH); Heterocycle ¼ 1.90,2.03 (4H, m, eCH2), 2.85 (1H, m,
eCH), 3.70 (4H, m, eCH2), 7.10e7.90 (3H, m, ArH); Elemental
Analysis: Calc. C ¼ 59.73, H ¼ 6.41, N ¼ 13.55, S ¼ 4.43, Found
C ¼ 59.70, H ¼ 6.38, N ¼ 13.53, S ¼ 4.45.
4.6.10. 2F-Urea derivative of G1F2G3F4P5-Heterocycle 1 (20)
IR nmax (nujol): 1634 (CO), 3280 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.18 (1H, s, NH), 7.97 (1H, m, NH), 7.13e7.90 (4H, m,
ArH); eNH ¼ 8.04e8.12 (3H, s); Gly1 ¼ 3.81 (2H, s, eaCH);
Phe2 ¼ 3.50, 3.60 (2H, m, ebCH2), 4.53 (1H, s, eaCH), 7.13e7.90 (5H,
m, ArH); Gly3 ¼ 4.28 (2H, s, eaCH); Phe4 ¼ 3.33, 3.72 (2H, m,
ebCH2), 4.84 (1H, s, eaCH), 7.13e7.90 (5H, m, ArH);
Pro5
¼
2.11e3.68 (6H, m, eCH2), 4.36 (1H, m, eaCH);
Heterocycle ¼ 1.86 (4H, m, eCH2), 2.89 (1H, m, eCH), 3.77, 3.92 (4H,
m, eCH2), 7.13e7.90 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 64.03, H ¼ 5.61, N ¼ 12.99, Found C ¼ 64.02, H ¼ 5.58,
N ¼ 12.98.
4.6.16. 2F-Thiourea derivative of G1G2F3P4-Heterocycle 1 (26)
IR nmax (nujol): 1641 (CO), 2027 (CS), 3281 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.88 (1H, s, NH), 8.02 (1H, m, NH),
6.97e7.95 (4H, m, ArH); eNH ¼ 8.11e8.50 (2H, s); Gly1 ¼3.80 (2H, s,
eaCH); Gly2 ¼ 4.07 (2H, s, eaCH); Phe3 ¼ 3.57, 3.70 (2H, d, ebCH2),
4.91 (1H, t, eaCH); 6.97e7.95 (5H, m, ArH); Pro4 ¼ 2.01e3.98 (6H,
m, eCH2), 4.62 (1H, m, eaCH); Heterocycle ¼ 1.88e1.96 (4H, m,
eCH2), 2.96 (1H, m, eCH), 3.49, 3.57 (4H, m, eCH2), 6.97e7.95 (3H,
m, ArH); Elemental Analysis: Calc. C ¼ 60.73, H ¼ 5.37, N ¼ 13.40,
S ¼ 4.38, Found C ¼ 60.59, H ¼ 5.35, N ¼ 13.37, S ¼ 4.35.
4.6.11. 4Cl-Urea derivative of G1F2G3F4P5-Heterocycle 1 (21)
IR nmax (nujol): 1635 (CO), 3294 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.20 (1H, s, NH), 7.92 (1H, m, NH), 7.09e7.78 (4H, m,
ArH); eNH ¼ 8.00e8.14 (3H, s); Gly1 ¼ 3.85 (2H, s, eaCH);
Phe2 ¼ 3.55, 3.62 (2H, m, ebCH2), 4.49 (1H, s, eaCH), 7.09e7.78 (5H,
m, ArH); Gly3 ¼ 4.26 (2H, s, eaCH); Phe4 ¼ 3.31, 3.70 (2H, m,
ebCH2), 4.80 (1H, s, eaCH), 7.09e7.78 (5H, m, ArH);
4.6.17. 4Cl-Thiourea derivative of G1G2F3P4-Heterocycle 1 (27)
IR nmax (nujol): 1618 (CO), 2039 (CS), 3280 (NH); 1H NMR data
Pro5
¼
2.09e3.72 (6H, m, eCH2), 4.39 (1H, m, eaCH);
Heterocycle ¼ 1.84 (4H, m, eCH2), 2.90 (1H, m, eCH), 3.72, 3.90
(4H, m, eCH2), 7.09e7.78 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 62.83, H ¼ 5.50, N ¼ 12.74, Found C ¼ 62.81, H ¼ 5.48,
N ¼ 12.75.
(CDCl3,
d
ppm): Thiourea ¼ 8.86 (1H, s, NH), 8.07 (1H, m, NH),
6.94e7.92 (4H, m, ArH); eNH ¼ 8.08e8.49 (2H, s); Gly1 ¼ 3.79 (2H,
s, eaCH); Gly2 ¼ 4.10 (2H, s, eaCH); Phe3 ¼ 3.52, 3.74 (2H, d, ebCH2),
4.95 (1H, t, eaCH); 6.94e7.92 (5H, m, ArH); Pro4 ¼ 2.04e3.96 (6H,
m, eCH2), 4.65 (1H, m, eaCH); Heterocycle ¼ 1.82e1.91 (4H, m,
eCH2), 2.94 (1H, m, eCH), 3.45, 3.53 (4H, m, eCH2), 6.94e7.92 (3H,
m, ArH); Elemental Analysis: Calc. C ¼ 59.39, H ¼ 5.25, N ¼ 13.10,
S ¼ 4.29, Found C ¼ 59.36, H ¼ 5.18, N ¼ 13.14, S ¼ 4.30.
4.6.12. 4OMe-Urea derivative of G1F2G3F4P5-Heterocycle 1 (22)
IR nmax (nujol): 1634 (CO), 3296 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.15 (1H, s, NH), 7.96 (1H, m, NH), 7.10e7.82 (4H, m,
ArH), 3.65 (3H, s, OMe); eNH ¼ 8.04e8.13 (3H, s); Gly1 ¼ 3.86 (2H,
s, eaCH); Phe2 ¼ 3.52, 3.60 (2H, m, ebCH2), 4.44 (1H, s, eaCH),
7.10e7.82 (5H, m, ArH); Gly3 ¼ 4.25 (2H, s, eaCH); Phe4 ¼ 3.33, 3.65
(2H, m, ebCH2), 4.78 (1H, s, eaCH), 7.10e7.82 (5H, m, ArH);
4.6.18. 4OMe-Thiourea derivative of G1G2F3P4-Heterocycle 1 (28)
IR nmax (nujol): 1625 (CO), 2041 (CS), 3275 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.80 (1H, s, NH), 8.09 (1H, m, NH),
Pro5
¼
2.12e3.73 (6H, m, eCH2), 4.40 (1H, m, eaCH);
6.96e7.94 (4H, m, ArH), 3.61 (3H, s, OMe); eNH ¼ 8.06e8.42 (2H,
s); Gly1 ¼ 3.83 (2H, s, eaCH); Gly2 ¼ 4.14 (2H, s, eaCH); Phe3 ¼ 3.50,
3.77 (2H, d, ebCH2), 4.94 (1H, t, eaCH); 6.96e7.94 (5H, m, ArH);
Heterocycle ¼ 1.82 (4H, m, eCH2), 2.93 (1H, m, eCH), 3.69, 3.88 (4H,
m, eCH2), 7.10e7.82 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 64.52, H ¼ 5.88, N ¼ 12.81, Found C ¼ 64.55, H ¼ 5.83,
N ¼ 12.83.
Pro4
¼
2.00e3.91 (6H, m, eCH2), 4.64 (1H, m, eaCH);
Heterocycle ¼ 1.80e1.94 (4H, m, eCH2), 2.99 (1H, m, eCH), 3.44,
3.58 (4H, m, eCH2), 6.96e7.94 (3H, m, ArH); Elemental Analysis:
Calc. C ¼ 61.36, H ¼ 5.69, N ¼ 13.18, S ¼ 4.31, Found C ¼ 61.40,
H ¼ 5.68, N ¼ 13.20, S ¼ 4.30.
4.6.13. 2F-Thiourea derivative of Trp-Heterocycle 1 (23)
IR nmax (nujol): 1614 (CO), 2119 (CS), 3307 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.79 (1H, s, NH), 8.03 (1H, m, NH),
7.10e7.89 (4H, m, ArH); Trp ¼ 3.59e3.73 (2H, d, ebCH2), 4.64 (1H,
t, eaCH), 7.00 (1H, s, eCH of indole), 7.06e7.85 (4H, m, ArH),
Exchanged (eNH of indole); Heterocycle ¼ 1.95e1.99 (4H, m,
eCH2), 2.99 (1H, m, eCH), 3.84e3.88 (4H, m, eCH2), 7.10e7.89
(3H, m, ArH); Elemental Analysis: Calc. C ¼ 64.39, H ¼ 4.86,
N ¼ 12.51, S ¼ 5.73, Found C ¼ 64.41, H ¼ 4.90, N ¼ 12.48,
S ¼ 5.73.
4.6.19. 2F-Thiourea derivative of G1V2G3V4P5-Heterocycle 1 (29)
IR nmax (nujol): 1633 (CO), 2134 (CS), 3285 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.79 (1H, s, NH), 8.13 (1H, m, NH),
6.89e7.72 (4H, m, ArH); eNH ¼ 8.01e8.09 (3H, s); Gly1 ¼ 3.86 (2H,
s, eaCH); Val2 ¼ 1.02 (6H, m, e(CH3)2), 2.78 (1H, m, ebCH), 4.72 (1H,
s, eaCH); Gly3 ¼ 4.14 (2H, s, eaCH); Val4 ¼ 1.00 (6H, m, e(CH3)2),
2.96 (1H, m, ebCH), 4.95 (1H, s, eaCH); Pro5 ¼ 2.10e3.47 (6H, m,
eCH2), 4.37 (1H, m, eaCH); Heterocycle ¼ 1.90e2.11 (4H, m, eCH2),
2.85 (1H, m, eCH), 3.59, 3.72 (4H, m, eCH2), 6.89e7.72 (3H, m,
ArH); Elemental Analysis: Calc. C ¼ 58.30, H ¼ 6.18, N ¼ 14.31,
S ¼ 4.10, Found C ¼ 58.34, H ¼ 6.15, N ¼ 14.33, S ¼ 4.11.
4.6.14. 4Cl-Thiourea derivative of G1G2I3P4-Heterocycle 1 (24)
IR nmax (nujol): 1644 (CO), 2139 (CS), 3301 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.85 (1H, s, NH), 8.04 (1H, m, NH),
7.02e7.87 (4H, m, ArH); eNH ¼ 7.95e8.02 (2H, m); Gly1 ¼ 3.97 (2H,
s, eaCH); Gly2 ¼ 4.22 (2H, s, eaCH); Ile3 ¼ 0.90e1.00 (6H, m,
e(CH3)2), 1.41 (2H, m, egCH2), 2.17 (1H, m, ebCH), 4.71 (1H, m,
eaCH); Pro4 ¼ 1.94e3.67 (6H, m, eCH2), 4.65 (1H, m, eaCH);
Heterocycle ¼ 1.87,1.99 (4H, m, eCH2), 2.83 (1H, m, eCH), 3.66 (4H,
m, eCH2), 7.02e7.87 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 57.72, H ¼ 5.95, N ¼ 13.46, S ¼ 4.40, Found C ¼ 57.75, H ¼ 5.98,
N ¼ 13.43, S ¼ 4.42.
4.6.20. 4Cl-Thiourea derivative of G1V2G3V4P5-Heterocycle 1 (30)
IR nmax (nujol): 1648 (CO), 2129 (CS), 3272 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.82 (1H, s, NH), 8.14 (1H, m, NH),
6.86e7.70 (4H, m, ArH); eNH ¼ 8.02e8.11 (3H, s); Gly1 ¼ 3.88 (2H,
s, eaCH); Val2 ¼ 1.01 (6H, m, e(CH3)2), 2.74 (1H, m, ebCH), 4.70 (1H,
s, eaCH); Gly3 ¼ 4.10 (2H, s, eaCH); Val4 ¼ 0.99 (6H, m, e(CH3)2),
2.95 (1H, m, ebCH), 4.94 (1H, s, eaCH); Pro5 ¼ 2.13e3.49 (6H, m,

186
R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
eCH2), 4.34 (1H, m, eaCH); Heterocycle ¼ 1.89e2.10 (4H, m, eCH2),
2.81 (1H, m, eCH), 3.57, 3.75 (4H, m, eCH2), 6.86e7.70 (3H, m,
ArH); Elemental Analysis: Calc. C ¼ 57.10, H ¼ 6.05, N ¼ 14.02,
S ¼ 4.01, Found C ¼ 57.10, H ¼ 6.04, N ¼ 14.05, S ¼ 4.02.
4.75 (1H, m, eaCH); Phe ¼ 3.55, 3.78 (10H, m, ebCH2), 4.20, 4.63
(5H, m, eaCH), 7.02e7.86 (25H, m, ArH); Pro ¼ 1.98, 3.64, 3.70 (36H,
m, eCH2), 4.68 (6H, m, eaCH); Heterocycle ¼ 1.95, 1.97 (4H, m,
eCH2), 2.99 (1H, m, eCH), 3.64, 3.68 (4H, m, eCH2), 7.02e7.86 (3H,
m, ArH); Elemental Analysis: Calc. C ¼ 61.59, H ¼ 6.81, N ¼ 14.46,
Found C ¼ 61.51, H ¼ 6.89, N ¼ 14.40.
4.6.21. 4OMe-Thiourea derivative of G1V2G3V4P5-Heterocycle 1 (31)
IR nmax (nujol): 1630 (CO), 2119 (CS), 3265 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.80 (1H, s, NH), 8.12 (1H, m, NH),
4.6.26. 4Cl-Thiourea derivative of GE(OcHx)GFPGVGVPGVGVPGVG
VPGFGFPGFGFP-Heterocycle 1 (41)
6.80e7.74 (4H, m, ArH), 3.62 (3H, s, OMe); eNH ¼ 8.03e8.10 (3H, s);
Gly1 ¼ 3.84 (2H, s, eaCH); Val2 ¼ 0.98 (6H, m, e(CH3)2), 2.71 (1H, m,
ebCH), 4.74 (1H, s, eaCH); Gly3 ¼ 4.14 (2H, s, eaCH); Val4 ¼ 1.00 (6H,
m, e(CH3)2), 2.94 (1H, m, ebCH), 4.92 (1H, s, eaCH);
IR nmax (nujol): 1616 (CO), 2124 (CS), 3297 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.87 (1H, s, NH), 8.14 (1H, m, NH),
7.14e7.92 (4H, m, ArH); eNH ¼ 8.02e8.13 (24H, m); Gly ¼ 4.00, 4.81
(24H, m, eaCH); Val ¼ 0.89, 0.98 (36H, m, (eCH3)2), 2.41, 2.67 (6H,
m, ebCH), 4.41 (6H, m, eaCH); Glu ¼ 1.15e1.27 (10H, m, eCH2 of
Pro5
¼
2.10e3.52 (6H, m, eCH2), 4.33 (1H, m, eaCH);
Heterocycle ¼ 1.90e2.12 (4H, m, eCH2), 2.84 (1H, m, eCH), 3.60,
3.72 (4H, m, eCH2), 6.80e7.74 (3H, m, ArH); Elemental Analysis:
Calc. C ¼ 58.93, H ¼ 6.47, N ¼ 14.10, S ¼ 4.03, Found C ¼ 58.97,
H ¼ 6.44, N ¼ 14.12, S ¼ 4.06.
cyclohexyl ring), 2.03, 2.08 (4H, m, eb gCH2), 3.73 (1H, m, eCH of
,
cyclohexyl ring), 4.77 (1H, m, eaCH); Phe ¼ 3.50, 3.77 (10H, m,
ebCH2), 4.19, 4.60 (5H, m, eaCH), 7.14e7.92 (25H, m, ArH);
Pro ¼ 1.96, 3.60, 3.75 (36H, m, eCH2), 4.72 (6H, m, eaCH);
Heterocycle ¼ 1.97,1.99 (4H, m, eCH2), 2.85 (1H, m, eCH), 3.66, 3.70
(4H, m, eCH2), 7.14e7.92 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 59.37, H ¼ 6.57, N ¼ 13.94, S ¼ 1.00, Found C ¼ 59.39, H ¼ 6.50,
N ¼ 13.88, S ¼ 0.99.
4.6.22. 2F-Thiourea derivative of G1F2G3F4P5-Heterocycle 1 (32)
IR nmax (nujol): 1628 (CO), 2028 (CS), 3280 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.74 (1H, s, NH), 8.10 (1H, m, NH),
7.11e7.85 (4H, m, ArH); eNH ¼ 8.01e8.10 (3H, s); Gly1 ¼ 3.79 (2H, s,
eaCH); Phe2 ¼ 3.51, 3.60 (2H, m, ebCH2), 4.56 (1H, s, eaCH),
7.11e7.85 (5H, m, ArH); Gly3 ¼ 4.29 (2H, s, eaCH); Phe4 ¼ 3.33, 3.78
(2H, m, ebCH2), 4.87 (1H, s, eaCH), 7.11e7.85 (5H, m, ArH);
4.6.27. 4OMe-Thiourea derivative of GE(OcHx)GFPGVGVPGVGVPGV
GVPGFGFPGFGFP-Heterocycle 1 (42)
Pro5
¼
2.16e3.68 (6H, m, eCH2), 4.38 (1H, m, eaCH);
IR nmax (nujol): 1630 (CO), 2129 (CS), 3321 (NH); 1H NMR data
Heterocycle ¼ 1.82 (4H, m, eCH2), 2.88 (1H, m, eCH), 3.79, 3.90 (4H,
m, eCH2), 7.11e7.85 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 62.86, H ¼ 5.50, N ¼ 12.75, S ¼ 3.65, Found C ¼ 62.85, H ¼ 5.48,
N ¼ 12.95, S ¼ 3.74.
(CDCl3,
d
ppm): Thiourea ¼ 8.88 (1H, s, NH), 8.13 (1H, m, NH),
7.06e7.98 (4H, m, ArH), 3.64 (3H, m, OMe); eNH ¼ 8.00e8.13 ¼ 1
(24H, m); Gly ¼ 3.99, 4.79 (24H, m, eaCH); Val ¼ 0.92, 1.05 (36H, m,
(eCH3)2), 2.44, 2.68 (6H, m, ebCH), 4.45 (6H, m, eaCH);
Glu ¼ 1.12e1.27 (10H, m, eCH2 of cyclohexyl ring), 2.04, 2.07 (4H,
4.6.23. 4Cl-Thiourea derivative of G1F2G3F4P5-Heterocycle 1 (33)
IR nmax (nujol): 1620 (CO), 2044 (CS), 3310 (NH); 1H NMR data
m, eb gCH2), 3.76 (1H, m, eCH of cyclohexyl ring), 4.79 (1H, m,
,
eaCH); Phe ¼ 3.52, 3.79 (10H, m, ebCH2), 4.20, 4.65 (5H, m, eaCH),
7.06e7.98 (25H, m, ArH); Pro ¼ 1.97, 3.63, 3.77 (36H, m, eCH2), 4.75
(6H, m, eaCH); Heterocycle ¼ 1.94, 1.98 (4H, m, eCH2), 2.86 (1H, m,
eCH), 3.67, 3.72 (4H, m, eCH2), 7.06e7.98 (3H, m, ArH); Elemental
Analysis: Calc. C ¼ 59.83, H ¼ 6.67, N ¼ 13.96, S ¼ 1.10, Found
C ¼ 59.89, H ¼ 6.72, N ¼ 13.99, S ¼ 1.01.
(CDCl3,
d
ppm): Thiourea ¼ 8.80 (1H, s, NH), 8.12 (1H, m, NH),
7.22e7.79 (4H, m, ArH); eNH ¼ 8.04e8.12 (3H, s); Gly1 ¼ 3.83 (2H,
s, eaCH); Phe2 ¼ 3.54, 3.62 (2H, m, ebCH2), 4.52 (1H, s, eaCH),
7.22e7.79 (5H, m, ArH); Gly3 ¼ 4.25 (2H, s, eaCH); Phe4 ¼ 3.30, 3.72
(2H, m, ebCH2), 4.84 (1H, s, eaCH), 7.22e7.79 (5H, m, ArH);
Pro5
¼
2.11e3.72 (6H, m, eCH2), 4.39 (1H, m, eaCH);
Heterocycle ¼ 1.84 (4H, m, eCH2), 2.85 (1H, m, eCH), 3.73, 3.89 (4H,
m, eCH2), 7.22e7.79 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 61.70, H ¼ 5.40, N ¼ 12.51, S ¼ 3.58, Found C ¼ 61.73, H ¼ 5.38,
N ¼ 12.83, S ¼ 3.59.
4.6.28. 2F-Urea derivative of Trp-Heterocycle 2 (53)
IR nmax (nujol): 1624 (CO), 3327 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.19 (1H, s, NH), 8.05 (1H, m, NH), 7.12e7.96 (4H, m,
ArH); Trp ¼ 3.59e3.74 (2H, d, ebCH2), 4.71 (1H, t, eaCH), 6.94 (1H, s,
eCH of indole), 7.12e7.96 (4H, m, ArH), Exchanged (eNH of indole);
Heterocycle ¼ 3.70e3.93 (4H, m, eCH2), 7.12e7.96 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 60.66, H ¼ 4.73, N ¼ 12.63, Found
C ¼ 60.62, H ¼ 4.75, N ¼ 12.66.
4.6.24. 4OMe-Thiourea derivative of G1F2G3F4P5-Heterocycle 1 (34)
IR nmax (nujol): 1638 (CO), 2021 (CS), 3254 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.78 (1H, s, NH), 8.14 (1H, m, NH),
7.05e7.68 (4H, m, ArH), 3.67 (3H, s, OMe); eNH ¼ 8.00e8.12 (3H, s);
Gly1 ¼ 3.87 (2H, s, eaCH); Phe2 ¼ 3.50, 3.69 (2H, m, ebCH2), 4.46
(1H, s, eaCH), 7.05e7.68 (5H, m, ArH); Gly3 ¼ 4.22 (2H, s, eaCH);
Phe4 ¼ 3.34, 3.74 (2H, m, ebCH2), 4.82 (1H, s, eaCH), 7.05e7.68 (5H,
m, ArH); Pro5 ¼ 2.13e3.68 (6H, m, eCH2), 4.41 (1H, m, eaCH);
Heterocycle ¼ 1.80 (4H, m, eCH2), 2.81 (1H, m, eCH), 3.70, 3.83 (4H,
m, eCH2), 7.05e7.68 (3H, m, ArH); Elemental Analysis: Calc.
C ¼ 63.35, H ¼ 5.77, N ¼ 12.58, S ¼ 3.60, Found C ¼ 63.59, H ¼ 5.75,
N ¼ 12.60, S ¼ 3.57.
4.6.29. 2F-Urea derivative of G1G2I3P4-Heterocycle 2 (54)
IR nmax (nujol): 1620 (CO), 3296 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.17 (1H, s, NH), 7.97 (1H, m, NH), 7.02e7.84 (4H, m,
ArH); eNH ¼ 8.07e8.17 (2H, m); Gly1 ¼ 3.94 (2H, s, eaCH);
Gly2 ¼ 4.59 (2H, s, eaCH); Ile3 ¼ 0.88e0.91 (6H, m, e(CH3)2), 1.45
(2H, m, egCH2), 2.13 (1H, m, ebCH), 4.63 (1H, m, eaCH);
Pro4
¼
1.95e3.59 (6H, m, eCH2), 4.58 (1H, m, eaCH);
Heterocycle ¼ 3.70,3.95 (8H, m, eCH2), 7.02e7.84 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 56.09, H ¼ 5.99, N ¼ 13.88, Found
C ¼ 56.05, H ¼ 6.01, N ¼ 13.84.
4.6.25. 2F-Urea derivative of GE(OcHx)GFPGVGVPGVGVPGVGVPGFG
FPGFGFP-Heterocycle 1 (40)
IR nmax (nujol): 1621 (CO), 3327 (NH); 1H NMR data (CDCl3,
4.6.30. 4Cl-Urea derivative of G1G2F3P4-Heterocycle 2 (55)
d
ppm): Urea ¼ 8.17 (1H, s, NH), 8.02 (1H, m, NH), 7.02e7.86 (4H, m,
IR nmax (nujol): 1624 (CO), 3318 (NH); 1H NMR data (CDCl3,
ArH); eNH ¼ 7.98e8.01 (24H, m); Gly ¼ 4.03, 4.84 (24H, m, eaCH);
Val ¼ 1.00, 1.03 (36H, m, (eCH3)2), 2.43, 2.60 (6H, m, ebCH), 4.44
(6H, m, eaCH); Glu ¼ 1.18e1.29 (10H, m, eCH2 of cyclohexyl ring),
d
ppm): Urea ¼ 8.18 (1H, s, NH), 7.97 (1H, m, NH), 6.79e7.63 (4H, m,
ArH); eNH ¼ 7.95e8.13 (2H, s); Gly1 ¼ 3.85 (2H, s, eaCH);
Gly2 ¼ 3.93 (2H, s, eaCH); Phe3 ¼ 3.16, 3.55 (2H, d, ebCH2), 4.91 (1H,
t, eaCH); 6.79e7.63 (5H, m, ArH); Pro4 ¼ 1.90e3.66 (6H, m, eCH2),
2.05, 2.10 (4H, m, eb gCH2), 3.76 (1H, m, eCH of cyclohexyl ring),
,

R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
187
4.81 (1H, m, eaCH); Heterocycle ¼ 2.80e2.94 (4H, m, eCH2),
6.79e7.63 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 56.57,
H ¼ 5.15, N ¼ 13.19, Found C ¼ 56.60, H ¼ 5.13, N ¼ 13.16.
(1H, m, eaCH); Heterocycle ¼ 3.74, 3.99 (4H, m, eCH2), 7.05e7.89
(3H, m, ArH); Elemental Analysis: Calc. C ¼ 55.58, H ¼ 6.17,
N ¼ 13.34, S ¼ 4.36, Found C ¼ 55.61, H ¼ 6.21, N ¼ 13.37, S ¼ 4.33.
4.6.31. 4OMe-Urea derivative of G1G2F3P4-Heterocycle 2 (56)
IR nmax (nujol): 1629 (CO), 3307 (NH); 1H NMR data (CDCl3,
4.6.37. 4Cl-Thiourea derivative of G1G2F3P4-Heterocycle 2 (62)
IR nmax (nujol): 1611 (CO), 2020 (CS), 3298 (NH); 1H NMR data
d
ppm): Urea ¼ 8.13 (1H, s, NH), 7.95 (1H, m, NH), 7.02e7.86 (4H, m,
(CDCl3,
d
ppm): Thiourea ¼ 8.78 (1H, s, NH), 8.08 (1H, m, NH),
ArH), 3.61 (3H, s, OMe); eNH ¼ 7.91e8.07 (2H, s); Gly1 ¼3.93 (2H, s,
eaCH); Gly2 ¼ 4.10 (2H, s, eaCH); Phe3 ¼ 3.18, 3.58 (2H, d, ebCH2),
4.89 (1H, t, eaCH); 7.02e7.86 (5H, m, ArH); Pro4 ¼ 1.94e3.70 (6H,
m, eCH2), 4.90 (1H, m, eaCH); Heterocycle ¼ 2.80e2.97 (4H, m,
eCH2), 7.02e7.86 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 58.54,
H ¼ 5.59, N ¼ 13.27, Found C ¼ 58.51, H ¼ 5.61, N ¼ 13.26.
6.74e7.69 (4H, m, ArH); eNH ¼ 7.93e8.12 (2H, s); Gly1 ¼3.88 (2H, s,
eaCH); Gly2 ¼ 3.97 (2H, s, eaCH); Phe3 ¼ 3.14, 3.58 (2H, d, ebCH2),
4.94 (1H, t, eaCH); 6.74e7.69 (5H, m, ArH); Pro4 ¼ 1.93e3.67 (6H,
m, eCH2), 4.85 (1H, m, eaCH); Heterocycle ¼ 2.84e2.99 (4H, m,
eCH2), 6.74e7.69 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 55.37,
H ¼ 5.05, N ¼ 12.92, S ¼ 4.22, Found C ¼ 55.38, H ¼ 5.02, N ¼ 12.95,
S ¼ 4.25.
4.6.32. 2F-Urea derivative of G1V2G3V4P5-Heterocycle 2 (57)
IR nmax (nujol): 1617 (CO), 3300 (NH); 1H NMR data (CDCl3,
4.6.38. 4OMe-Thiourea derivative of G1G2F3P4-Heterocycle 2 (63)
IR nmax (nujol): 1604 (CO), 2014 (CS), 3325 (NH); 1H NMR data
(CDCl3,
d
ppm): Urea ¼ 8.10 (1H, s, NH), 7.84 (1H, m, NH), 7.01e7.94 (4H, m,
ArH); eNH ¼ 8.04e8.09 (3H, s); Gly1 ¼ 3.85 (2H, s, eaCH);
Val2 ¼ 1.02 (6H, m, (eCH3)2), 2.54 (1H, m, ebCH), 4.58 (1H, m,
eaCH); Gly3 ¼ 4.17 (2H, s, eaCH); Val4 ¼ 0.99 (6H, m, (eCH3)2), 2.64
(1H, m, ebCH), 4.53 (1H, m, eaCH); Pro5 ¼ 2.09e3.67 (6H, m, eCH2),
4.54 (1H, m, eaCH); Heterocycle ¼ 2.25e2.97 (8H, m, eCH2),
7.01e7.94 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 55.60,
H ¼ 6.09, N ¼ 14.41, Found C ¼ 55.57, H ¼ 6.12, N ¼ 14.44.
d
ppm): Thiourea ¼ 8.83 (1H, s, NH), 8.07 (1H, m, NH),
6.79e7.75 (4H, m, ArH), 3.59 (3H, s, Ome); eNH ¼ 7.94e8.09 (2H,
s); Gly1 ¼ 3.91 (2H, s, eaCH); Gly2 ¼ 4.05 (2H, s, eaCH); Phe3 ¼ 3.20,
3.60 (2H, d, ebCH2), 4.99 (1H, t, eaCH); 6.79e7.75 (5H, m, ArH);
Pro4
¼
1.97e3.69 (6H, m, eCH2), 4.88 (1H, m, eaCH);
Heterocycle ¼ 2.80e2.97 (4H, m, eCH2), 6.79e7.75 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 57.29, H ¼ 5.48, N ¼ 12.99, S ¼ 4.25,
Found C ¼ 57.32, H ¼ 5.51, N ¼ 12.96, S ¼ 4.22.
4.6.33. 2F-Urea derivative of G1F2G3F4P5-Heterocycle 2 (58)
IR nmax (nujol): 1610 (CO), 3294 (NH); 1H NMR data (CDCl3,
4.6.39. 4Cl-Thiourea derivative of G1V2G3V4P5-Heterocycle 2 (64)
IR nmax (nujol): 1625 (CO), 2041 (CS), 3320 (NH); 1H NMR data
(CDCl3,
d
ppm): Urea ¼ 8.06 (1H, s, NH), 7.81 (1H, m, NH), 6.99e7.92 (4H, m,
ArH); eNH ¼ 8.02e8.11 (3H, s); Gly1 ¼ 3.86 (2H, s, eaCH);
Phe2 ¼ 3.58, 3.68 (2H, m, ebCH2), 4.62 (1H, m, eaCH), 6.99e7.92
(5H, m, ArH); Gly3 ¼ 4.14 (2H, s, eaCH); Phe4 ¼ 3.45, 3.67 (2H, m,
ebCH2), 4.68 (1H, m, eaCH), 6.99e7.92 (5H, m, ArH);
d
ppm): Thiourea ¼ 8.83 (1H, s, NH), 8.14 (1H, m, NH),
7.04e7.88 (4H, m, ArH); eNH ¼ 8.01e8.09 (3H, s); Gly1 ¼ 3.84 (2H, s,
eaCH); Val2 ¼1.00 (6H, m, (eCH3)2), 2.56 (1H, m, ebCH), 4.57 (1H, m,
eaCH); Gly3 ¼ 4.15 (2H, s, eaCH); Val4 ¼ 0.97 (6H, m, (eCH3)2), 2.62
(1H, m, ebCH), 4.54 (1H, m, eaCH); Pro5 ¼ 2.11e3.68 (6H, m, eCH2),
4.57 (1H, m, eaCH); Heterocycle ¼ 2.20e2.91 (8H, m, eCH2),
7.04e7.88 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 53.37, H ¼ 5.85,
N ¼ 13.83, S ¼ 3.96, Found C ¼ 53.40, H ¼ 5.88, N ¼ 13.88, S ¼ 3.94.
Pro5
¼
2.12e3.64 (6H, m, eCH2), 4.50 (1H, m, eaCH);
Heterocycle ¼ 3.42e3.74 (8H, m, eCH2), 6.99e7.92 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 60.48, H ¼ 5.42, N ¼ 12.82, Found
C ¼ 60.45, H ¼ 5.39, N ¼ 12.81.
4.6.34. 2F-Thiourea derivative of Trp-Heterocycle 2 (59)
4.6.40. 4OMe-Thiourea derivative of G1V2G3V4P5-Heterocycle 2
(65)
IR nmax (nujol): 1622 (CO), 2124 (CS), 3276 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.79 (1H, s, NH), 8.11 (1H, m, NH),
IR nmax (nujol): 1620 (CO), 2012 (CS), 3285 (NH); 1H NMR data
7.04e7.92 (4H, m, ArH); Trp ¼ 3.60e3.71 (2H, d, ebCH2), 4.74 (1H, t,
eaCH), 6.98 (1H, s, eCH of indole), 7.04e7.92 (4H, m, ArH),
Exchanged (eNH of indole); Heterocycle ¼ 3.72e3.94 (4H, m,
eCH2), 7.04e7.92 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 58.95,
H ¼ 4.59, N ¼ 12.28, S ¼ 5.62, Found C ¼ 58.99, H ¼ 4.60, N ¼ 12.31,
S ¼ 5.64.
(CDCl3,
d
ppm): Thiourea ¼ 8.89 (1H, s, NH), 8.17 (1H, m, NH),
7.07e7.96 (4H, m, ArH), 3.64 (3H, s, Ome); eNH ¼ 8.08e8.22 (3H,
s); Gly1 ¼ 3.88 (2H, s, eaCH); Val2 ¼ 1.07 (6H, m, (eCH3)2), 2.54 (1H,
m, ebCH), 4.53 (1H, m, eaCH); Gly3 ¼ 4.10 (2H, s, eaCH); Val4 ¼ 1.05
(6H, m, (eCH3)2), 2.68 (1H, m, ebCH), 4.56 (1H, m, eaCH);
Pro5
¼
2.10e3.67 (6H, m, eCH2), 4.56 (1H, m, eaCH);
Heterocycle ¼ 2.16e2.94 (8H, m, eCH2), 7.07e7.96 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 55.15, H ¼ 6.25, N ¼ 13.91, S ¼ 3.98,
Found C ¼ 55.18, H ¼ 6.28, N ¼ 13.94, S ¼ 3.97.
4.6.35. 4Cl-Thiourea derivative of G1G2I3P4-Heterocycle 2 (60)
IR nmax (nujol): 1618 (CO), 2118 (CS), 3308 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.89 (1H, s, NH), 8.09 (1H, m, NH),
7.00e7.82 (4H, m, ArH); eNH ¼ 8.01e8.08 (2H, m); Gly1 ¼ 3.93 (2H,
s, eaCH); Gly2 ¼ 4.61 (2H, s, eaCH); Ile3 ¼ 0.86e0.90 (6H, m,
e(CH3)2), 1.43 (2H, m, egCH2), 2.11 (1H, m, ebCH), 4.61 (1H, m,
eaCH); Pro4 ¼ 1.97e3.61 (6H, m, eCH2), 4.56 (1H, m, eaCH);
Heterocycle ¼ 3.73, 3.97 (4H, m, eCH2), 7.00e7.82 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 53.62, H ¼ 5.73, N ¼ 13.26, S ¼ 4.34,
Found C ¼ 53.60, H ¼ 5.72, N ¼ 13.22, S ¼ 4.38.
4.6.41. 4Cl-Thiourea derivative of G1F2G3F4P5-Heterocycle 2 (66)
IR nmax (nujol): 1632 (CO), 2029 (CS), 3310 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.76 (1H, s, NH), 8.11 (1H, m, NH),
7.02e7.84 (4H, m, ArH); eNH ¼ 8.01e8.39 (3H, s); Gly1 ¼ 3.83 (2H,
s, eaCH); Phe2 ¼ 3.50, 3.63 (2H, m, ebCH2), 4.65 (1H, m, eaCH),
7.02e7.84 (5H, m, ArH); Gly3 ¼ 4.18 (2H, s, eaCH); Phe4 ¼ 3.47, 3.69
(2H, m, ebCH2), 4.70 (1H, m, eaCH), 7.02e7.84 (5H, m, ArH);
Pro5
¼
2.10e3.66 (6H, m, eCH2), 4.54 (1H, m, eaCH);
4.6.36. 4OMe-Thiourea derivative of G1G2I3P4-Heterocycle 2 (61)
IR nmax (nujol): 1624 (CO), 2124 (CS), 3314 (NH); 1H NMR data
Heterocycle ¼ 3.40e3.79 (8H, m, eCH2), 7.02e7.84 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 58.31, H ¼ 5.23, N ¼ 12.36, S ¼ 3.54,
Found C ¼ 58.27, H ¼ 5.26, N ¼ 12.28, S ¼ 3.51.
(CDCl3,
d
ppm): Thiourea ¼ 8.91 (1H, s, NH), 8.12 (1H, m, NH),
7.05e7.89 (4H, m, ArH), 3.64 (3H, s, OMe); eNH ¼ 8.03e8.11 (2H,
m); Gly1 ¼ 3.97 (2H, s, eaCH); Gly2 ¼ 4.65 (2H, s, eaCH);
Ile3 ¼ 0.82e0.94 (6H, m, e(CH3)2), 1.47 (2H, m, egCH2), 2.14 (1H, m,
ebCH), 4.64 (1H, m, eaCH); Pro4 ¼ 1.98e3.64 (6H, m, eCH2), 4.58
4.6.42. 4OMe-Thiourea derivative of G1F2G3F4P5-Heterocycle 2 (67)
IR nmax (nujol): 1611 (CO), 2033 (CS), 3296 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.79 (1H, s, NH), 8.17 (1H, m, NH),

188
R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
Fig. 1. Diagramatic representation of antibacterial activity of the compounds against E. coli.
7.11e7.90 (4H, m, ArH), 3.68 (3H, s, Ome); eNH ¼ 8.04e8.40 (3H, s);
Gly1 ¼ 3.87 (2H, s, eaCH); Phe2 ¼ 3.49, 3.67 (2H, m, ebCH2), 4.61
(1H, m, eaCH), 7.11e7.90 (5H, m, ArH); Gly3 ¼ 4.15 (2H, s, eaCH);
Phe4 ¼ 3.44, 3.61 (2H, m, ebCH2), 4.75 (1H, m, eaCH), 7.11e7.90 (5H,
m, ArH); Pro5 ¼ 2.08e3.61 (6H, m, eCH2), 4.55 (1H, m, eaCH);
Heterocycle ¼ 3.44e3.80 (8H, m, eCH2), 7.11e7.90 (3H, m, ArH);
Elemental Analysis: Calc. C ¼ 59.93, H ¼ 5.59, N ¼ 12.42, S ¼ 3.56,
Found C ¼ 59.90, H ¼ 5.55, N ¼ 12.38, S ¼ 3.53.
7.12e7.69 (4H, m, ArH); eNH ¼ 8.02e8.16 (23H, m); Gly ¼ 4.10,
4.93 (24H, m, eaCH); Val ¼ 1.00, 1.05 (36H, m, (eCH3)2), 2.44,
2.68 (6H, m, ebCH), 4.40 (6H, m, eaCH); Glu ¼ 1.10e1.24 (10H,
,
m, eCH2 of cyclohexyl ring), 2.06, 2.22 (4H, m, eb gCH2), 3.72
(1H, m, eCH of cyclohexyl ring), 4.70 (1H, m, eaCH); Phe ¼ 3.51,
3.74 (10H, m, ebCH2), 4.22, 4.64 (5H, m, eaCH), 7.12e7.69 (25H,
m, ArH); Pro ¼ 2.04, 3.57, 3.76 (36H, m, eCH2), 4.75 (6H, m,
eaCH); Heterocycle ¼ 3.47, 3.65 (8H, m, eCH2), 7.12e7.69 (3H,
m, ArH); Elemental Analysis: Calc.
C
¼
57.87,
H
¼
6.48,
4.6.43. 2F-Urea derivative of GE(OcHx)GFPGVGVPGVGFPGFGFPGVG
VPGVGFP-Heterocycle 2 (73)
N ¼ 14.19, S ¼ 1.00, Found C ¼ 57.92, H ¼ 6.55, N ¼ 14.25,
S ¼ 0.97.
IR nmax (nujol): 1604 (CO), 3311 (NH); 1H NMR data (CDCl3,
d
ppm): Urea ¼ 8.18 (1H, s, NH), 8.07 (1H, m, NH), 7.16e7.75 (4H, m,
4.6.45. 4OMe-Thiourea derivative of GE(OcHx)GFPGVGVPGVGFPGF
GFPGVGVPGVGFP-Heterocycle 2 (75)
ArH); eNH ¼ 8.04e8.17 (23H, m); Gly ¼ 4.05, 4.94 (24H, m, eaCH);
Val ¼ 0.99, 1.02 (36H, m, (eCH3)2), 2.43, 2.64 (6H, m, ebCH), 4.44
(6H, m, eaCH); Glu ¼ 1.12e1.27 (10H, m, eCH2 of cyclohexyl ring),
IR nmax (nujol): 1621 (CO), 2104 (CS), 3290 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.85 (1H, s, NH), 8.12 (1H, m, NH),
2.08, 2.20 (4H, m, eb gCH2), 3.74 (1H, m, eCH of cyclohexyl ring),
7.09e7.80 (4H, m, ArH), 3.62 (3H, m, Ome); eNH ¼ 8.00e8.10 (23H,
m); Gly ¼ 4.08, 4.95 (24H, m, eaCH); Val ¼ 0.98, 1.01 (36H, m,
(eCH3)2), 2.45, 2.68 (6H, m, ebCH), 4.41 (6H, m, eaCH);
Glu ¼ 1.09e1.22 (10H, m, eCH2 of cyclohexyl ring), 2.05, 2.20 (4H,
,
4.78 (1H, m, eaCH); Phe ¼ 3.54, 3.76 (10H, m, ebCH2), 4.24, 4.66
(5H, m, eaCH), 7.16e7.75 (25H, m, ArH); Pro ¼ 2.00, 3.54, 3.72 (36H,
m, eCH2), 4.72 (6H, m, eaCH); Heterocycle ¼ 3.43, 3.60 (8H, m,
eCH2), 7.16e7.75 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 58.75,
H ¼ 6.58, N ¼ 14.41, Found C ¼ 58.79, H ¼ 6.65, N ¼ 14.50.
,
m, eb gCH2), 3.71 (1H, m, eCH of cyclohexyl ring), 4.73 (1H, m,
eaCH); Phe ¼ 3.54, 3.73 (10H, m, ebCH2), 4.21, 4.65 (5H, m, eaCH),
7.09e7.80 (25H, m, ArH); Pro ¼ 2.00, 3.60, 3.80 (36H, m, eCH2),
4.78 (6H, m, eaCH); Heterocycle ¼ 3.41, 3.68 (8H, m, eCH2),
7.09e7.80 (3H, m, ArH); Elemental Analysis: Calc. C ¼ 58.32,
H ¼ 6.58, N ¼ 14.21, S ¼ 1.00, Found C ¼ 58.39, H ¼ 6.65, N ¼ 14.15,
S ¼ 1.04.
4.6.44. 4Cl-Thiourea derivative of GE(OcHx)GFPGVGVPGVGFPGFGFP
GVGVPGVGFP-Heterocycle 2 (74)
IR nmax (nujol): 1610 (CO), 2111 (CS), 3305 (NH); 1H NMR data
(CDCl3,
d
ppm): Thiourea ¼ 8.88 (1H, s, NH), 8.17 (1H, m, NH),
Fig. 2. Diagramatic representation of antibacterial activity of the compounds against X. oryzae.

R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
189
Fig. 3. Diagramatic representation of antibacterial activity of the compounds against K. pneumoniae.
4.7. Biology
4.7.1.2. Microdilution method. All the microorganisms were grown
in MullereHinton broth. After cultivation for 16e18 h at 37 ꢂC, the
bacteria were harvested and their density was determined by
measuring O.D at A600. MIC of the compounds was determined by
agar dilution method. Suspension of each microorganism was
prepared to contain approximately (1 ꢃ 104e2 ꢃ 104 CFU/mL) and
applied to the plates with serially diluted compounds (dissolved in
DMSO) to be tested and also reference drug and incubated at 37 ꢂC
overnight. The minimum inhibitory concentration was considered
to be the lowest concentration that completely inhibited the
growth of microorganisms on the plates. Zone of inhibition (mm)
was measured after 24 h and MIC values were determined.
4.7.1. Antibacterial activity
In vitro antibacterial activity was evaluated against human
pathogens of both gram positive organisms namely C. positive
staphylococcus and K. pneumoniae and gram negative organisms
namely X. oryzae and E. coli by agar well diffusion method
(Figs. 1e4) as well as microdilution method.
4.7.1.1. Agar well diffusion method. The microorganisms were
inoculated in to the sterilized nutrient broth and maintained at
37 ꢂC for 24 h. On the day of testing, bacteria were subcultured
separately into 25 mL of sterilized nutrient broth. Inoculated sub-
cultured broths were kept at room temperature for the growth of
inoculums. Each final compound and standard drug (amoxicillin) of
10 mg was dissolved in 10 mL of DMSO to get a concentration of
4.7.2. Antifungal activity
In vitro antifungal activity was evaluated against three fungal
species namely A. niger, A. flavus and F. oxysporum by agar well
diffusion method (Figs. 5e7) as well as microdilution method
(Fig. 8).
1 mg/mL and further diluted to get a final concentration of 30 mg/
mL. About 15e20 mL of molten nutrient agar was poured into each
of the sterile plates. With the help of cork borer of 6 mm diameter,
the cups were punched and scooped out of the set agar and the
plates were inoculated with the suspension of particular organism
by spread plate technique. The cups of inoculated plates were then
filled with 0.1 mL of the test solution, amoxicillin solution and
DMSO (negative control). The plates were allowed to stay for 24 h at
37 ꢂC and zone of inhibition (mm) was then measured.
4.7.2.1. Agar well diffusion method. The fungal strains were sub-
cultured separately into 25 mL of sterilized nutrient broth and
incubated for one day to obtain the inoculums. Each final
compound and standard drug (bavistin) of 10 mg was dissolved in
10 mL of DMSO to get a concentration of 1 mg/mL and further
diluted to get a final concentration of 30 mg/mL. Molten media of
Fig. 4. Diagramatic representation of antibacterial activity of the compounds against C. positive staphylococcus.

190
R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
Fig. 5. Diagramatic representation of antifungal activity of the compounds against A. niger.
Sabouraud agar of 10e15 mL was poured into the petriplates and
allowed to solidify. Fungal subculture was inoculated on the
solidified media. With the help of 6 mm cork borer, the cups were
punched and scooped out of the set agar. The cups of inoculated
plates were then filled with 0.1 mL of the test solution, bavistin
solution and DMSO (negative control). The plates were allowed to
stay for 3 days at room temperature and zone of inhibition (mm)
was then measured.
4.7.2.2. Microdilution method. Sabouraud agar was used for the
preparation of plates. Suspension of each microorganism was
prepared to contain 105 CFU/mL. The agar plates were inoculated
Fig. 6. Diagramatic representation of antifungal activity of the compounds against A. flavus.
Fig. 7. Diagramatic representation of antifungal activity of the compounds against F. oxysporum.

R. Suhas et al. / European Journal of Medicinal Chemistry 48 (2012) 179e191
191
Fig. 8. Diagramatic representation of antibacterial and antifungal activities of the compounds by microdilution method.
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