Synthesis, characterization and antimicrobial studies on some newer imidazole analogs

Article abstract of DOI:10.3797/scipharm.0803-04

A novel series of 3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoic acid analogs of amino acids, dipeptides and tripeptides was synthesized by using dicyclohexylcarbodiimide and diisopropylcarbodiimide (DCC/DIPC) as coupling agents and triethylamine (TEA) as base. Structures of all the newly synthesized compounds were confirmed by elemental analysis and IR, ¹H NMR, ¹³C NMR and mass spectral data. Imidazolopeptides were investigated for their antimicrobial activity and some of newly synthesized compounds 2c, 2d, 2h and their hydrolyzed analogs 3b, 3d exhibited potent bioactivity against pathogenic fungi Candida albicans and dermatophytes Trichophyton mentagrophytes and Microsporum audouinii with MIC values of 12.5-6 μg/ml, as compared to the reference drug - griseofulvin. In addition, moderate activity against gram negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae was also observed for synthesized imidazolopeptides. Oesterreichische Apotheker-Verlagsgesellschaft m. b. H.

Full text of DOI:10.3797/scipharm.0803-04

Sci Pharm. 2008; 76: 217–239
doi:10.3797/scipharm.0803-04
217
© Österreichische Apotheker-Verlagsgesellschaft m. b. H., Vienna, Austria
Reproduction is permitted for non-commercial purposes.
Synthesis, Characterization and Antimicrobial
Studies on Some Newer Imidazole Analogs
Rajiv DAHIYA
Department of Pharmaceutical Chemistry, Rajiv Academy for Pharmacy,
Mathura – 281001, Uttar Pradesh, India
Abstract
A novel series of 3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoic acid analogs
of amino acids, dipeptides and tripeptides was synthesized by using
dicyclohexylcarbodiimide and diisopropylcarbodiimide (DCC/DIPC) as coupling
agents and triethylamine (TEA) as base. Structures of all the newly synthesized
1
13
compounds were confirmed by elemental analysis and IR, H NMR, C NMR and
mass spectral data. Imidazolopeptides were investigated for their antimicrobial
activity and some of newly synthesized compounds 2c, 2d, 2h and their hydrolyzed
analogs 3b, 3d exhibited potent bioactivity against pathogenic fungi Candida
albicans and dermatophytes Trichophyton mentagrophytes and Microsporum
audouinii with MIC values of 12.5-6 μg/ml, as compared to the reference drug –
griseofulvin. In addition, moderate activity against gram negative bacteria
Pseudomonas aeruginosa and Klebsiella pneumoniae was also observed for
synthesized imidazolopeptides.
Keywords
Imidazolopeptides • p-Amino-3,5-diiodobenzoic acid • Peptide coupling •
Antifungal activity • Antibacterial activity
Introduction
In past decades, imidazoles have proved their potential in development of
pharmaceutically important organic compounds both of natural and synthetic origin
E-mail: rajivdahiya04@yahoo.co.in (R. Dahiya).

218
R. Dahiya:
[1]. Imidazole analogs deal with a variety of bioactivities viz. antitumor [2, 3], anti-
HIV [4], antimicrobial [5–8], anticonvulsant [9], antitubercular [10], antiprotozoal
[11], anti-inflammatory [12], FTase and MAP kinase p38 inhibitory activities [13, 14].
Literature is enriched with lot of work on synthesis of potent substituted imidazole
derivatives with diverse pharmacological activities [15, 16] but only few reports
have been received on peptide coupling of imidazoles. Thus keeping in view the
biological potency of imidazole derivatives as well as taking advantage of
biodegradability and biocompatibility of amino acids/peptides and further, in
continuation of our research work on synthesizing peptide derivatives of
heterocyclic and other aromatic compounds [17–29], a novel series of 3,5-diiodo-4-
(2-methyl-1H-5-imidazolyl)benzoyl amino acids and peptides with an anticipation to
get potent agents of more therapeutic efficacy with lesser adverse effects.
Chemistry
4-Amino-3,5-diiodobenzoic acid (1) was prepared according to literature
procedure [30] in good yields by iodination of p-aminobenzoic acid (PABA) using
iodine monochloride. 3,5-Diiodo-4-(2-methyl-1H-5-imidazolyl)benzoic acid (2) was
synthesized by diazotization of compound 1 followed by subsequent interaction with
2-methylimidazole in presence of aqueous cupric chloride. Dipeptides Boc-his-tyr-
OMe, Boc-phe-try-OMe and Boc-gly-gly-OMe were prepared from the
corresponding Boc-amino acids viz. Boc-his-OH, Boc-phe-OH and Boc-gly-OH, and
amino acid methyl ester hydrochlorides such as tyr-OMe.HCl, try-OMe.HCl and gly-
OMe.HCl using DCC and N-methylmorpholine (NMM) in chloroform [31]. Similarly,
tripeptides Boc-pro-val-pro-OMe, Boc-ile-phe-leu-OMe and tetrapeptide Boc-gly-
his-ala-try-OMe were prepared by coupling Boc-dipeptides with corresponding
amino acid methyl ester hydrochlorides and dipeptide methyl esters. All Boc-
di/tri/tetrapeptide methyl esters were deprotected at amino terminals using
trifluoroacetic acid (TFA) prior to coupling.
3,5-Diiodo-4-(2-methyl-1H-5-imidazolyl)benzoic acid (2) was coupled with
various L-amino acid methyl ester hydrochlorides/peptide methyl esters using

Synthesis, Spectral and Antimicrobial Studies …
219
DCC/DIPC and TEA to get newly synthesized 3,5-diiodo-4-(2-methyl-1H-5-
imidazolyl)benzoyl amino acid methyl esters (2a–b), dipeptide methyl esters (2c–e)
and tri/tetrapeptide methyl esters (2f–h). Finally, compounds 2b–c and 2g–h were
hydrolyzed with lithium hydroxide (LiOH) to get the corresponding acid derivatives
3a–d. Structures of all the newly synthesized compounds were confirmed by IR, 1H
NMR, 13C NMR and mass spectral data. Elemental analysis of the novel
compounds was performed for carbon, hydrogen and nitrogen content. The
synthesis of compounds 2a–3d is mentioned in Scheme 1 and their physico-
chemical data is described in Table 1.
Results and Discussion
All imidazolopeptide derivatives 2a–h were synthesized in good yields using
DCC/DIPC as coupling agents and TEA as base. Presence of bands at 3307–2499,
1696 and 593 cm−1 in IR spectrum of compound 2 clearly indicated presence of
functional groups like –COOH and –I but no free –NH2 group which was present in
starting material p-amino-3,5-diiodobenzoic acid (1). Furthermore, IR spectra of
peptide derivatives 2a–h showed Amide I and Amide II bands at 1662-1639 cm–1
and 1538-1531 cm−1 indicating formation of peptide bonds and successfulness of
coupling reaction. This fact was further confirmed by appearance of broad singlets
1
at 9.32–6.96 ppm (for imino proton of CO–NH moiety) in H NMR spectra and
13
singlets at 179.5–167.2 ppm (for carbonyl carbon of CO–NH moiety) in C NMR
spectra of compounds 2a–h. Mass spectra of peptide ester derivatives showed
molecular ion peaks along with isotopic peaks at m/z values, consistent with their
respective molecular formulas. All peptide ester derivatives showed easily
distinguishable R−C≡O+ ion peaks at M − 31 along with characteristic fragmentation
pattern after and before the carbonyl moiety in their respective structures.
Furthermore, [CH3O+] and [CH3OCO+] fragment ion peaks appeared at m/z values
31 and 59 in mass spectra of peptide ester derivatives.

220
R. Dahiya:
I
I
O
OH
O
Iodination
ICl
H2N
H2N
OH
1
Diazotization NaNO2, HCl
I
I
N
O
CuCl2
O
N
N N+
-
Cl
+
Me
N
H
OH
OH
Me
N
H
I
I
2
I
I
H-X-OMe,
DCC/DIPC
N
O
Coupling
OMe
Me
N
H
N X
H
2a–h
I
N
O
Hydrolysis
LiOH
OH
2b–c, 2g–h
Me
N
H
N X
H
I
3a–d
Sch. 1. X = pro (2a), leu (2b), his-tyr (2c), phe-try (2d), gly-gly (2e), pro-val-pro (2f),
ile-phe-leu (2g), gly-his-ala-try (2h), leu (3a), his-tyr (3b), ile-phe-leu (3c), gly-his-
ala-try (3d).
Structures of hydrolyzed analogs 3a–d were confirmed by appearance of
strong bands at 1713–1708 cm−1 (C=O str, COOH) in IR spectra, broad singlets at
1
8.69 ppm (for hydroxyl proton of COOH) in H NMR spectra and singlets at 175.0
ppm (for carbonyl carbon of COOH) in 13C NMR spectra. This fact was further
supported by disappearance of medium to strong bands at 1754–1748 cm−1 (C=O
str, ester) and 1274-1269 cm–1 (C−O str, ester) in IR spectra and singlets at 52.5
ppm (for carbonyl carbon of OCH3) in 13C NMR spectra of compounds 3a–d.

Synthesis, Spectral and Antimicrobial Studies …
221
All hydrolyzed peptide derivatives showed peaks at M − 17 and M − 45 in their
mass spectra by loss of OH and COOH respectively. Moreover, [COOH+] fragment
ion peak appeared at m/z value 45 in mass spectra of compound 3c and 3d along
with characteristic fragmentation pattern after and before the carbonyl moiety.
Moreover, the results of elemental analysis revealed the variation by a factor of
±0.03 from calculated values.
Biological activity
All the newly synthesized compounds 2a–3d were evaluated for its
antimicrobial activity against four bacterial strains Bacillus subtilis (NCIM 2063),
Staphylococcus aureus (NCIM 2079), Pseudomonas aeruginosa (NCIM 2034) and
Klebsiella pneumoniae (NCIM 2011) and four fungal strains Microsporum audouinii
(MUCC 545), Trichophyton mentagrophytes (MUCC 665), Candida albicans
(MUCC 29) and Aspergillus niger (MUCC 177) at 50-6 μg ml−1 concentration,
according to modified Kirby-Bauer’s disk diffusion method [32]. MIC values of test
compounds were determined by tube dilution technique. The solvents DMF/DMSO
were used as negative controls and ciprofloxacin/griseofulvin were used as
standards. Calculated average diameters (for triplicate sets) of the zones of
inhibition (in mm) for test samples were compared with that produced by the
standard drugs.
Almost, all the synthesized compounds were found to exhibit moderate to
good antifungal activity and mild to moderate antibacterial activity. Analysis of
antimicrobial data suggested that compounds 2c, 2d, 2h, 3b and 3d possessed
higher antifungal activity against dermatophytes and Candida sp. in comparison to
standard drug.

222
R. Dahiya:
Tab. 1. Physico-chemical characterization of synthesized compounds
Elemental analysis
[Calcd. (found)]
Mol.
formula
(Mol. wt.)
C11H8I2N2O2
(454)
C17H17I2N3O3
(565)
C18H21I2N3O3
(581)
C27H26I2N6O5
(768)
C32H29I2N5O4
(801)
C16H16I2N4O4
(582)
C27H33I2N5O5
(761)
C33H41I2N5O5
(841)
C34H35I2N9O6
(919)
C17H19I2N3O3
(567)
C26H24I2N6O5
(754)
C33H41I2N5O5
(841)
C33H33I2N9O6
(905)
M.p. Yield
(°C) (%) Value*
Rf
Compd.
X
%C
29.10
%H
1.78
%N
6.17
2
–
118
–
72
77
82
75
79
71
80
84
69
86
89
92
90
0.791
0.58
0.67
0.81
0.74
0.51
0.59
0.72
0.612
0.49
0.66
0.63
0.852
(29.09) (1.80) (6.19)
36.13
(36.11) (3.06)
37.20 3.64
3.03
7.44
(7.46)
7.23
2a
2b
2c
2d
2e
2f
pro
leu
105
120
84
(37.23) (3.62) (7.25)
42.21 3.41 10.94
(42.19) (3.44) (10.95)
47.96 3.65 8.74
(47.98) (3.65) (8.77)
33.01 2.77 9.62
(33.04) (2.80) (9.59)
42.59 4.37 9.20
(42.58) (4.35) (9.23)
47.10 4.91 8.32
(47.10) (4.92) (8.29)
44.41 3.84 13.71
(44.42) (3.85) (13.69)
36.00 3.38 7.41
(35.98) (3.41) (7.40)
41.40 3.21 11.14
(41.43) (3.19) (11.15)
46.45 4.75 8.46
(46.46) (4.77) (8.44)
43.77 3.67 13.92
(43.75) (3.68) (13.90)
his-tyr
phe-try
gly-gly
pro-val-pro
ile-phe-leu
142
–
–
–
2g
2h gly-his-ala-try
3a
3b
3c
leu
63
his-tyr
159
–
ile-phe-leu
–
3d gly-his-ala-try
* (CHCl3:MeOH / 9:1), 1(CHCl3:AcOH:H2O / 3:2:5), 2(CHCl3:MeOH / 7:3)

Synthesis, Spectral and Antimicrobial Studies …
223
Tab. 2. Antimicrobial activity of synthesized compounds
Diameter of zone of inhibition (mm)
Bacterial strains
Fungal strains
Compd.
B.
S.
P.
K.
C.
M. A.
T.
sub.
aur.
aeru.
pneu.
alb.
audo. niger menta.
2a
2b
2c
9(25)† 11(50)
11(25) 13(25)
10(12.5) 9(50)
11(6) 10(12.5) 14(6) 14(6) 12(12.5) 14(6)
17(6) 13(12.5) 15(6) 13(6) 14(12.5) 13(6)
14(6) 11(12.5) 21(6) 19(6) 12(12.5) 21(6)
2d
2e
2f
2g
15(6) 10(12.5) 20(6) 13(12.5) 23(6) 22(6) 15(12.5) 24(6)
16(6) 9(12.5) 24(6) 19(12.5) 17(6) 12(6) 9(12.5) 16(12.5)
15(12.5)13(12.5) 25(6) 18(12.5) 11(12.5) 10(6) 12(12.5) 9(25)
13(25) 11(25) 17(12.5) 14(12.5) 17(12.5) 10(6) 14(12.5) 11(25)
2h
3a
3b
11(12.5) 10(25)
15(25) 16(25)
16(12.5) 10(50)
13(6) 12(12.5) 22(6) 18(6) 15(12.5) 21(6)
19(6) 16(12.5) 17(6) 15(6) 15(12.5) 17(6)
17(6) 15(12.5) 25(6) 20(6) 14(12.5) 23(6)
3c
16(25) 13(25) 19(12.5) 16(12.5) 19(12.5) 14(6) 16(12.5) 14(25)
13(12.5) 12(25) 18(6) 15(12.5) 25(6) 21(6) 17(12.5) 23(6)
3d
Control‡
–
–
–
–
–
–
–
–
–
–
–
–
Ciprofloxacin 20(6) 20(12.5) 25(6) 19(12.5)
Griseofulvin
† Values in bracket are MIC values (μg/ml).
–
–
–
–
20(6) 17(6) 18(12.5) 20(6)
‡ Dimethylformamide (DMF) / Dimethylsulfoxide (DMSO)
Moreover, all the synthesized compounds exhibited moderate activity against
gram negative bacteria. Compounds 2e and 2f exhibited bioactivity equivalent or
closer to reference compound, against P. aeruginosa and K. pneumoniae.
Moreover, comparison of antimicrobial data further suggested that amino acid and
peptide derivatives 3a–d possessed more antimicrobial activity as compared to
corresponding methyl ester derivatives 2b–c and 2g–h (Table 2).
Newly synthesized compounds 2a–3d were found to be more potent in
comparison to previously synthesized diiododimethylbenzimidazole analogs against
K. pneumoniae and M. audouinii. Even some of the synthesized analogs 2c, 2d,

224
R. Dahiya:
2h, 3b and 3d displayed better activity against P. aeruginosa and compounds 2d–f
exhibited better activity against C. albicans when compared to their corresponding
dimethylbenzimidazolopeptides [18]. However, activity of compounds 2a–3d
against gram positive bacteria was found to be less in comparison to earlier
synthesized analogs. Moreover, presence of iodine atoms in nucleus was found to
confer more antimicrobial activity especially against P. aeruginosa, K. pneumoniae,
C. albicans and dermatophytes, as evident from previously synthesized non-
iodinated benzimidazolopeptide analogs [26].
Experimental
Melting points were determined by open capillary method and are uncorrected.
L-amino acids, DIPC, DCC, TFA, NMM and TEA were procured from SpectroChem
Ltd, Mumbai, India. IR spectra were recorded on Shimadzu 8700 fourier transform
infrared spectrophotometer using a thin film supported on KBr pellets for solids and
1
13
CHCl3 as solvent for semisolids. H NMR and C NMR spectra were recorded on
Bruker AC NMR spectrometer (300 and 50 MHz) using DMSO-d6 and CDCl3 as
solvents and TMS as internal standard. Mass spectra were recorded on Jeol JMS
DX 303 Mass spectrometer operating at 70 eV. Elemental analysis of all
compounds was performed on Elementar vario EL III. Purity of all the compounds
was checked by TLC on precoated silica gel G plates.
Preparation of peptides
Amino acid methyl ester hydrochloride/dipeptide methyl ester (0.01 mol) was
dissolved in CHCl3 (15 ml). To this, NMM (0.021 mol) was added at 0 °C and the
reaction mixture was stirred for 10 min. Boc-amino acid/dipeptide (0.01 mol) in
CHCl3 (15 ml) and DCC (0.01 mol) were added with stirring. After 36 h, the reaction
mixture was filtered and the residue was washed with CHCl3 (30 ml) and added to
the filtrate. The filtrate was washed with 25 ml each of 5% NaHCO3 and saturated
NaCl solutions. The organic layer was dried over anhydrous Na2SO4, filtered and
evaporated in vacuum. The crude product was crystallized from a mixture of

Synthesis, Spectral and Antimicrobial Studies …
225
chloroform and n-hexane followed by cooling at 0 °C. Resulting Boc-
di/tri/tetrapeptide methyl ester (0.01 mol) was dissolved in CHCl3 (15 ml) and
treated with trifluoroacetic acid (TFA, 0.02 mol). The mixture was stirred at RT for
1 h and washed with 25 ml of saturated NaHCO3 solution. The resulting organic
layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Finally, crude product was purified by recrystallization with CHCl3 and petroleum
ether (b.p. 40–60 °C) to get the deprotected di/tri/tetrapeptide methyl esters.
Preparation of 3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoic acid (2)
A mixture of 4-amino-3,5-diiodobenzoic acid (1) (38.9 g, 0.1 mol), dil.
hydrochloric acid (15%, 60 ml) and water (90 ml) was heated to get a clear solution.
After cooling, the solution was diazotized by addition of sodium nitrite solution
(30%, 24 ml). To the filtrate of diazotized salt solution, 2-methylimidazole (8.2 g, 0.1
mol) and aqueous cupric chloride solution (2.5 g in 10 ml of water) were added with
stirring followed by slow addition of water (50 ml). Stirring was continued for 4 h and
kept overnight in the refrigerator. The separated solid was collected by filtration and
washed with cold water. The crude product was recrystallized from acetone to get
the title compound. White crystals; m.p. 118 °C; IR (KBr) v (cm−1): 3488 (N−H str,
ring), 3307-2499 (O−H str, COOH), 3074, 3054 (Ar−H str), 2969, 2873 (C−H str,
CH3), 1696 (C=O str, COOH), 1587, 1425, 1422 (skeletal bands), 869, 833, 748
(C−H def, out-of-plane (oop)), 593 (C−I str); 1H-NMR (DMSO-d6) δ (ppm): 9.22 (2H,
br. s, NH, imz and OH, COOH), 8.15 (2H, s, H-2 and H-6, iodobenzoic acid moiety
(iba)), 7.45 (1H, s, H-δ, imidazole moiety (imz)), 2.64 (3H, s, β-CH3, imz); 13C-NMR
(CDCl3) δ (ppm): 170.2 (C=O, COOH), 159.0 (C-2, imz), 150.1 (C-4, imz), 149.3 (C-
4, iba), 146.7 (C-5, imz), 141.2 (2C, C-2 and C-6, iba), 124.4 (C-1, iba), 105.8 (2C,
C-3 and C-5, iba), 18.9 (β-CH3, imz).
General procedure for synthesis of 3,5-diiodo-4-(2-methyl-1H-imidazol-
5-yl)benzoyl amino acid and peptide methyl esters (2a–h)

226
R. Dahiya:
To a mixture of amino acid methyl ester hydrochloride/di/tri/tetrapeptide methyl
ester (0.01 mol) in 50 ml of DMF, 2.8 ml of TEA was added at 0 °C with stirring.
Compound 2 (4.54 g, 0.01 mol) in DMF (50 ml) and DCC/DIPC (0.01 mol) were
added to the above mixture and stirring was done for 24 h. After this, reaction
mixture was filtered and filtrate was diluted with equal proportion of water and
aqueous layer was washed with ether (3 × 50 ml). The organic layer was separated
and dried over anhydrous Na2SO4, filtered and evaporated. The product obtained
was dissolved in chloroform, washed with 30 ml each of 10% HCl, saturated
NaHCO3 solution and water followed by evaporation in vacuum. Crude product was
crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 40–60 °C).
Methyl 1-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]-L-prolinate (2a)
IR (CHCl3) v (cm−1): 3486 (N−H str, ring), 3077, 3052 (Ar−H str), 2997-2992
(C−H str, CH2, pro), 2968, 2875 (C−H str, CH3), 1744 (C=O str, ester), 1658 (C=O
str, 3° amide), 1589, 1421 (skeletal bands), 1272 (C−O str, ester), 865, 838, 752
(C−H def, out-of-plane (oop)), 590 (C−I str); 1H-NMR (DMSO-d6) δ (ppm): 8.32 (1H,
s, H-δ, imz), 8.20 (2H, s, H-2 and H-6, iba), 7.59 (1H, br. s, NH, imz), 4.17 (1H, t, J
= 6.9 Hz, H-α, pro), 3.72 (2H, t, J = 7.15 Hz, H-δ, pro), 3.62 (3H, s, OCH3), 2.65
13
(3H, s, β-CH3, imz), 2.20-2.14 (2H, m, H-γ, pro), 2.05-2.01 (2H, q, H-β, pro); C-
NMR (CDCl3) δ (ppm): 174.4 (C=O, pro), 173.9 (C=O, ArCO), 159.0 (C-2, imz),
151.7 (C-4, iba), 146.6 (C-5, imz), 141.2 (2C, C-2 and C-6, iba), 137.9 (C-1, iba),
137.4 (C-4, imz), 102.6 (2C, C-3 and C-5, iba), 60.2 (C-α, pro), 54.4 (OCH3), 50.1
(C-δ, pro), 28.9 (C-β, pro), 27.0 (C-γ, pro), 19.1 (β-CH3, imz).
Methyl 1-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]-L-leucinate (2b)
IR (KBr) v (cm−1): 3489 (N−H str, ring), 3134 (NH str, amide), 3075, 3048
(Ar−H str), 2966 (C−H str, CH3), 2929, 2853 (C−H str, CH2), 1742 (C=O str, ester),
1641 (C=O str, 2° amide), 1586, 1424 (skeletal bands), 1533 (N−H def, amide),
1385, 1362 (C−H bend, propyl-i), 1269 (C−O str, ester), 862, 839, 756 (C−H def,
1
oop), 588 (C−I str); H-NMR (DMSO-d6) δ (ppm): 8.35 (2H, s, H-2 and H-6, iba),

Synthesis, Spectral and Antimicrobial Studies …
227
8.32 (1H, s, H-δ, imz), 7.63 (1H, br. s, NH, imz), 6.05 (1H, br. s, NH, leu), 4.23–4.16
(1H, m, H-α, leu), 3.60 (3H, s, OCH3), 2.68 (3H, s, β-CH3, imz), 1.50–1.44 (3H, m,
13
H-β and H-γ, leu), 0.95 (6H, d, J = 6.2 Hz, H-δ, leu); C-NMR (CDCl3) δ (ppm):
179.5 (C=O, leu), 168.9 (C=O, ArCO), 159.2 (C-2, imz), 152.1 (C-4, iba), 145.9 (C-
5, imz), 140.4 (2C, C-2 and C-6, iba), 138.2 (C-1, iba), 136.7 (C-4, imz), 104.8 (2C,
C-3 and C-5, iba), 52.5 (OCH3), 51.3 (C-α, leu), 45.5 (C-β, leu), 27.2 (C-γ, leu), 26.4
(2C, C-δ, leu), 19.4 (β-CH3, imz).
Methyl 1-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]-L-histidyl-L-
tyrosinate (2c)
IR (KBr) v (cm−1): 3488, 3483 (N−H str, rings), 3359 (O−H str, Ar−OH), 3079-
3075, 3055-3051 (Ar−H str), 2967, 2872 (C−H str, CH3), 2932, 2928, 2855, 2851
(C−H str, CH2), 1749 (C=O str, ester), 1645-1639 (C=O str, amide), 1592-1588,
1426-1419 (skeletal bands), 1270 (C−O str, ester), 1224 (C–O str, phenolic), 867-
1
863, 835, 788, 750, 654 (C−H def, oop), 589 (C−I str); H-NMR (CDCl3) δ (ppm):
9.32 (1H, br. s, NH, his), 8.40 (2H, s, H-2 and H-6, iba), 8.31 (1H, s, H-δ, imz), 7.67
(1H, s, H-4, his), 7.55 (3H, br. s, NH, imz, his and OH, tyr), 7.38 (1H, d, J = 7.75 Hz,
H-2, his), 6.96 (1H, br. s, NH, tyr), 6.89 (2H, dd, J = 8.6, 5.25 Hz, H-o, tyr), 6.77
(2H, dd, J = 8.65, 4.9 Hz, H-m, tyr), 5.05–5.01 (1H, m, H-α, his), 3.94–3.89 (1H, m,
H-α, tyr), 3.56 (3H, s, OCH3), 3.02 (2H, d, J = 5.45 Hz, H-β, tyr), 2.94 (2H, d, J = 5.8
Hz, H-β, try), 2.66 (3H, s, β-CH3, imz); 13C-NMR (CDCl3) δ (ppm): 172.3 (C=O, his),
171.6 (C=O, ArCO), 170.1 (C=O, tyr), 159.0 (C-2, imz), 153.9 (C-p, tyr), 150.4 (C-4,
iba), 148.8 (C-2, his), 145.0 (C-5, imz), 143.6 (2C, C-m, tyr), 139.2 (2C, C-2 and C-
6, iba), 137.1 (C-1, iba), 136.5 (C-4, imz), 135.4 (C-4, his), 129.7 (2C, C-o, tyr),
126.5 (C-γ, tyr), 117.2 (C-5, his), 105.5 (2C, C-3 and C-5, iba), 60.3 (C-α, his), 56.1
(C-α, tyr), 52.8 (OCH3), 38.5 (C-β, tyr), 20.2 (C-β, his), 19.1 (β-CH3, imz).
Methyl 1-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]-L-phenylalanyl-L-
tryptophanate (2d)

228
R. Dahiya:
IR (KBr) v (cm−1): 3487, 3483 (N−H str, rings), 3138-3135 (NH str, amide),
3079-3075, 3049-3046 (Ar−H str), 2965 (C−H str, CH3), 2927, 2923, 2855, 2851
(C−H str, CH2), 1746 (C=O str, ester), 1644-1639 (C=O str, amide), 1589-1585,
1428-1422 (skeletal bands), 1538, 1532 (N−H def, amide), 1267 (C−O str, ester),
1
868-861, 839, 759-756, 685 (C−H def, oop), 585 (C−I str); H-NMR (DMSO-d6) δ
(ppm): 9.35 (1H, br. s, NH, phe), 8.42 (2H, s, H-2 and H-6, iba), 8.30 (1H, s, H-δ,
imz), 8.27 (2H, br. s, NH, imz and try), 7.50 (1H, d, J = 7.8 Hz, H-2, try), 7.22 (2H,
tt, J = 7.8, 4.65 Hz, H-m, phe), 7.16-7.04 (4H, m, H-4–7, try), 6.99 (1H, t, J = 6.15
Hz, H-p, phe), 6.92 (1H, br. s, NH, try), 6.82 (2H, dd, J = 8.75, 4.1 Hz, H-o, phe),
4.60-4.56 (1H, m, H-α, phe), 4.22-4.17 (1H, m, H-α, try), 3.56 (3H, s, OCH3), 3.20
(2H, d, J = 5.75 Hz, H-β, try), 2.89 (2H, d, J = 5.6 Hz, H-β, phe), 2.66 (3H, s, β-CH3,
13
imz); C-NMR (CDCl3) δ (ppm): 175.2 (C=O, try), 172.6 (C=O, phe), 165.4 (C=O,
ArCO), 158.7 (C-2, imz), 152.0 (C-4, iba), 140.8 (C-γ, phe), 144.4 (C-5, imz), 140.1
(2C, C-2 and C-6, iba), 138.3 (C-1, iba), 137.8 (C-4, imz), 136.2 (C-2′, try), 130.4
(2C, C-o, phe), 129.2 (C-2′, try), 128.6 (2C, C-m, phe), 127.1 (C-p, phe), 122.9 (C-
2, try), 121.6, 119.5, 118.2 (3C, C-6, C-5, C-4, try), 112.4, 109.5 (2C, C-7 and C-3,
try), 105.0 (2C, C-3 and C-5, iba), 56.2 (C-α, try), 53.6 (C-α, phe), 51.4 (OCH3),
40.8 (C-β, phe), 28.3 (C-β, try), 19.1 (β-CH3, imz).
Methyl N-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]glycylglycinate (2e)
IR (KBr) v (cm−1): 3488 (N−H str, ring), 3075, 3050 (Ar−H str), 2969, 2870
(C−H str, CH3), 2928, 2923, 2856, 2852 (C−H str, CH2), 1747 (C=O str, ester),
1644-1640 (C=O str, amide), 1587, 1425 (skeletal bands), 1536, 1532 (N−H def,
amide), 1268 (C−O str, ester), 868, 839, 751 (C−H def, oop), 592 (C−I str); 1H-NMR
(DMSO-d6) δ (ppm): 8.65 (1H, br. s, NH, gly-2), 8.46 (1H, br. s, NH, gly-1), 8.42
(2H, s, H-2 and H-6, iba), 8.30 (1H, s, H-δ, imz), 7.65 (1H, br. s, NH, imz), 4.05 (2H,
d, J = 5.15 Hz, H-α, gly-2), 3.90 (2H, d, J = 5.2 Hz, H-α, gly-1), 3.53 (3H, s, OCH3),
2.69 (3H, s, β-CH3, imz); 13C-NMR (CDCl3) δ (ppm): 176.6 (C=O, gly-1), 170.2
(C=O, gly-2), 168.4 (C=O, ArCO), 158.7 (C-2, imz), 151.6 (C-4, iba), 146.3 (C-5,

Synthesis, Spectral and Antimicrobial Studies …
229
imz), 141.2 (2C, C-2 and C-6, iba), 138.8 (C-1, iba), 137.4 (C-4, imz), 105.0 (2C, C-
3 and C-5, iba), 54.5 (OCH3), 46.3 (C-α, gly-1), 41.4 (C-α, gly-2), 17.8 (β-CH3, imz).
Methyl 1-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]-L-prolyl-L-valyl-L-
prolinate (2f)
IR (CHCl3) v (cm−1): 3486 (N−H str, ring), 3136 (N−H str, amide), 3078, 3047
(Ar−H str), 2998-2993 (C−H str, CH2, pro), 2969, 2872 (C−H str, CH3), 1746 (C=O
str, ester), 1662-1657, 1643 (C=O str, 3° and 2° amide), 1588, 1426 (skeletal
bands), 1535 (N−H def, amide), 1386, 1360 (C−H bend, propyl-i), 1269 (C−O str,
1
ester), 863, 839, 755 (C−H def, oop), 587 (C−I str); H-NMR (DMSO-d6) δ (ppm):
9.25 (1H, br. s, NH, val), 8.36 (2H, s, H-2 and H-6, iba), 8.30 (1H, s, H-δ, imz), 7.63
(1H, br. s, NH, imz), 4.70 (1H, dd, J = 5.9, 4.35 Hz, H-α, val), 4.08 (1H, t, J = 6.9
Hz, H-α, pro-1), 3.66 (1H, t, J = 6.85 Hz, H-α, pro-2), 3.61 (3H, s, OCH3), 3.45 (2H,
t, J = 7.15 Hz, H-δ, pro-1), 3.45 (2H, t, J = 7.2 Hz, H-δ, pro-2), 2.65 (3H, s, β-CH3,
imz), 2.62 (2H, q, H-β, pro-1), 2.10-2.05 (1H, m, H-β, val), 2.02-1.96 (4H, m, H-γ,
13
pro-1 and pro-2), 1.93 (2H, q, H-β, pro-2), 1.05 (6H, d, J = 4.65 Hz, H-γ, val); C-
NMR (CDCl3) δ (ppm): 176.4 (C=O, pro-1), 173.1 (C=O, pro-2), 170.8 (C=O, ArCO),
167.2 (C=O, val), 159.0 (C-2, imz), 150.9 (C-4, iba), 146.6 (C-5, imz), 141.5 (2C, C-
2 and C-6, iba), 138.0 (C-1, iba), 136.6 (C-4, imz), 104.2 (2C, C-3 and C-5, iba),
66.2 (C-α, pro-1), 60.7 (C-α, pro-2), 54.2 (OCH3), 53.0 (C-α, phe), 45.3 (C-δ, pro-2),
43.1 (C-δ, pro-1), 30.2 (C-β, val), 29.3 (C-β, pro-2), 27.7 (C-β, pro-1), 27.0 (C-γ,
pro-1), 23.5 (C-γ, pro-2), 19.8 (2C, C-γ, val), 18.8 (β-CH3, imz).
Methyl 1-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]-L-isoleucyl-L-
phenylalanyl-L-leucinate (2g)
IR (CHCl3) v (cm−1): 3484 (N−H str, ring), 3079, 3052-3047 (Ar−H str), 2973,
2968, 2870 (C−H str, CH3), 2929-2925, 2855-2852 (C−H str, CH2), 1748 (C=O str,
ester), 1647-1642 (C=O str, amide), 1587, 1422 (skeletal bands), 1538-1531 (N−H
def, amide), 1386, 1360 (C−H bend, propyl-i), 1274 (C−O str, ester), 869, 832, 786-
781, 748 (C−H def, oop), 590 (C−I str); 1H-NMR (DMSO-d6) δ (ppm): 8.39 (2H, s, H-

230
R. Dahiya:
2 and H-6, iba), 8.30 (1H, s, H-δ, imz), 7.98 (1H, br. s, NH, phe), 7.65 (1H, br. s,
NH, imz), 7.20 (2H, tt, J = 7.75, 4.8 Hz, H-m, phe), 7.12 (1H, br. s, NH, phe), 6.98
(1H, t, J = 6.2 Hz, H-p, phe), 6.84 (2H, dd, J = 8.7, 4.15 Hz, H-o, phe), 6.74 (1H, br.
s, NH, leu), 4.59 (1H, dd, J = 5.35, 3.7 Hz, H-α, ile), 4.32 (1H, q, H-α, phe), 3.60
(3H, s, OCH3), 3.48 (1H, q, H-α, leu), 2.80 (2H, d, J = 5.65 Hz, H-β, phe), 2.62 (3H,
s, β-CH3, imz), 2.02-1.96 (1H, m, H-β, ile), 1.65-1.59 (2H, m, H-γ, ile), 1.50-1.43
(3H, m, H-β and H-γ, leu), 1.02 (3H, d, J = 5.9 Hz, H-γ′, ile), 0.98 (3H, d, J = 5.9 Hz,
H-δ, ile), 0.95 (6H, d, J = 6.25 Hz, H-δ, leu); 13C-NMR (CDCl3) δ (ppm): 178.2 (C=O,
leu), 171.5 (C=O, phe), 168.7 (C=O, ile), 168.0 (C=O, ArCO), 159.4 (C-2, imz),
152.2 (C-4, iba), 139.9 (2C, C-2 and C-6, iba), 146.5 (C-5, imz), 137.8 (C-1, iba),
137.2 (C-4, imz), 134.6 (C-γ, phe), 130.9 (2C, C-o, phe), 130.2 (2C, C-m, phe),
128.5 (C-p, phe), 105.6 (2C, C-3 and C-5, iba), 58.4 (C-α, ile), 52.3 (OCH3), 50.7
(C-α, leu), 49.5 (C-α, phe), 45.2 (C-β, leu), 38.8 (C-β, phe), 36.5 (C-β, ile), 31.2 (C-
γ, ile), 26.4 (C-γ, leu), 25.6 (2C, C-δ, leu), 17.9 (β-CH3, imz), 14.4 (C-γ′, ile), 10.5
(C-δ, ile); MASS m/z (% rel. int.): 843(2.3), 842(3.8), 841(M+, 4.5), 826(12.5),
810(33.6), 782(10.9), 697(59.2), 669(18.7), 550(100), 522(25.8), 437(65.4),
408(24.5), 328(10.9), 203(11.7), 126(6.5), 120(11.5), 91(12.4), 86(19.5), 82(13.1),
81(10.4), 65(17.2), 59(16.5), 57(14.2), 56(17.2), 55(11.6), 43(16.2), 42(11.7),
31(14.4), 29(10.2), 15(3.7).
Methyl N-[3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]glycyl-L-histidyl-L-
alanyl-L-tryptophanate (2h)
IR (CHCl3) v (cm−1): 3489-3483 (N−H str, rings), 3078-3073, 3053 (Ar−H str),
2964, 2872, 2869 (C−H str, CH3), 2929-2922, 2855, 2850 (C−H str, CH2), 1754
(C=O str, ester), 1645-1641 (C=O str, amide), 1589-1584, 1428-1423 (skeletal
bands), 1538-1533 (N−H def, amide), 1272 (C−O str, ester), 869-864, 838-835, 749
1
(C−H def, oop), 590 (C−I str); H-NMR (DMSO-d6) δ (ppm): 9.10 (1H, br. s, NH,
gly), 8.58 (3H, br. s, NH, imz, his and try), 8.42 (2H, s, H-2 and H-6, iba), 8.30 (1H,
s, H-δ, imz), 8.15 (1H, br. s, NH, ala), 7.78 (1H, br. s, NH, his), 7.65 (1H, s, H-δ,

Synthesis, Spectral and Antimicrobial Studies …
231
imz, his), 7.52 (1H, d, J = 7.75 Hz, H-2, try), 7.36 (1H, d, J = 7.8 Hz, H-2, his), 7.15-
7.04 (4H, m, H-4–7, try), 6.77 (1H, br. s, NH, try), 4.30-4.25 (1H, m, H-α, ala), 4.23-
4.17 (1H, m, H-α, try), 4.15-4.11 (1H, m, H-α, his), 4.08 (2H, d, J = 5.1 Hz, H-α,
gly), 3.57 (3H, s, OCH3), 3.05-2.96 (4H, m, H-β, his and try), 2.66 (3H, s, β-CH3,
13
imz), 1.49 (3H, d, J = 5.85 Hz, H-β, ala); C-NMR (CDCl3) δ (ppm): 177.8 (C=O,
gly), 175.2 (C=O, try), 174.4 (C=O, ala), 170.7 (C=O, ArCO), 169.9 (C=O, his),
159.1 (C-2, imz), 152.0 (C-4, iba), 148.6 (C-2, his), 146.2 (C-5, imz), 141.4 (2C, C-2
and C-6, iba), 137.7 (C-2′, try), 136.8 (C-4, imz), 136.0 (C-1, iba), 135.6 (C-4, his),
129.3 (C-3′, try), 122.8 (C-2, try), 121.4, 119.7, 118.2 (3C, C-4–6, try), 117.1 (C-5,
his), 112.4, 109.5 (2C, C-7 and C-3, try), 105.2 (2C, C-3 and C-5, iba), 63.2 (C-α,
his), 60.5 (C-α, ala), 55.6 (C-α, try), 51.7 (OCH3), 48.2 (C-α, gly), 28.5 (C-β, try),
20.1 (C-β, ala), 19.6 (C-β, his), 18.7 (β-CH3, imz); MASS m/z (% rel. int.): 920(2.5),
919(M+, 3.6), 904(14.9), 888(30.9), 860(10.7), 702(59.8), 674(16.6), 631(100),
603(20.4), 494(72.5), 466(23.3), 437(38.6), 408(12.7), 328(10.6), 203(12.2),
159(17.4), 130(9.9), 126(8.8), 116(8.5), 110(14.8), 82(13.3), 81(19.7), 67(5.9),
59(15.8), 56(17.4), 55(9.6), 44(12.2), 31(10.9), 30(5.7), 15(3.4).
Preparation of 3,5-diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl amino acids
and peptides (3a-d)
To a solution of the amino acid/peptide methyl esters (0.01 mol) in THF : H2O
(1 : 1, 36 ml), LiOH (0.36 g, 0.015 mol) was added at 0 °C. The mixture was stirred
at RT for 1 h and then acidified to pH 3.5 with 1N H2SO4. The aqueous layer was
extracted with diethyl ether (3 × 25 ml). The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
products were crystallized from methanol and ether to get hydrolyzed peptide
derivatives.
3,5-Diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl-L-leucine (3a)
IR (KBr) v (cm−1): 3486 (N−H str, ring), 3298-2508 (O−H str, COOH), 3137 (NH
str, amide), 3078, 3046 (Ar−H str), 2965 (C−H str, CH3), 2927, 2852 (C−H str, CH2),

232
R. Dahiya:
1713 (C=O str, COOH), 1644 (C=O str, amide), 1588, 1423 (skeletal bands), 1536
(N−H def, amide), 1406 (O−H def, COOH), 1387, 1360 (C−H bend, propyl-i), 860,
836, 759 (C−H def, oop), 585 (C−I str); 1H-NMR (DMSO-d6) δ (ppm): 10.05 (2H, br.
s, NH, imz and OH, COOH), 8.32 (2H, s, H-2 and H-6, iba), 8.30 (1H, s, H-δ, imz),
8.07 (1H, br. s, NH, leu), 4.38-4.33 (1H, m, H-α, leu), 2.69 (3H, s, β-CH3, imz),
1.98-1.85 (1H, m, H-γ, leu), 1.55 (2H, t, H-β, leu), 0.97 (6H, d, J = 6.15 Hz, H-δ,
13
leu); C-NMR (CDCl3) δ (ppm): 175.0 (C=O, leu), 168.2 (C=O, ArCO), 159.0 (C-2,
imz), 154.5 (C-4, iba), 146.4 (C-5, imz), 140.2 (2C, C-2 and C-6, iba), 137.6 (C-4,
imz), 136.6 (C-1, iba), 106.7 (2C, C-3 and C-5, iba), 49.2 (C-α, leu), 39.9 (C-β, leu),
24.4 (C-γ, leu), 19.9 (2C, C-δ, leu), 18.3 (β-CH3, imz).
3,5-Diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl-L-histidyl-L-tyrosine (3b)
IR (KBr) v (cm−1): 3489, 3482 (N−H str, rings), 3356 (O−H str, Ar−OH), 3294-
2503 (O−H str, COOH), 3077-3072, 3054 (Ar−H str), 2965, 2870 (C−H str, CH3),
2930, 2929, 2852, 2848 (C−H str, CH2), 1708 (C=O str, COOH), 1644-1640 (C=O
str, amide), 1590-1587, 1425-1419 (skeletal bands), 1409 (O−H def, COOH), 866-
1
862, 839, 789, 754, 651 (C−H def, oop), 585 (C−I str); H-NMR (CDCl3) δ (ppm):
9.38 (1H, br. s, NH, his), 8.69 (4H, br. s, NH, imz, his and OH, tyr, COOH), 8.42
(2H, s, H-2 and H-6, iba), 8.32 (1H, s, H-δ, imz), 7.65 (1H, s, H-4, his), 7.39 (1H, d,
J = 7.8 Hz, H-2, try), 7.25 (1H, br. s, NH, tyr), 7.17 (2H, dd, J = 8.65, 5.3 Hz, H-o,
tyr), 6.79 (2H, dd, J = 8.7, 4.95 Hz, H-m, tyr), 5.80–5.75 (1H, m, H-α, his), 4.20–
4.15 (1H, m, H-α, tyr), 3.10 (2H, d, J = 5.5 Hz, H-β, tyr), 2.90 (2H, d, J = 5.85 Hz, H-
β, try), 2.65 (3H, s, β-CH3, imz); 13C-NMR (CDCl3) δ (ppm): 173.4 (C=O, tyr), 171.6
(C=O, his), 171.2 (C=O, ArCO), 159.2 (C-2, imz), 154.4 (C-p, tyr), 151.6 (C-4, iba),
149.3 (C-2, his), 146.2 (C-5, imz), 142.1 (2C, C-m, tyr), 139.6 (2C, C-2 and C-6,
iba), 137.1 (C-4, imz), 136.4 (C-1, iba), 135.0 (C-4, his), 128.8 (2C, C-o, tyr), 127.2
(C-γ, tyr), 117.0 (C-5, his), 105.2 (2C, C-3 and C-5, iba), 65.5 (C-α, his), 54.3 (C-α,
tyr), 37.7 (C-β, tyr), 19.8 (C-β, his), 18.6 (β-CH3, imz).

Synthesis, Spectral and Antimicrobial Studies …
233
3,5-Diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl-L-isoleucyl-L-phenylalanyl-L-
leucine (3c)
IR (CHCl3) v (cm−1): 3487 (N−H str, ring), 3308-2513 (O−H str, COOH), 3077,
3050-3046 (Ar−H str), 2971, 2966, 2872 (C−H str, CH3), 2928-2922, 2856-2853
(C−H str, CH2), 1711 (C=O str, COOH), 1646-1640 (C=O str, amide), 1588, 1420
(skeletal bands), 1536-1530 (N−H def, amide), 1408 (O−H def, COOH), 1388, 1362
1
(C−H bend, propyl-i), 867, 830, 785-780, 749 (C−H def, oop), 588 (C−I str); H-
NMR (DMSO-d6) δ (ppm): 10.05 (2H, br. s, NH, imz and OH, COOH), 8.41 (2H, s,
H-2 and H-6, iba), 8.30 (1H, s, H-δ, imz), 7.99 (1H, br. s, NH, phe), 7.22 (2H, tt, J =
7.8, 4.75 Hz, H-m, phe), 7.15 (1H, br. s, NH, leu), 7.10 (1H, br. s, NH, phe), 7.02
(1H, t, J = 6.15 Hz, H-p, phe), 6.82 (2H, dd, J = 8.75, 4.15 Hz, H-o, phe), 4.84 (1H,
q, H-α, phe), 4.58 (1H, dd, J = 5.4, 3.75 Hz, H-α, ile), 3.65 (1H, q, H-α, leu), 2.82
(2H, d, J = 5.65 Hz, H-β, phe), 2.66 (3H, s, β-CH3, imz), 2.05-1.98 (1H, m, H-β, ile),
1.95-1.88 (1H, m, H-γ, leu), 1.67-1.55 (4H, m, H-γ, ile and H-β, leu), 1.05 (3H, d, J =
5.85 Hz, H-γ′, ile), 0.99 (3H, d, J = 5.95 Hz, H-δ, ile), 0.94 (6H, d, J = 6.3 Hz, H-δ,
13
leu); C-NMR (CDCl3) δ (ppm): 174.3 (C=O, leu), 171.0 (C=O, phe), 168.9 (C=O,
ile), 168.4 (C=O, ArCO), 159.7 (C-2, imz), 152.0 (C-4, iba), 140.4 (2C, C-2 and C-6,
iba), 146.0 (C-5, imz), 137.5 (C-1, iba), 136.8 (C-4, imz), 135.2 (C-γ, phe), 130.7
(2C, C-o, phe), 130.0 (2C, C-m, phe), 128.2 (C-p, phe), 105.4 (2C, C-3 and C-5,
iba), 58.6 (C-α, ile), 51.1 (C-α, leu), 50.7 (C-α, phe), 39.9 (C-β, leu), 38.6 (C-β, ile),
38.0 (C-β, phe), 32.3 (C-γ, ile), 24.8 (C-γ, leu), 22.1 (2C, C-δ, leu), 18.3 (β-CH3,
imz), 14.5 (C-γ′, ile), 10.2 (C-δ, ile); MASS m/z (% rel. int.): 828(2.9), 827(M+, 3.7),
810(30.9), 782(12.5), 697(55.7), 669(19.2), 550(100), 522(23.7), 437(68.5),
408(22.9), 328(11.2), 203(10.9), 126(8.7), 120(10.6), 91(10.9), 86(18.2), 82(13.7),
81(11.2), 65(15.7), 57(13.6), 56(16.4), 55(10.9), 45(13.5), 43(15.5), 42(12.2),
29(9.8), 17(3.8), 15(4.2).
N-[3,5-Diiodo-4-(2-methyl-1H-imidazol-5-yl)benzoyl]glycyl-L-histidyl-L-alanyl-
L-tryptophan (3d)

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R. Dahiya:
IR (CHCl3) v (cm−1): 3487-3482 (N−H str, rings), 3295-2502 (O−H str, COOH),
3077-3072, 3050 (Ar−H str), 2965, 2870, 2869 (C−H str, CH3), 2927-2920, 2855,
2852 (C−H str, CH2), 1709 (C=O str, COOH), 1644-1640 (C=O str, amide), 1589-
1585, 1427-1422 (skeletal bands), 1536-1532 (N−H def, amide), 1405 (O−H def,
1
COOH), 867-863, 839-834, 747 (C−H def, oop), 586 (C−I str); H-NMR (DMSO-d6)
δ (ppm): 9.45 (4H, br. s, NH, imz, his, try and OH, COOH), 9.11 (1H, br. s, NH, gly),
8.43 (2H, s, H-2 and H-6, iba), 8.29 (1H, s, H-δ, imz), 8.16 (1H, br. s, NH, ala), 7.76
(1H, br. s, NH, his), 7.67 (1H, s, H-δ, imz, his), 7.56 (1H, d, J = 7.7 Hz, H-2, try),
7.53 (1H, br. s, NH, try), 7.38 (1H, d, J = 7.75 Hz, H-2, his), 7.13-6.98 (4H, m, H-4–
7, try), 4.77-4.72 (1H, m, H-α, ala), 4.48-4.42 (1H, m, H-α, try), 4.16-4.12 (1H, m, H-
α, his), 4.10 (2H, d, J = 5.15 Hz, H-α, gly), 3.08-2.97 (4H, m, H-β, his and try), 2.67
13
(3H, s, β-CH3, imz), 1.51 (3H, d, J = 5.9 Hz, H-β, ala); C-NMR (CDCl3) δ (ppm):
178.3 (C=O, gly), 172.8 (C=O, ala), 172.3 (C=O, try), 170.8 (C=O, ArCO), 170.2
(C=O, his), 159.3 (C-2, imz), 151.7 (C-4, iba), 149.2 (C-2, his), 145.9 (C-5, imz),
141.8 (2C, C-2 and C-6, iba), 138.5 (C-2′, try), 137.4 (C-4, imz), 136.7 (C-1, iba),
135.3 (C-4, his), 128.9 (C-3′, try), 124.4 (C-2, try), 123.1, 119.4, 118.0 (3C, C-4–6,
try), 116.8 (C-5, his), 113.6, 110.5 (2C, C-7 and C-3, try), 105.7 (2C, C-3 and C-5,
iba), 60.0 (C-α, ala), 59.2 (C-α, his), 54.3 (C-α, try), 49.1 (C-α, gly), 28.8 (C-β, try),
20.6 (C-β, ala), 19.8 (C-β, his), 18.9 (β-CH3, imz); MASS m/z (% rel. int.): 906(3.3),
905(M+, 4.2), 888(28.9), 860(11.9), 702(55.9), 674(15.2), 631(100), 603(23.2),
494(70.2), 466(23.9), 437(36.8), 408(11.9), 328(11.7), 203(10.5), 159(16.7),
130(8.7), 126(7.9), 116(9.3), 110(13.6), 82(12.8), 81(17.9), 67(6.2), 56(16.8),
55(7.9), 45(11.9), 44(11.6), 30(4.9), 17(3.6), 15(3.9).
Conclusion
Present investigation describes successful synthesis of title compounds via
coupling reaction in good yields. DCC proved to be effective coupling agent both
economically and yieldwise, in comparison to DIPC. Greater antifungal activity was
found in derivatives with tryptophan and histidine constituents in their amino acid

Synthesis, Spectral and Antimicrobial Studies …
235
chain. Gram negative bacteria were found to be more sensitive in comparison to
gram positive bacteria towards the newly synthesized peptide derivatives.
Hydrolyzed peptide derivatives exhibited more antimicrobial activity when
compared to corresponding methyl ester analogs. Among tested compounds, 2c,
2d, 2e, 2f, 2h, 3b and 3d possessed better antimicrobial activity as compared to
standard drugs. On passing toxicity tests, these compounds may prove good
candidates for clinical studies and may be potential antifungal and antibacterial
agents of future.
Acknowledgement
Appreciation is expressed to USIC, DU, Delhi (India) and CDRI, Lucknow
(India) for spectral and elemental analysis.
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Received March 14th, 2008
Accepted (after revision) April 14th, 2008
Available online at www.scipharm.at April 17th, 2008