Synthesis and antibacterial activity of some imidazole-5-(4H)one derivatives

Article abstract of DOI:10.1002/ardp.200400944

In the present study, several substituted oxazolones were synthesized by condensation of benzoylglycine with different aldehydes. From such oxazolones, substituted imidazolones were synthesized by condensation with ethylenediamine, urea and 4-N,N-dimethyl

Full text of DOI:10.1002/ardp.200400944

488
DOI 10.1002/ardp.200400944
Arch. Pharm. Chem. Life Sci. 2005, 338, 488−492
Synthesis and Antibacterial Activity of Some
Imidazole-5-(4H)one Derivatives
Sampath Saravanana, Perumal Senthamil Selvana, Natesan Gopala,
Jayanta Kumar Guptab, Biplap Dec
a Department of Medicinal Chemistry, Nandha College of Pharmacy, Erode, India
b Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India
c Regional Institute of Pharmaceutical Science and Technology, Agartala, India
In the present study, several substituted oxazolones were synthesized by condensation of benzoylgly-
cine with different aldehydes. From such oxazolones, substituted imidazolones were synthesized by
condensation with ethylenediamine, urea and 4-N,N-dimethylaminoaniline. All these synthesized com-
pounds produced significant antibacterial activities. Furthermore, compounds containing
ϪCH2CH2NH2, ϪCONH2 and ϪC6H4ϪN(CH3)2 groups as substitutents on the imidazolones were
found to be potent antibacterial agents. Thus, among the twelve compounds, 1-(2-aminoethyl)-2-
phenyl-4-(4-(dimethylamino)benzylidene)imidazole-5-(4H)one (4d), 1-carboxamido-2-phenyl-4-(4-(di-
methylamino)benzylidene)imidazole-5-(4H)one (4e) and 1-(4-(N,N-dimethylamino)phenyl)-2-phenyl-4-
(4-(dimethylamino)benzylidene)imidazole-5-(4H)one (4f) were found to have a significant higher anti-
bacterial activity than the other substituted imidazolones. Compound 4e was the most active one in
this series.
Keywords: Synthesis; Oxazolones; Imidazoleones; Antibacterial activity
Received: October 12, 2004; Accepted: July 7, 2005
Introduction
Analytical data for structure elucidation are given in the
Experimental section. The preparation of the resulting imid-
azolone derivatives 4aϪl is outlined in Scheme 1.
Imidazole derivatives have been found to be associated with
several biological activities [1Ϫ4] like CNS depressant,
monoamine oxidase (MAO) inhibitory, anticonvulsant
[5Ϫ7], antibacterial activities [8] and others. This obser-
vation prompted us to extend our earlier synthetic work to
synthesize some substituted imidazolones and to evaluate
their antimicrobial activity.
The compounds were tested in vitro for their antibacterial
activity against ten microorganisms belonging to both
gram-positive and gram-negative bacteria. It was observed
that more than 80% of the total samples tested showed
good antibacterial activities. Most of the compounds in-
hibited bacterial growth at concentrations of 50 µg/mL and
100 µg/mL for seven out of ten organisms. However, for S.
typhimurium NCTC 74, K. pneumoniae 14 and Ps. aerugi-
nosa APC 1, minimum inhibitory concentration (MIC) val-
ues were 100, 200 and >200 µg/mL. A close observation of
the MIC values obtained for the twelve compounds under
investigation indicates the importance of different chemical
moieties in the two specific positions, namely 1 and 4, of
the imidazolone ring while keeping a phenyl group in the 2-
position. Thus, the presence of a dimethylaminophenyl
group either in the 1- or 4-position on the imidazolone ring
yielded active compounds, e.g. 4c, 4d, 4e, 4f, 4i and 4l; out
of these, compound 4e containing a ϪC6H4ϪN(CH3)2
group in the 4-position and a ϪCONH2 group in the 1-
position had maximum antibacterial activity.
Twelve imidazolones substituted at the 1-, 2- and 4-position
were synthesized by treating the precursor oxazolones with
some amine or amino derivative in the presence of acetic
anhydride and sodium acetate. The oxazolones were pre-
pared in our laboratory by reacting benzoyl glycine with
aromatic aldehydes [9]. The synthesized compounds were
tested for their antibacterial activity by the agar dilution
method.
Results and discussion
The title imidazolone derivatives were synthesized by the
reaction of 4-substituted oxazolone (3) under reflux con-
ditions with the appropriate amines in dioxine/pyridine.
Other substituents present in the 4-position of the imidazo-
lone ring that impart activity are 4-hydroxy-3-methoxyphe-
nyl and furfuryl. Thus, compounds having ϪCH2CH2NH2
and ϪCONH2 groups in the 1-position and 3-hydroxy-4-
Correspondence: V. Sampath Saravanan, Department of Medicinal
Chemistry, Nandha College of Pharmacy, Erode-638052,
India. Phone: ϩ9194438-38566, Fax: ϩ91-4294-224622, e-mail:
saravecp@yahoo.co.in
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Arch. Pharm. Chem. Life Sci. 2005, 338, 488−492
Imidazole-5-(4H)one Derivatives
489
Scheme 1. Preparation of the resulting imidazolone derivatives 4aϪl.
methoxyphenyl or a furfuryl group in the 4-position are
moderately active. It is interesting to note that other com-
pounds having the same two substitutents, i.e.
ϪCH2CH2NH2 and ϪCONH2 in the 1-position and
ϪC6H5 only in the 4-position, yielded less active com-
pounds. Another point of interest is that compounds having
a ϪCONH2 group in the 1-position are found to exhibit
different degrees of activity, depending on the nature of the
other group in the 4-position; thus, a ϪC6H4ϪN(CH3)2
group in the 4-position yielded the most active compound,
while the activity gradually subsided, in descending order,
with the 4-hydroxy-3-methoxyphenyl, furfuryl and benzene
groups.
modification to obtain clinically useful antibacterial agents.
Acknowledgments
This work was supported by a scholarship to one of the
authors from the University Grants Commission, Bahadur
Shah Zafar Marg, New Delhi-110002, India, and technical
assistance was received also from the Indian Institute of
Chemical Biology (IICB), Kolkata. We acknowledge their
helpful assistance.
Experimental
Finally, on the basis of the observed MIC values of these
compounds, it can be concluded that the ϪC6H4ϪN(CH3)2
group exerts distinct antibacterial activity that is indepen-
dent of the presence of other substituents, and compound
4e was found to be the most active compound of this series
and could therefore serve as a lead molecule for further
Chemistry
The melting points of the synthesized compounds were taken in
open capillary tubes on an ADCO melting point apparatus and are
uncorrected. The IR spectra of the compounds were recorded in the
4000Ϫ400 cmϪ1 range using (KBr) disks on a Perkin-Elmer 297
spectrophotometer. The 1H-NMR spectra were recorded on a
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Saravanan et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 488−492
Varian Gemini 200 MHz spectrometer in CDCl3. Microanalyses for
C, H, and N were performed in a Heraeus CHN Rapid Analyzer.
All the compounds gave satisfactory elemental analyses ( 0.4%).
C). (Calc. for C18H17NO3: 291.35). Anal. Calc. for C18H17NO3: C,
74.20; H, 5.88; N, 14.42. Found: C, 74.02; H, 5.62; N, 14.26.
1-Carboxamido-2-phenyl-4-benzylidene imidazole-5-(4H)one (4b)
General procedure for the synthesis of oxazolones (3)
Yield ϭ 96%, mp 272Ϫ273°C. 1H-NMR (CDCl3) δ: 6.7Ϫ7.1 (m,
10H, ArϪH), 6.3 (s, 2H, CONH2), 5.3 (s, 1H, CHϭC). IR (KBr)
cmϪ1: 3226 (NH), 1655 (CϭO), 1635 (CϭN), 1580 (CϭC). (Calc.
for C17H13N3O2: 291.30). Anal. Calc. for C17H13N3O2: C, 71.80; H,
4.49; N, 14.42. Found: C, 71.62; H, 4.34; N, 14.28.
4-substituted-2-phenyloxazol-5-(4H)ones (3) were prepared by re-
fluxing benzoylglycine [10] (2) (hippuric acid; 0.25 mol) and appro-
priate aldehydes (4) (0.25 mol) in acetic anhydride (0.75 mol) with
freshly fused sodium acetate (0.25 mol) for 2 h. After cooling, etha-
nol (10 mL) was added and the mixture kept overnight at 5°C;
then, the solid obtained was filtered, washed with alcohol, dried in
vacuum and recrystallized from benzene (Scheme 1).
1-(4’-(N,N-Dimethylamino)phenyl)-2-phenyl-4-benzylidene imidaz-
ole-5-(4H)one (4c)
Yield ϭ 94%, mp 152Ϫ153°C. 1H-NMR (CDCl3) δ: 6.9Ϫ7.5 (m,
14H, ArϪH), 5.7 (s, 1H, CHϭC), 2.85 (s, 6H, N(CH3)2). IR (KBr)
4-Benzylidene-2-phenyl-oxazol-5-(4H)one (3a)
Yield ϭ 97%, mp 166Ϫ167°C. 1H-NMR (CDCl3) δ: 6.5Ϫ6.9 (m,
10H, (C6H5)2), 5.8 (s, 1H, CHϭC). IR (KBr) cmϪ1: 1652 (CϭO),
1628 (CϭN), 1592 (CϭC), 1121 (CϪOϪC). (Calc. for C16H11NO2:
249.26). Anal. Calc. for C16H11NO2: C, 77.09; H, 4.49; N, 5.61.
Found: C, 76.58; H, 4.78; N, 5.48.
cmϪ1
: 1654 (CϭO), 1610 (CϭN), 1550 (CϭC). (Calc. for
C24H21N3O: 367.45). Anal. Calc. for C24H21N3O: C, 78.44; H, 5.76;
N, 11.43. Found: C, 78.10; H, 5.54; N, 11.28.
1-(2-Aminoethyl)-2-phenyl-4-(4-(dimethylamino)benzylidene)-
imidazole-5-(4H)one (4d)
4-(4-(Dimethylamino)benzylidine)-2-phenyl-oxazol-5-(4H)one (3b)
Yield ϭ 57%, mp 250Ϫ251°C. 1H-NMR (CDCl3) δ: 6.5Ϫ7.2 (m,
9H, ArϪH), 3.8 (s, 2H, NH2), 3.2Ϫ3.4 (m, 4H, NCH2CH2), 2.4 (s,
6H, (CH3)2). IR (KBr) cmϪ1: 1645 (CϭO), 1605 (CϭN), 1580 (Cϭ
C). (Calc. for C20H22N4O: 334.42). Anal. Calc. for C20H22N4O: C,
71.83; H, 6.63; N, 16.75. Found: C, 71.66; H, 6.42; N, 16.56.
Yield ϭ 62%, mp 216Ϫ217°C. 1H-NMR (CDCl3) δ: 6.3Ϫ6.9 (m,
9H, ArϪH), 5.7 (s, 1H, CHϭC), 2.8 (s, 6H, ϪN(CH3)2). IR (KBr)
cmϪ1: 1660 (CϭO), 1618 (CϭN), 1612 (CϭC), 1136 (CϪOϪC).
(Calc. for C18H16N2O2: 292.33). Anal. Calc. for C18H16N2O2: C,
73.95; H, 5.51; N, 9.58. Found: C, 73.26; H, 5.72; N, 9.12.
1-Carboxamido-2-phenyl-4-(4-(dimethylamino)benzylidene)-
4-(4Ϫ-Hydroxy-3Ј-methoxy benzylidine)-2-phenyl-oxazol-5-(4H)-
one (3c)
imidazole-5-(4H)one (4e)
Yield ϭ 47%, mp 265Ϫ266°C. 1H-NMR (CDCl3) δ: 6.8Ϫ7.1 (m,
9H, ArϪH), 6.1 (s, 2H, CONH2), 5.5 (s, 1H, CHϭC), 2.98 (s, 4H,
N(CH3)2). IR (KBr) cmϪ1: 1655 (CϭO), 1620 (CϭN), 1610 (Cϭ
C). (Calc. for C19H18N4O2: 334.37). Anal. Calc. for C19H18N4O2:
C, 68.25; H, 5.42; N, 16.75. Found: C, 68.02; H, 5.12; N, 17.06.
Yield ϭ 95%, mp 192Ϫ193°C. 1H-NMR (CDCl3) δ: 9.7 (s, 1H,
ArϪOH), 6.8Ϫ7.8 (m, 8H, Ar-H), 6.1 (s, 1H, CHϭC), 4.1 (s, 3H,
OCH3). IR (KBr) cmϪ1: 3680 (OH), 1674 (CϭO), 1622 (CϭN),
1596 (CϭC), 1120 (CϪOϪC). (Calc. for C17H13NO4: 295.29). Anal.
Calc. for C17H13NO4: C, 69.14; H, 4.43; N, 4.74. Found: C, 68.76;
H, 4.12; N, 4.92.
1-(4Ј-(N,N-Dimethylamino)phenyl)-2-phenyl-4-(4-dimethylamino-
benzylidene)imidazole-5-(4H)one (4f)
4-(Furfur-2-yl)-2-phenyl-oxazol-5-(4H)one (3d)
Yield ϭ 71%, mp 243Ϫ244°C. 1H-NMR (CDCl3) δ: 6.8Ϫ7.4 (m,
13H, Ar-H), 5.8 (s, 1H, CHϭC), 2.8 (s, 6H, N(CH3)2). IR (KBr)
: 1652 (CϭO), 1622 (CϭN), 1595 (CϭC). (Calc. for
C26H26N4O: 410.51). Anal. Calc. for C26H26N4O: C, 76.07; H, 6.38;
Yield ϭ 78%, mp 168Ϫ169°C. 1H-NMR (CDCl3) δ: 6.3Ϫ6.8 (m,
8H, ArϪH), 5.7 (s, 1H, CHϭC). IR (KBr) cmϪ1: 1660 (CϭO), 1620
(CϭN), 1590 (CϭC), 1132 (CϪOϪC), (Calc. for C14H10NO3:
239.23). Anal. Calc. for C14H10NO3: C, 70.29; H, 3.79; N, 5.85.
Found: C, 70.02; H, 3.12; N, 5.24.
cmϪ1
N, 13.64. Found: C, 75.82; H, 6.12; N, 13.72.
1-(2-Aminoethyl)-2-phenyl-4-(4Ј-hydroxy-3Ј-methoxybenzylidene)-
imidazole-5-(4H)one (4g)
General procedure for the synthesis of 1,4-disubstituted imidazolones
(4)
Yield ϭ 53%, mp 181Ϫ182 sC. 1H-NMR (CDCl3) δ: 9.8 (s, 1H,
ArϪOH), 7.1Ϫ7.4 (m, 8H, ArϪH), 6.2 (s, 1H, CHϭC), 3.9 (s, 3H,
OCH3), 3.1 (s, 2H, NCH2CH2). IR (KBr) cmϪ1: 3680 (OH) 1654
(CϭO), 1628 (CϭN), 1590 (CϭC). (Calc. for C19H19N3O3: 334.37).
Anal. Calc. for C19H19N3O3: C, 67.64; H, 5.67; N, 12.45. Found: C,
67.44; H, 5.78; N, 12.04.
The respective 4-substituted oxazolones (3) (0.1 mol) were refluxed
with an equimolar quantity (0.1 mol) of ethylenediamine in dioxan
(10 mL) in a water bath for 6 h, with N,N-dimethylaminobenzene
in dioxan (10 mL) in a water bath for 6 h, and with urea in pyridine
(10 mL) in an oil bath at 150°C for 6 h, separately, to yield the
respective 1-substituted imidazolones. The excess of solvent was dis-
tilled off from the reaction mixture in vacuum. The mixture was
cooled and poured into crushed ice. The solid obtained was filtered
and recrystallized from rectified spirit 4aϪl (Scheme 1).
1-Carboxamido-2-phenyl-4-(4Ј-hydroxy-3Ј-methoxybenzylidene)-
imidazole-5-(4H)one (4h)
Yield ϭ 95%, mp 198Ϫ199°C. 1H-NMR (CDCl3) δ: 9.5 (s, 1H,
ArϪH), 7.3Ϫ8.2 (m, 8H, ArϪH), 6.2 (s, 2H, CONH2), 3.8 (s, 3H,
OCH3). IR (KBr) cmϪ1: 3782 (OH), 1645 (CϭO), 1610 (CϭN),
1595 (CϭC). (Calc. for C18H15N3O4: 337.33). Anal. Calc. for
C18H15N3O4: C, 64.09; H, 4.48; N, 12.45. Found: C, 63.82; H, 4.52;
N, 12.18.
1-Aminoethyl-2-phenyl-4-benzylidene imidazole-5-(4H)one (4a)
Yield ϭ 58%, mp 171Ϫ172°C. 1H-NMR (CDCl3) δ: 6.6Ϫ7.1 (m,
10H, (C6H5)2), 5.8 (s, 1H, CHϭC), 3.2 (s, 2H, NH2), 2.6 (m, 4H,
NCH2CH2). IR (KBr) cmϪ1: 1655 (CϭO), 1622 (CϭN), 1590 (Cϭ
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Arch. Pharm. Chem. Life Sci. 2005, 338, 488−492
Imidazole-5-(4H)one Derivatives
491
1-(4Ј-(N,N-Dimethylamino)phenyl)-2-phenyl-4-(4Ј-hydroxy-3Ј-
methoxybenzylidene)imidazole-5-(4H)one (4i)
NCTC 6571, Bacillus pumilus NCTC 8241, Salmonella typhimurium
NCTC 74, Shigella sonnei NCTC 9774, Shigella dysenteriae 7
NCTC 519/66, Escherichia coli ATCC 25922, Klebsiella pneumoniae
14, Pseudomonas aeruginosa APC 1, Vibrio cholerae ATCC 14033.
The test drugs were added at concentrations of 0 (control), 25, 50,
100, 200 µg/mL in molten nutrient agar (oxoid) and poured into
petri dishes. The organisms were grown in peptone water, and the
overnight culture corresponding to 0.5 McFarland standard was
spot-inoculated on the nutrient agar plates such that each inoculum
contained 2 ϫ 106 colony forming units (CFU). The plates were
incubated at ϩ37°C, examined after 24 h and incubated for a
further 72 h, if necessary. The lowest concentration of the com-
pounds (4aϪl) in a plate that failed to show any visible macroscopic
growth was considered as its MIC. MIC determination was per-
formed in duplicate for each organism, and the experiment was re-
peated when necessary. The MIC values for a given isolate were
either identical or within one dilution. The MIC of the test com-
pounds were compared with the reference drug Ciprofloxacin. The
results of antibacterial screening (MIC values) of the synthesized
compounds are given in Table 1.
Yield ϭ 97%, mp 210Ϫ211°C. 1H-NMR (CDCl3) δ: 9.9 (s, 1H,
ArϪOH), 6.9Ϫ7.6 (m, 12H, ArϪH), 5.9 (s, 1H, CHϭC), 3.9 (s, 3H,
OCH3), 2.95 (s, 6H; N(CH3)2). IR (KBr) cmϪ1: 3705 (OH), 1655
(CϭO), 1630 (CϭN), 1595 (CϭC). (Calc. for C25H23N3O3: 413.47).
Anal. Calc. for C25H23N3O3: C, 72.62; H, 5.28; N, 10.16. Found: C,
72.12; H, 5.28; N, 10.42.
1-(2-Aminoethyl)-2-phenyl-4-(furfur-2-yl)imidazole-5-(4H)one (4j)
Yield ϭ 82%, mp 166Ϫ167°C. 1H-NMR (CDCl3) δ: 7.2Ϫ7.6 (m,
8H, ArϪH), 5.8 (s, 1H, CHϭC), 3.4 (s, 2H, NH2), 2.6Ϫ2.9 (m, 4H,
NCH2CH2). IR (KBr) cmϪ1: 1665 (CϭO), 1640 (CϭO), 1580 (Cϭ
C). (Calc. for C16H15N3O2: 281.31). Anal. Calc. for C16H15N3O2:
C, 68.31; H, 5.37, N, 14.93. Found: C, 62.98; H, 5.18; N, 15.12.
1-Carboxamido-2-phenyl-4-(furfur-2-yl)imidazole-5-(4H)one (4k)
Yield ϭ 81%, mp 258Ϫ259°C. 1H-NMR (CDCl3) δ: 6.7Ϫ7.1 (m,
8H, ArϪH), 6.1 (s, 2H, CONH2), 5.3 (s, 1H, CHϭC). IR (KBr)
cmϪ1
: 1665 (CϭO), 1622 (CϭN), 1592 (CϭC). (Calc. for
C15H11N3O3: 281.27). Anal. Calc. for C15H11N3O3: C, 64.05; H,
3.94; N, 14.93. Found: C, 64.28; H, 3.64; N, 14.28.
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Table 1. Antimicrobial screening data of the synthesized compounds.
Bacterial strains tested
MIC (µg/mL)
4g 4h
4a
4b
50
50
100
4c
4d
4e
4f
4i
4j
4k
4l
Std.†
S. aureus ATCC 25923
S. aureus NCTC 6571
B. pumilus NCTC 8241
S. typhimurium NCTC 74
S. sonnei NCTC 9774
Sh. dysenteriae 7 NCTC 519/66
E. coli ATCC 25922
K. pneumoniae 14
P. aeruginosa APC 1
V. cholerae ATCC 14033
100
100
100
200
100
50
50
50
50
50
50
50 100
50
50 100
50
50
100 100
50
100
2
2
2
2
2
2
2
5
5
2
50 100
50
50 100
100 50
200 100 > 200 100
100
100
200 100
50
50
50 100
50 100
200 100 100 100 200 200 100
100
50 100 100 100
50
50
50 100
50
50
50
50
50
50
50
50
50
100 > 200 100
50 100 50
50
50
50
50
50
100 100
200 200
100 100
50 100
200 > 200 200 200 100 200 100 100 > 200 200
200
100
200 200 100 100 100 200 200 > 200 200
50 100 50 50 50 50 100 50 100
†
Standard compound Ciprofloxacin.
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Arch. Pharm. Chem. Life Sci. 2005, 338, 488−492
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