Synthesis of some novel imidazolinones as potent anticonvulsant agents

Article abstract of DOI:10.1016/S0223-5234(03)00117-X

Imidazolinone derivatives of IIa-IIc, IIIa-IIIf and IVa-IVf have been synthesised by the condensation of some known sulpha drugs with 5-oxazolone derivatives, which were prepared by Erlenmeyer condensation of benzoyl glycine with different aldehydes in th

Full text of DOI:10.1016/S0223-5234(03)00117-X

European Journal of Medicinal Chemistry 38 (2003) 837Á840
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Short communication
Synthesis of some novel imidazolinones
as potent anticonvulsant agents
Hashmukh Joshi a,*, Paresh Upadhyay b, Denish Karia c, A.J. Baxi d
a Department of Home Science, Saurashtra University, Rajkot 5, India
b Mishir Technocrats, Rajkot 5, India
c Bahuaddin Science College, Junagadh, India
d Department of Chemistry, Saurashtra University, Rajkot 5, India
Received 27 June 2002; received in revised form 2 May 2003; accepted 9 May 2003
Abstract
Imidazolinone derivatives of IIaÁ
/
IIc, IIIaÁ
/
IIIf and IVaÁIVf have been synthesised by the condensation of some known sulpha
/
drugs with 5-oxazolone derivatives, which were prepared by Erlenmeyer condensation of benzoyl glycine with different aldehydes in
the presence of sodium acetate and acetic anhydride. The constitution of the products has been supported by elemental analysis and
IR, 1H-NMR spectral data. The products have been screened for their (a) in vitro growth inhibitory activity against several
microorganisms and (b) in vivo anticonvulsant activity.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: Imidazolinones; Oxazolone; Sulpha drugs; Antibacterial anticonvulsant agent
1. Introduction
5-(4H)-oxazolones (IaÁIc) were prepared by the con-
/
densation of aryl aldehyde with benzoyl glycine in the
presence of sodium acetate and acetic anhydride (Er-
lenmeyer oxazolone condensation). The constitution of
the products was supported by elemental analysis and
spectral data. The products were screened for their in
vitro growth inhibition activity against different Gram-
positive and Gram-negative bacterial strains.
Identification of pharmacophore and its verification
have always been the subject of interest to medicinal
chemist. The therapeutic importance of imidazolinones
has been reported [5,6]. Sulpha drugs are potent
Literature survey reveals that various imidazolinone
derivatives possess a broad spectrum of pharmacologi-
cal actions which are reflected by their use as antic-
onvulsant [1], anti-Parkinsonian [2] and monoamine
oxidase (MAO) inhibitory [3] agents. Some novel
disubstituted imidazolinones were investigated as antic-
onvulsant, MAO and succinate dehydrogenase (SDH)
inhibitory agents [4]. So, it was thought worthwhile to
synthesise various imidazolinones and to evaluate them
for their anticonvulsant activity.
antibacterial agents [7Á12]. A study on the influence of
/
structure on activity shows that variation in ring systems
or minor group modifications confer distinct pharma-
cological effects upon the drug molecules.
2. Chemistry
Some new imidazolinone derivatives (IIaÁ
/
IIc, IIIaÁ
/
IIIf and IVaÁIVf) (Scheme 1) bearing sulphonamide
/
moiety have been synthesised by the condensation of
some known sulpha drugs with oxazolones of different
aromatic aldehydes. Intermediates 4-arylidene-2-phenyl-
3. Pharmacology
3.1. Antimicrobial activity
The activity was determined using cup-plate agar
diffusion method [13] by measuring the inhibition zones
* Corresponding author.
E-mail address: hdjoshi1@rediffmail.com (H. Joshi).
´
0223-5234/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0223-5234(03)00117-X

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H. Joshi et al. / European Journal of Medicinal Chemistry 38 (2003) 837Á840
/
Table 1
Anticonvulsant and antimicrobial activity of compounds 1Á15
/
in millimetres. All the compounds were screened in vitro
for their antimicrobial activities against a variety of
bacterial strains such as Staphylococcus aureus, Bacillus
megaterium, Escherichia coli, pSeudomonas fluorescens
and fungi such as Aspergillus flavus and Caudida
albicans. Known antibiotics like ampicillin, norfloxacin
sulphacetamide and gresiofluvin were used for compar-
ison. Most of the compounds exhibited maximum
activity in the range 17Á/33 mm against P. fluorescens.
Compounds IIa, IIIb, IIIf and IVb showed highest

H. Joshi et al. / European Journal of Medicinal Chemistry 38 (2003) 837Á
/840
839
These observations led to the conclusion that the
group increases the
pharmacological activity.
presence of Ã
/
CH3Ã
/
or Ã
/
OCH3Ã
/
4. Experimental protocols
4.1. Chemistry
All the recorded melting points were determined in
open capillary tubes and are as observed. Completion of
the reaction was monitored by TLC (silica gel GF254 (E.
Merck), benzene:ethyl acetateꢁ80:20). The final pro-
/
ducts were purified by column chromatography using
silica gel in increasing percentage of ethyl acetate in
benzene. IR (KBr) (nmax, cmꢀ1) spectra were recorded
1
on SHIMADZU-435 IR spectrophotometer. H-NMR
spectra were recorded on Varian EM-360 spectrometer
wear in d ppm, relative to TMS as internal standard.
Elemental analyses are quite comparable with their
structures. In all cases, analytical values for microana-
lysis were 90.05% of theoretical values.
/
4.1.1. 4-Arylidene-2-phenyl-5-(4H)-oxazolones
4-Arylidene-2-phenyl-5-(4H)-oxazolones were pre-
pared according to the reported method [16] (IaÁ
/Ic).
4.1.2. 1-N-substituted sulphonyl amino-2-phenyl-4-
substituted benzylidene-5-imidazolinones (II, III and IV)
2-Phenyl-4-benzylidene-5-oxazolone (2.49 g, 0.01
mol) was heated with an equimolar quantity of sulpha-
cetamide (2.14 g, 0.01 mol) in an oil bath at 140 8C for 1
h. The resulting jelly-like mass was taken in an organic
solvent and refluxed for 8 h with continuous removal of
water, cooled, excess solvent removed under vacuum
and the resultant solid was worked up and purified over
a column of silica gel, and the solid recrystallised from
light petroleum to get flakes of 5-imidazolinone and
found chromatographically homogeneous when de-
tected with iodine in 62% yield, m.p. 148 8C. Similarly,
other compounds were also synthesised by this method.
Found: C, 72.95; H, 4.90; N, 13.60; for C14H19N3O4S
required C, 73.00; H, 4.94; N, 13.64%.
Scheme 1.
activity (20Á
/
33 mm) against above microbes. Other
compounds showed moderate activity (18Á25 mm)
against these organisms.
/
3.2. Anticonvulsant activity
Out of 15 compounds (Table 1), 13 compounds were
screened for their in vitro anticonvulsant activity [14]. It
appears that compounds IIb, IIc and IVf were most
effective with highest protection and minimum mortality
rate. Compounds IIa, IIIb and IIIe displayed significant
activity (80% protection) while most of the compounds
exhibited moderate activity.
IR (KBr) nmax (cmꢀ1): 3020Á
2910 (CÄC str.), 1750 (CÄO str.), 1640 (CÄ
1150 (SÄO str.), 1180 (CÄO str.).
1H-NMR (DMSO-d6, d) 2.42 (s, 3H, COCH3), 6.4 (s,
CH), 7.1Á H), 8.1 (s, H,
/
3100 (ArÃ
/
CH), 3000Á
/
/
/
/
N str.), 1320,
/
/
1H, CÄ
/
/
7.6 (m, 14H, ArÃ
/
SO2NH).
3.3. Toxicity test
Approximate lethal doses (ALD50) of the compounds
were determined in albino mice following reported
method [15]. ALD50 values of these compounds were
Acknowledgements
The authors wish to thank Dr. A.R. Parikh, Prof. &
Head, Department of Chemistry, Saurashtra University,
for encouraging and providing research facility, to the
in the range 300Á
/
900 mg kgꢀ1 i.p. This indicates their
low toxicity.

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H. Joshi et al. / European Journal of Medicinal Chemistry 38 (2003) 837Á840
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[6] P.S. Upadhyay, S.N. Joshi, A.J. Baxi, A.R. Parikh, J. Indian
Chem. Soc. 68 (1991) 364Á365.
[7] K. Ladva, P. Patel, P. Upadhyay, H. Parekh, Indian J. Chem. B
35 (1996) 1062Á1066.
[8] V.K. Kapoor, in: K. Florey (Ed.), Analytical Profile of
Drug Substances, vol. 17, Academic Press, New York, 1988, p.
571.
authorities of MJIR, Baroda, for pharmacological
screening, to Head, RSIC, CDRI, Lucknow, for spectral
analysis. We are grateful to Gujarat state government
for awarding JRF to one of us (H.D.J.). This work was
supported by Saurashtra University, Rajkot, Gujarat,
India.
/
/
[9] The Merck Index, 12th ed., Merck & Co., Inc., 1998.
[10] T. Ahmd, I. Ahmad, Pharmazie 36 (1981) 619.
[11] R.D. Houtsby, et al., J. Pharm. Sci. 72 (1983) 1401.
[12] P.S. Upadhyay, H.D. Joshi, A.J. Baxi, A.R. Parikh, Indian J.
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