Synthesis and biological evaluation of some novel-3-(5-substituted benzimidazol-2-yl)-5-arylisoxazolines

Article abstract of DOI:10.1016/j.cclet.2010.06.017

The synthesis of a new series of 3-(5-substituted benzimidazol-2-yl)-5-arylisoxazolines (6a-h) was achieved in excellent yields by the condensation of 1-(1H-benzimidazol-2-yl)-3-(substituted phenyl)prop-2-en-1-ones (5a-h) with hydroxylamine at room temperature. These 1-(1H-benzimidazol-2-yl)-3-(substituted phenyl)prop-2-en-1-ones (5a-h) were obtained by the condensation of 2-acetyl benzimidazoles (4a-d) with different aromatic aldehydes, which in turn were obtained by the oxidation of 2-(α-hydroxy)ethyl benzimidazoles (3a-d) prepared by the reaction of o-phenylenediamines (1a-d) with α-hydroxy propionic acid 2. The synthesized compounds were characterized by their IR, ¹H NMR and MS analyses. These compounds were screened for their antibacterial and antifungal activity by standard methods and found some of them active.

Full text of DOI:10.1016/j.cclet.2010.06.017

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Chinese Chemical Letters 21 (2010) 1145–1148
www.elsevier.com/locate/cclet
Synthesis and biological evaluation of some novel-3-(5-substituted
benzimidazol-2-yl)-5-arylisoxazolines
*
Vanga Malla Reddy , Kunduru Ravinder Reddy
Dr. Ch. Ravishanker Memorial Medicinal Chemistry Research Laboratory, University College of Pharmaceutical Sciences,
Kakatiya University, Warangal 506009, India
Received 28 December 2009
Abstract
The synthesis of a new series of 3-(5-substituted benzimidazol-2-yl)-5-arylisoxazolines (6a–h) was achieved in excellent yields
by the condensation of 1-(1H-benzimidazol-2-yl)-3-(substituted phenyl)prop-2-en-1-ones (5a–h) with hydroxylamine at room
temperature. These 1-(1H-benzimidazol-2-yl)-3-(substituted phenyl)prop-2-en-1-ones (5a–h) were obtained by the condensation
of 2-acetyl benzimidazoles (4a–d) with different aromatic aldehydes, which in turn were obtained by the oxidation of 2-(a-
hydroxy)ethyl benzimidazoles (3a–d) prepared by the reaction of o-phenylenediamines (1a–d) with a-hydroxy propionic acid 2.
The synthesized compounds were characterized by their IR, 1H NMR and MS analyses. These compounds were screened for their
antibacterial and antifungal activity by standard methods and found some of them active.
# 2010 Vanga Malla Reddy. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Benzimidazolyl-5-arylisoxazolines; Antibacterial; Antifungal activity
Benzimidazoles are known to exhibit significant activity against several viruses such as human cytomegalovirus,
HIV [1], herpes [2], RNA [3] and influenza [4]. In view of varied biological activities of benzimidazoles, their
preparation has gained considerable attention in recent years and many strategies are reported [5–8]. Synthesis of
isoxazoles [9,10] has been a developing field within the realm of heterocyclic chemistry. Isoxazoles are also equally
important for their biological and pharamacological properties [11–18].
Inspired by the biological profile of benzimidazoles and isoxazoles and in connection of our work on the design and
synthesis of biologically active and pharmacologically important new heterocycles [19], it was thought worthwhile to
synthesize the new compounds. Containing two of the specified pharmacophores in order to obtain the molecules
having enhanced biological activities and to evaluate them for their antimicrobial activity to begin with further it is
also noted from the literature that there is no report, on the synthesis of 3-(5-substituted benzimidazol-2-yl)-5-
arylisoxazolines.
The synthetic strategy developed Scheme 1 to obtain the 3-(5-substituted benzimidazol-2-yl)-5-arylisoxazoline 6
from 1-(1H-benzimidazol-2-yl)-3-(substituted phenyl)prop-2-en-1-one 5 with hydroxylamine hydrochloride. For
the synthesis of target compounds, 2-(a-hydroxy)ethylbenzimidazole 3 was prepared from the reaction of substituted
* Corresponding author.
E-mail address: vanga_mreddy@rediffmail.com (V.M. Reddy).
1001-8417/$ – see front matter # 2010 Vanga Malla Reddy. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.017

[(Scheme_1)TD$FIG]
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V.M. Reddy, K.R. Reddy / Chinese Chemical Letters 21 (2010) 1145–1148
Scheme 1. (i) 4N HCl, reflux, 24 h, (ii) K2Cr207, H2SO4, 2.5 h, (iii) Ar–CHO, EtOH, 60% KOH, 4 h, (iv) NH2OH, EtOH, AcOH, NaOAc, reflux, 6 h.
o-phenylenediamine 1 with a-hydroxypropionic acid 2 in the presence of hydrochloric acid under reflux. It was
followed by oxidation of compound 3 with potassium dichromate and sulfuric acid, at room temperature to get 2-
acetyl benzimidazole 4 which on condensation reaction with aromatic aldehydes at room temperature in ethanol and
60% KOH gave benzimidazolyl propenone 5. These chalcones on the cyclocondensation reaction with
hydroxylamine in the presence of sodium acetate in ethanol and acetic acid afforded the title compound 6. The
synthetic route leading to the title compounds is summarized in Scheme 1. The newly synthesized compounds were
characterized by their IR, 1H NMR, and MS analyses and further the compounds were screened for their antibacterial
and antifungal activity.
1. Antibacterial activity
The antibacterial activity of the synthesized compounds was evaluated against two Gram-positive bacteria viz.,
Bacillus subtilis, Staphylococcus aureus and two Gram-negative bacteria viz., Escherichia coli and Klebsiella
pneumoniae, using streptomycin and benzyl penicillin as standard drugs, respectively by the ‘Cup–plate method’ [20]
using DMSO as the solvent and the results are given in Table 1. It has been observed that the compounds exhibited
interesting biological activity, however, with a degree of variation. Among all the compounds, compound 6c displayed
relatively high activity against B. subtilis and S. aureus, compounds 6d and 6g were also active against S. aureus.
Table 1
Antibacterial and antifungal activity of 3-(5-substituted benzimidazol-2-yl)-5-arylisoxazolines 6a–h.
Compound
Antibacterial activitya,b
Antifungal activitya,b
B. subtilis
S. aureus
E. coli
K. pneumoniae
F. oxysporum
A. niger
6a
6b
05/03
12/11
15/12
13/11
08/06
12/12
13/11
08/06
–
07/05
12/11
15/11
15/13
09/07
12/11
15/13
09/07
–
06/04
08/07
12/10
13/10
06/05
05/03
10/10
05/04
16
06/03
08/08
12/10
13/10
06/05
05/03
10/10
05/04
16
02/02
05/03
03/02
05/02
03/01
00/00
05/03
03/02
–
02/01
05/02
02/01
03/02
02/01
00/00
05/03
03/02
–
6c
6d
6e
6f
6g
6h
Streptomycinc
Benzyl penicillinc
Fluconazolec
16
16
–
–
–
–
–
–
–
–
06
06
a
Zone of inhibition in mm at 500 mg/mL concentration.
Zone of inhibition in mm at 250 mg/mL concentration.
Zone of inhibition in mm at 40 mg/mL concentration.
b
c

V.M. Reddy, K.R. Reddy / Chinese Chemical Letters 21 (2010) 1145–1148
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Compounds 6b and 6f showing reasonable activity against B. subtilis and S. aureus 6d and 6g were active against B.
subtilis, whereas compounds 6c and 6d were active against E. coli and K. pneumoniae. The rest of the compounds
showed low activity against all the organisms employed.
2. Antifungal activity
The newly prepared 3-(5-substituted benzimidazol-2-yl)-5(4-substiuted phenyl)- isoxazolines were also screened
for their antifungal activity against two fungi viz., F. oxysporum and Aspergillus niger by the ‘Cup–plate method’
using fluconazole as a standard drug and DMSO as the solvent. It has been observed that the compounds exhibited
good to excellent activity, with a degree of variation. Among all the compounds, compounds 6b, 6d and 6g showed
excellent activity against F. oxysporum, compounds 6b and 6g also have high activity against A. niger. Compound 6f is
inactive against both fungal organisms. The remaining compounds exhibited low to moderate activity against two
organisms.
3. Experimental
All reagents and solvents were purchased and used without further purification. Melting points were determined on
a Fisher–Johns melting point apparatus and are uncorrected. Crude products were purified by column chromatography
on silica gel of 60–120 mesh. IR spectra were obtained on a Perkin Elmer BX serried FTIR 5000 spectrometer using
1
KBr pellet. NMR spectra were recorded on a varian 300 MHz spectrometer for H NMR. The chemical shifts were
reported as ppm down field using TMS as an internal standard. Mass spectra were recorded on a VG-Micromass
7070H spectrometer operating at 70 eV.
3.1. 2-(a-Hydroxy)ethyl benzimidazoles 3a–d
o-Phenelenediamine (0.01 mol) was mixed with lactic acid (0.01 mol) added to 4N-hydrochloric acid (5 mL) and
refluxed for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and
neutralized with NH3 solution. The solid was separated through filter and recrystallized from ethanol.
3.2. 2-Acetyl benzimidazoles 4a–d
To a solution of 2-(a-hydroxy)ethyl benzimidazoles 3 (0.01 mol) in dil. H2SO4 (25%, 40 mL) was dropwise added
the solution of K2Cr2O7 (0.15 mol) and H2SO4 (5%, 80 mL) with constant stirring at room temperature over a period
of 20 min. Further the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction
(monitored by TLC), the reaction mixture was neutralized with NH3 solution (1:1) and resultant orange solid was
filtered, washed with water and dried, recrystallized from ethyl acetate.
3.3. 1-(1H-Benzimidazol-2-yl)-3-(substituted phenyl) prop-2-en-1-ones 5a–h
2-Acetyl benzimidazoles 4 (0.01 mol) and appropriately substituted benzaldehydes (0.01 mol) were mixed in
ethanol (20 mL) containing 60% aq. KOH (5 mL) and stirred constantly at room temperature for 4 h. After completion
of the reaction (monitored by TLC), the reaction mixture ethanol was removed mostly and residue poured into ice-cold
water and neutralized with dil. HCl solution. The solid formed was filtered and dried, recrystallized from absolute
ethanol.
3.4. 3-(5-Substituted benzimidazol-2-yl)-5-arylisoxazolines 6a–h
A mixture of 5 (0.01 mol) was dissolved in ethanol (15 mL) and anhydrous sodium acetate (0.01 mol) in acetic
acid (10 mL) was added. It was followed by a solution of hydroxylamine hydrochloride (0.01 mol) in ethanol
(10 mL). Then the reaction mixture was refluxed for 7–8 h. After completion of reaction (monitored by TLC), the
reaction mixture was poured into ice-cold water and the solid separated was filtered and dried, recrystallized from
ethyl acetate.

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V.M. Reddy, K.R. Reddy / Chinese Chemical Letters 21 (2010) 1145–1148
3.5. Some selected product characterization data
3a: Yellow solid, yield 90%, mp 180–182 8C; IR (KBr): 2971, 1623, 1458, 1215, 1103 cmÀ1; 1H NMR (300 MHz,
CDCl3): d 10.30 (bs, 1H), 7.52 (d, 2H, J = 7.8 Hz), 7.32 (d, 2H, J = 1.9 Hz), 4.8 (s, 1H), 3.05 (q, 1H, J = 7.4 Hz), 1.62
(d, 3H, J = 7.2 Hz); MS: m/z 163.4 (M++1).
4a: Yellow solid, yield 78%, mp 189–191 8C; IR (KBr): 3289, 3059, 3015, 1674, 1580, 1445, 1235, 1147 cmÀ1; 1H
NMR (300 MHz, CDCl3): d 13.02 (s, 1H), 7.85 (d, 1H, J = 7.8 Hz), 7.52 (d, 1H, J = 7.6 Hz), 7.32 (t, 2H, J = 7.4 Hz),
2.74 (s, 3H); MS: m/z 161.3 (M++1).
1
5a: Pale yellow solid, yield 69%, mp 162–164 8C; IR (KBr): 3276, 2856, 1589, 1487, 1238 cmÀ1; H NMR
(300 MHz, CDCl3): d 8.77 (s, 1H), 8.11 (d, 3H, J = 12.8 Hz), 7.76 (dd, 3H, J = 2.8, 7.2 Hz), 7.43 (d, 2H, J = 12.9 Hz),
7.23 (dd, 2H, J = 2.4, 7.6 Hz), 6.90 (d, 1H, J = 13.1 Hz); MS: m/z 249.3 (M++1).
1
6a: Colorless solid, yield 75%, mp 216–218 8C; IR (KBr): 3370, 3025, 2210, 1560, 1425, 1080 cmÀ1; H NMR
(300 MHz, CDCl3): d 10.17 (s, 1H), 7.50 (dd, 2H, J = 9.3, 16.0 Hz), 7.40 (d, 2H, J = 11.5 Hz), 7.17 (d, 2H,
J =11.8 Hz), 7.14 (dd, 2H, J = 9.2, 15.6 Hz), 7.12 (dd, 1H, J = 9.2, 15.8 Hz), 5.62 (d, 1H, J = 12.4 Hz), 3.89 (d, 2H,
J = 12.9 Hz); MS: m/z 264.3 (M++1).
Acknowledgments
The authors are thankful to the authorities of Kakatiya University, Warangal, AP (India) for the facilities and
encouragement.
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