Microwave assisted nano (ZnO-TiO2) catalyzed synthesis of some new 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3- c]pyridine as antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2013.01.041

Combined nano zinc oxide and titanium dioxide [nano (ZnO-TiO₂)] has been reported first time for the synthesis of novel series of 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c] pyridine. All the synthesized compo

Full text of DOI:10.1016/j.bmcl.2013.01.041

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2250–2253
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Microwave assisted nano (ZnO–TiO2) catalyzed synthesis of some
new 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)meth-
yl)thieno[2,3-c]pyridine as antimicrobial agents
a
a
a
a
Jaiprakash N. Sangshetti a, , Priyanka P. Dharmadhikari , Rashmi S. Chouthe , Bibi Fatema , Vishal Lad ,
⇑
Vikram Karande b, Sunil N. Darandale c, Devanand B. Shinde c
a Dr. Rafiq Zakaria Campus, Y.B. Chavan College of Pharmacy, Aurangabad 431 001 (M.S.), India
b NK Orchid College of Engineering and Technology, Solapur (M.S.), India
c Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004 (M.S.), India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Revised 31 December 2012
Accepted 12 January 2013
Available online 22 January 2013
Combined nano zinc oxide and titanium dioxide [nano (ZnO–TiO2)] has been reported first time for the
synthesis of novel series of 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thie-
no[2,3-c]pyridine. All the synthesized compounds (7a–7m) are novel and were screened for their antimi-
crobial activity against four different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus
aureus and Bacillus subtilis and antifungal activity was determined against two strains Candida albicans
and Aspergillus niger. SAR for the newly synthesised derivatives has been developed by comparing their
MIC values with ampicillin, ciprofloxacin and miconazole for antibacterial and antifungal activities,
respectively. Among the synthesized compounds, 2,6 dichlorophenyl analogue (7f), 4 fluorophenyl ana-
logue (7k) and 2,6 dichlorophenyl analogue (7l) shows promising antibacterial as well as antifungal
activity whereas thiophene substituted compound (7j) shows promising antibacterial activity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Microwave assisted synthesis
Nano (ZnO–TiO2) catalyst
Hydrazides
1,3,4 Oxadiazole
4,5,6,7-Tetrahydro thieno[2,3-c]pyridine
In vitro antimicrobial activity
MIC values
1,3,4-Oxadiazole and their analogues acts as an important bio-
active class of heterocycles.1 A variety of biological activities of
substituted 1,3,4-oxadiazoles and 1,3,4-oxadiazole derivatives
have been reported in the literature such as anti-inflammatory,2
antimicrobial,3 anti-convulsant and hypoglycemic activities,4 anti-
viral,5 antimalerial,6 analgesic,7 anticancer,8–10 hypnotic and seda-
tive.9 4,5,6,7-tetrahydrothienopyridine and its derivatives are
important heterocycle with different activities like antibacterial,11
antifungal12 and antimicrobial.13
ZnO is a cheap heterogeneous catalyst with high catalytic activ-
ity; it is non-toxic, insoluble in polar as well as non-polar solvents.
A wide range of organic reactions such as N-benzylation of amines
with alkyl halides,14 Friedel–Craft’s acylation,15 dehydration of
aldoximes into nitriles,16 nucleophilic ring opening of epoxides
by amines to synthesize b-amino alcohols,17 microwave assisted
preparation of cyclic urea,18 N-formylation of amines19 and other
organic transformation20 are efficiently catalyzed by ZnO. Reduc-
tion of the ZnO particles to nanometer size leads to increased sur-
face area with enhanced catalytic activity of nano ZnO.21 Recently,
zinc oxide nanoparticles have attracted the attention due to the
potentially wide-ranging therapeutic applications.22
Nanocrystalline TiO2 has been used as a solid acid catalyst in or-
ganic reactions like chemoselective trimethylsilylation of alcohols
and phenols,23 deprotection of silyl ethers,24 Friedel–Crafts
alkylation of indoles with epoxides,25 synthesis of bis (indolyl)
methanes,26 Mannich synthesis of b-aminocarbonyls27 and esteri-
fication of free fatty acids.28
Nano ZnO and nano TiO2 both are important reagents in organic
transformation. In the present work we have reported first time
the use of combined nano (ZnO–TiO2) as a catalyst in synthesis
of some novel 1,3,4 oxadiazole analogues using microwave and
conventional method.
Both 1,3,4-oxadiazole and 4,5,6,7-tetrahydrothienopyridine
moieties have potential antimicrobial activities. Hence, it was
thought worthwhile to synthesize coupled heterocyclic system
containing 1,3,4-oxadiazole and 4,5,6,7-tetrahydrothienopyridine
ring with the hope to have enhanced antimicrobial activities. Con-
sidering the above facts we report the synthesis of a novel series of
1,3,4-oxadiazole by one pot reaction of hydrazide, aromatic alde-
hyde in ethanol using combined nano (ZnO–TiO2) as a catalyst.
The synthesized compounds are novel and evaluated for in vitro
antimicrobial activity.
⇑
Corresponding author.
E-mail address: jnsangshetti@rediffmail.com (J.N. Sangshetti).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.041

J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2250–2253
2251
The ester compound 3 was prepared from commercially avail-
able 4,5,6,7-tetrahydrothienopyridine and ethyl bromo acetate 2
in presence of triethylamine described in reported method29
(Scheme 1). Starting hydrazide compound 5 has been prepared
from ester compound 3 using hydrazine hydrate 4, glacial acetic
acid in n-butanol (Scheme 1). Hydrazide compound 5 and different
aromatic aldehydes were subjected to reflux in ethanol using com-
bined nano (ZnO–TiO2) (1 mmol each) as a catalyst to get the target
compounds 7a–7m as shown in (Scheme 2).
fungal activity. Dimethyl sulfoxide was used as solvent control.
MIC values of the tested compounds are presented in Table 3.
Many of the newly synthesized compounds were found to show
moderate to good antibacterial and antifungal activity.
From the antibacterial activity data (Table 3), scaffold contain-
ing 1,3,4-oxadiazole and 4,5,6,7-tetrahydrothienopyridine shows
considerable antibacterial activity. Also it was observed that com-
pound 7a, 7f, 7k and 7l are the most active against most of the
tested organisms. Unsubstituted phenyl analogue (7b) shows sig-
nificant activity against S. aureus and B. subtilis than activity against
E. coli and P. aeruginosa. Substituted phenyl analogues are more ac-
tive than unsubstituted phenyl analogues against almost all of the
tested organisms except for the compound (7g) and (7h) where the
activity has reduced due to substitution. Introduction of –Cl at para
position of phenyl (7a) increases the antibacterial activity against
all of the tested organisms. Replacement of –Cl with –OCH3 at para
position of phenyl (7c) decreases the activity. Introduction of –OH
at 3 and 4 position of phenyl (7d) shows decrease in activity
against P. aeruginosa and B. subtilis compared to unsubstituted phe-
nyl analogues. Introduction of –Cl at 2 position of phenyl (7e) in-
creases the activity compared to unsubstituted phenyl analogues
but the activity is decreases as compared to 4-Cl substituted phe-
nyl analogues except against E. coli. Addition of one more –Cl at
6 position of phenyl (7f) enhances the activity compared to the
mono chloro (7a) substituted analogues. This compound shows
significant activity against all tested organisms compared with
standard. 2,4-Dimethoxy substitution on phenyl (7g) is not favor-
able against mono substituted analogue. Introduction of –OH at 4
position of phenyl (7h) in general decreases the activity compared
to unsubstituted phenyl analogues. The di-chloro substitution on 2
and 4 position of phenyl (7l) gives comparatively more active com-
pound compared with its 4-Cl substituted phenyl analogues (7a).
Introduction of –F at 4 position of phenyl (7k) gives potent com-
pound against E. coli, (MIC-25), S. aureus (MIC-25) and B. subtilis
(MIC-50) compared to ciprofloxacin. Replacement of phenyl ring
by other hetero rings like pyrrole (7i), thiophene (7g), and pyridine
(7m) enhances antibacterial activity against all tested organisms.
Among these analogues (7j) is most active compound against
E. coli and B. subtilis compared to standard. Thus, compound 7f,
7k, and 7j are the most active antibacterial compound from the
present series.
The formation of oxadiazole proceeds via cyclodehydro conden-
sation reaction with the loss of water molecule, to form a cyclic
intermediate which upon aromatic stabilization leads to formation
of oxadiazole. Catalysts can be easily removed from the reaction
mixture by simple filtration. The reaction was initially carried
out using ZnO, nano ZnO and nano TiO2 and combined nano
(ZnO–TiO2). The effect of these catalysts on the yield of the product
(7a) was studied and the data is presented in Table 1. Among the
results, the good yields are obtained by the use of catalyst in nano
form. Also it is observed that combined nano (ZnO–TiO2) gives bet-
ter yield in short time as compared with other catalysts (96%;
12 min, and 91%; 6 h using microwave and conventional method,
respectively). The synthetic procedure was extended for synthesis
of all the compounds 7a–7m using hydrazides and aromatic alde-
hydes. Results are summarized in Table 2. The yields were obtained
in the range of 91–96% and 87–91% for microwave assisted and
conventional method, respectively. All synthesized derivatives
were characterized using MASS, 1H NMR and 13C NMR. Nano ZnO
and Nano TiO2 has been synthesized and characterized using re-
ported methods34
.
All the synthesized compounds were screened for in vitro anti-
bacterial and antifungal activity. The antibacterial activity was
evaluated against four different bacterial strains such as Escherichia
coli (NCIM-2256), Pseudomonas aeruginosa (NCIM-2036), Staphylo-
coccus aureus (NCIM-2901) and Bacillus subtilis (NCIM-2063). The
antifungal activity was evaluated against two fungal strains Can-
dida albicans (NCIM-3471) and Aspergillus niger (NCIM-1196). Min-
imum inhibitory concentration (MIC) values were determined
using standard agar method.30–33 Ciprofloxacin and Ampicillin
were used as a standard for the comparison of antibacterial activity
and Miconazole was used as a standard for the comparison of anti-
Triethylamine
O
O
Br
C2H5
+
NH
N
C2H5
S
Acetonitrile
Reflux
4-5 hrs.
S
O
O
1
3
2
Acetic Acid
NH2-NH2.H20
Butanol
Reflux
15-17 hrs.
4
NHNH2
N
S
O
5
Scheme 1. Synthetic route of the intermediate 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide (5).

2252
J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2250–2253
R
NHNH2
Nano (ZnO-TiO2
Ethanol Reflux
)
N
O
S
R-CHO
+
N
O
N
S
N
5
6
7a-7m
Scheme 2. Synthesis of 4,5,6,7-tetrahydro-5-((5-substituted-1,3,4-oxadiazol-2-yl) methyl) thieno [3,2-c]pyridine (7).
Table 1
Effect of the individual catalysts and in combined form on yield and reaction time for 7a
Catalyst
Mol of
Microwave
Reaction time (min)
Conventional
Reaction time (h)
Yield (%)
Yield (%)
No catalyst
ZnO
Nano ZnO
TiO2
Nano TiO2
Nano (ZnO–TiO2)
—
60
22
16
24
15
12
12
72
88
70
90
96
24
15
8
16
9
—
1 mmol
1 mmol
1 mmol
1 mmol
1 mmol each
68
81
65
84
91
6
Table 2
Experimental data of the synthesized compounds 7a–7m
R
O
N
N
S
N
Compound
R
Microwave
Time in min
Conventional
Molecular formula/molecular weight
Yield
96
Time in h
06
Yield
91
7a
7b
7c
7d
7e
7f
Ph-4-Cl
12
12
13
14
12
12
14
13
15
14
13
12
15
C
16H14ClN3OS
311.5
C16H15N3OS
Ph
91
95
91
95
91
94
94
95
94
94
92
95
06
6.5
7
88
91
87
91
88
90
89
87
88
90
89
87
297
C17H17N3O2S
327
Ph-4-OCH3
Ph-3,4-di OH
Ph-2-Cl
C
16H15N3O3S
329
06
6.5
7
C
16H14ClN3OS
311.5
C16H13Cl2N3OS
366
C18H19N3O3S
357
C16H15N3O2S
313
C14H14N4OS
286
C14H13N3OS2
303
Ph-2,6-di Cl
Ph-2,4-di OCH3
Ph-4-OH
C4H3N
7g
7h
7i
6.5
7
7j
C4H3S
6.5
6
7k
7l
Ph-4-F
C
16H14FN3OS
315
Ph-2,4-di Cl
C5H4N
7
C
16H13Cl2N3OS
366
C15H14N4OS
298
7m
6.5
From the antifungal activity data Table 3, it is observed that,
some of the compounds like 7f, 7k, and 7l shows significant activ-
ity against C. albicans. No significant activity was observed against
A. niger. Unsubstituted phenyl analogues (7b) not showing any
considerable antifungal activity. Introduction of –Cl at para posi-
tion (7a) enhance activity against C. albicans and A. niger. Replace-
ment of –Cl by –OCH3 (7c) reduces activity compared with (7a).
3,4-Dihydroxy phenyl analogue (7d) shows considerable rise in
antifungal activity against C. albicans. 2-Cl substitution on phenyl
(7e) does not affect activity compared to unsubstituted analogue
where as 2,6-dichloro analogue (7f) significantly enhance anti-
fungal activity giving the potent compound against C. albicans.
2,4-Dichloro and 4-F substitution (7l) and (7k), respectively also
leads to a potent compound against C. albicans in the series. 2,4-
Dimethoxy substitution (7g) leads to decrease in activity compared
to 4-OCH3 substitution. Introduction of 4-OH on phenyl (7h)
reduces the activity compared to its 3,4-dihydroxy substituted
analogue. Replacement of phenyl by other hetero nuclei like thio-

J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2250–2253
2253
Table 3
Antimicrobial activity of the synthesized compounds
R
O
N
N
S
N
Compound
R
MIC values in
Antibacterial activity
l
g/mLa
MIC values in
Antifungal activity
l
g/mLa
E. coli
P. aeruginosa
S. aureus
B. subtilis
C. albicans A. niger
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
Ph-4-Cl
Ph
100 2.11
150 2.43
125 1.25
125 0.65
125 0.78
50 1.09
150 2.02
175 1.67
50 0.53
25 1.45
25 0.57
50 1.17
50 0.43
100 1.24
25 1.00
250 2.89
300 2.57
75 1.83
125 0.55
100 2.34
100 1.37
100 2.00
50 0.17
150 1.22
175 2.05
75 1.76
75 1.51
25 0.52
75 1.77
50 0.76
250 2.99
50 1.44
100 2.11
150 1.44
60 1.52
80 1.12
80 0.48
40 0.32
80 1.12
20 0.15
120 0.64
60 0.34
60 0.23
40 0.98
20 0.73
20 2.57
40 1.04
100 2.08
160 2.01
140 1.15
100 1.68
140 1.87
120 1.75
180 2.55
140 2.96
120 0.48
80 1.31
60 1.14
60 1.92
60 0.87
Ph-4-OCH3
Ph-3,4-di OH
Ph-2-Cl
Ph-2,6-di Cl
Ph-2,4-di OCH3
Ph-4-OH
C4H3N
175 1.07
125 2.12
*
*
200 1.97
100 0.98
100 1.54
50 1.89
150 1.47
150 1.42
*
*
125 1.46
150 2.90
100 1.47
125 2.49
150 1.86
100 2.14
25 1.15
100 2.01
50 1.15
50 1.12
75 0.56
100 1.35
250 0.88
50 0.96
C4H3S
Ph-4-F
Ph-2,4-di Cl
C5H4N
Ampicillin
Ciprofloxacin
Miconazole
7m
Standard
Standard
Standard
25 1.24
12.5 1.17
*
No activity was observed up to 400
Values are the average of three readings standard deviation.
l
g/mL.
a
8. (a) Somani, R. R.; Shirodkar, P. Y.; Kadam, V. J. Lett. Drug Des. Disc. 2008, 5, 348;
(b) Ouyang, X.; Patnitski, E. Bioorg. Med. Chem. Lett. 2006, 16, 1191.
9. Lee, C. H.; Cho, H. I.; Lee, K. J. Bull. Korean Chem. Soc. 2001, 22, 1153.
10. Bondock, S.; Adel, S.; Etman, H. A.; Badria, F. A. Eur. J. Med. Chem. 2012, 48, 192.
11. Brijesh Kumar, S. Bioorg. Med. Chem. Lett. 2007, 17, 1924.
12. Bakhite, E. A.; Abdel Rahman, A. E.; Mohammad, O. S. Bull. Korean Chem. Soc.
2002, 23, 1709.
13. Salahuddin, M.; Shantakumar, S. M. Rasayan J. Chem. 2009, 2, 167.
14. Dhakshinamoorthy, A.; Visuvamithiran, P.; Tharmaraj, V.; Pitchumani, K. Catal.
Commun. 2011, 16, 15.
phene (7i), pyrrole (7j) and pyridine (7m) ring seems to be advan-
tageous in terms of antifungal activity against both C. albicans and
A. niger. Thus, compound 7f, 7k and 7l are the most potent anti-
fungal compound from the series.
In conclusion, we have reported for the first time use of com-
bined nano (ZnO–TiO2) for the synthesis of substituted 1,3,4-oxadi-
azole from hydrazide and aromatic aldehydes using conventional
as well as microwave assisted method in good yields. All the syn-
thesized compounds are novel and were tested for antibacterial
and antifungal activity. Based on the activity data, SAR for the ser-
ies has been developed. From the series 7f, 7k and 7j serve as an
important pharmacophore for the design and development of
new lead as antibacterial agent where as compound 7f, 7k and 7l
shows promising antifungal activity indicating the future scope
for optimization.
15. Sarvari, M. H.; Sharghi, H. J. Org. Chem. 2004, 69, 6953.
16. Sarvari, M. H. Synthesis 2005, 5, 787.
17. Sarvari, M. H. Acta Chim. Slovenica 2008, 55, 440.
18. Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45, 7205.
19. Sarvari, M. H.; Sharaghi, H. J. Org. Chem. 2006, 71, 6652.
20. Thakuria, H.; Borah, B. M.; Das, G. J. Mol. Catal. A: Chem. 2007, 274, 1.
21. Hariharan, C. Appl. Catal., A 2006, 304, 55.
22. George, S.; Pokhrel, S.; Xia, T.; Gilbert, B.; Ji, Z.; Schowalter, M.; Rosenauer, A.;
Damoiseaux, R.; Bradley, K. A.; Madler, L.; Nel, A. E. ACS Nano 2010, 4, 15.
23. Shirini, F.; Alipour Khoshdel, M.; Abedini; Atghia, S. V. Chin. Chem. Lett. 2011,
1211.
24. Shirini, F.; Atghia, S. V.; Jirdehi, M. Catal. Commun. 2012, 18, 5.
25. Lakshmi Kantam, M.; Laha, S.; Yadav, J.; Sreedhar, B. Tetrahedron Lett. 2006, 47,
6213.
26. Hosseini-Sarvari, M. Acta Chim. Slovenica 2007, 54, 354.
27. Kassaee, M. Z.; Mohammadi, R.; Masrouri, H.; Movahedi, F. Chin. Chem. Lett.
2011, 22, 1203.
Acknowledgments
The authors thankful to the Mrs. Fatima Rafiq Zakaria Chairman
Maulana Azad Educational Trust and Dr. M. H. G. Dehghan, Princi-
pal, Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus,
Aurangabad 431 001 (M.S.), India for providing the laboratory
facility.
28. Ropero-Vega, J. L.; Aldana-Pereza, A.; Gomez, R.; Nino-Gomez, M. E. Appl. Catal.
A: Gen. 2010, 379, 24.
29. Patel, H. S.; Patel, P. N.; Modi, V. P. Pharm. Lett. 2011, 3, 120.
30. , 2nd ed.Medicinal Microbiology; Cruickshank, R., Duguid, J. P., Marmion, B. P.,
Swain, R. H. A., Eds.; Churchill Livingstone: London, 1975; Vol. 2,.
31. Collins, A. H. Microbiological Methods, 2nd ed.; Butterworth: London, 1976.
32. Khan, Z. K. In vitro and in vivo screening techniques for bioactivity screening
and evaluation, Proc. Int. Workshop UNIDO-CDRI, 1997, 210.
33. (a) Duraiswamy, B.; Mishra, S. K.; Subhashini, V.; Dhanraj, S. A.; Suresh, B.
Indian J. Pharm. Sci. 2006, 68, 389; (b) Saundane, A. R.; Rudresh, K.;
Satynarayan, N. D.; Hiremath, S. P. Indian J. Pharm. Sci. 1989, 60, 379; (c)
Therese, K. L.; Bhagylaxmi, R.; Madhavan, H. N.; Deepa, P. Indian J. Med.
Microbiol. 2006, 24, 273.
References and notes
1. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 879.
2. Amir, M.; Shawano, S. Indian J. Heterocycl. Chem. 1998, 8, 107.
3. Ashour, F. A.; Al Mazoroa, S. A. J. Pharm. Sci. 1990, 4, 29.
4. Nassar, O. M. Indian J. Heterocycl. Chem. 1997, 7, 105.
5. Kucukguzel, S. G.; Kocatepe, A.; De Clercq, E.; Sahin, F.; Gulluce, M. Eur. J. Med.
Chem. 2006, 41, 353.
6. Akhter, M.; Husain, A.; Azad, B.; Ajma, M. Eur. J. Med. Chem. 2009, 44, 2372.
7. Unangast, P. C.; Shrum, G. P.; Conner, D. T.; Dyer, C. D.; Schrier, D. J. J. Med.
Chem. 1992, 35, 3691.
34. (a) Patil, S. L.; Chougule, M. A.; Pawar, S. G.; Raut, B. T.; Sen, S.; Patil, V. B. J.
Alloys Compd. 2011, 509, 10055; (b) Patil, S. L.; Pawar, S. G.; Mane, A. T.;
Chougule, M. A.; Patil, V. B. J. Mater. Sci.: Mater. Electron. 2010, 21, 1332.