Synthesis of novel quinolone and coumarin based 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl N-mannich bases as potential antimicrobials

Article abstract of DOI:10.2174/157017812802139681

Two series of 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives have been synthesized and characterized by elemental and spectral (IR, ¹H-NMR) data. The hydrazide derivatives of 4-hydroxy quinolone and coumarin moiety were refluxed in carbon disulfide in ethanolic potassium hydroxide to obtain the corresponding hydrazinecarbodithioate salts which were then treated in two ways with (i) sulfuric acid and (ii) hydrochloric acid at cooled temperature to furnish the corresponding 1,3,4-thiadiazole and 1,3,4-oxadiazole intermediates, respectively, which were then treated with piperazine bases in the presence of formalin in methanol to furnish the final N-Mannich products 7i-10vi. The newer analogs were examined for their antimicrobial activity against five bacteria (S. aureus and B. cereus, E. coli, P. aeruginosa and K. pneumoniae) and two fungi (A. niger and C. albicans) and the results revealed that compounds demonstrated excellent activity (MICs: 3.12-25 μg/mL) as compared with the standards (MICs: 6.25-25 μg/mL).

Full text of DOI:10.2174/157017812802139681

478
Letters in Organic Chemistry, 2012, 9, 478-486
Synthesis of Novel Quinolone and Coumarin Based 1,3,4-Thiadiazolyl and
1,3,4-Oxadiazolyl N-Mannich Bases as Potential Antimicrobials
Rahul V. Patela*, Jigar K. Patela, Premlata Kumaria and Kishor H. Chikhaliab
aDepartment of Applied Chemistry, S. V. National Institute of Technology, Surat- 395 007, Gujarat, India
bDepartment of Chemistry, School of Science, Gujarat University, Ahmedabad-380 009, Gujarat, India
Received February 29, 2012: Revised April 20, 2012: Accepted May 02, 2012
Abstract: Two series of 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives have been synthesized and characterized by
elemental and spectral (IR, 1H-NMR) data. The hydrazide derivatives of 4-hydroxy quinolone and coumarin moiety were
refluxed in carbon disulfide in ethanolic potassium hydroxide to obtain the corresponding hydrazinecarbodithioate salts
which were then treated in two ways with (i) sulfuric acid and (ii) hydrochloric acid at cooled temperature to furnish the
corresponding 1,3,4-thiadiazole and 1,3,4-oxadiazole intermediates, respectively, which were then treated with piperazine
bases in the presence of formalin in methanol to furnish the final N-Mannich products 7i-10vi. The newer analogs were
examined for their antimicrobial activity against five bacteria (S. aureus and B. cereus, E. coli, P. aeruginosa and K.
pneumoniae) and two fungi (A. niger and C. albicans) and the results revealed that compounds demonstrated excellent ac-
tivity (MICs: 3.12-25 ꢀg/mL) as compared with the standards (MICs: 6.25-25 ꢀg/mL).
Keywords: 1,3,4-thiadiazole, 1,3,4-oxadiazole, antimicrobial activity, coumarin, piperazine, quinolone.
INTRODUCTION
extensive studies have been conducted to examine the antim-
icrobial efficacy of 1,3,4-oxa/thiadiazole derivatives involv-
ing substitution of different aromatic or heterocyclic moie-
ties via substitution to the sulphur atom [20, 21]. In connec-
tion with these studies, we planned to modify the said de-
rivatives via structural modification to the nitrogen atom of
the oxa/thiadiazole ring rather than the said sulphur linkage
to develop new antimicrobial agents with novel mechanism
of action. Furthermore, the type of 1,3,4-oxadiazole scaf-
folds we plan to design have found intrinsic biological appli-
cations as anti-inflammatory [22, 23] antitubercular [24],
antifungal [25] and anticancer activities [26], where as Ag-
garwal et al. recently synthesized potential active antimicro-
bial 1,3,4-oxa/thiadiazoles [27] based on similar structural
features as with quinoline moiety as a core molecules in the
form of nalidixic acid. In a view of these findings, we are
directed to furnish similar scaffolds with quinolone and
coumarin nucleus. It is well known that many currently
available first line antimicrobial drugs are quinolones as
ciprofloxacin, norfloxacin etc, whereas, the presence of 4-
hydroxy-chromen-2-one is also found to enhance the various
biological activities [28-30]. In addition, fluoropiperazines
are found to play an important role by enhancing the antimi-
crobial and antituberculosis properties [31] of the resultant
molecule and the results are recently published by us in con-
tinuation of our research towards novel biologically active
agents [32-34]. Furthermore, thiadiazole condensed with the
moieties having methoxy functional group is reported to ex-
hibit antituberculosis activity against isoniazid resistant
clinical strain [35].
Nowadays, many Gram-positive and Gram-negative bac-
teria such as Staphylococcus aureus and fungi like Candida
species are found to withstand the attack of currently avail-
able chemotherapeutic agents, the so-called antimicrobial
resistance [1-3]. The issue has raised fears that such oppor-
tunistic microbial infections may once again become major
cause of death in developing/developed countries immerging
with the steady increase of immunocompromised individu-
als, patients with malignancies and transplant recipients [4].
The mechanism of resistantce is continuously evolving in
pathogenic bacteria to currently used antimicrobial regimen,
thereby jeopardizing the medical successes achieved at
healthcare systems. To meet this crisis successfully, many
researchers across the globe are working to unearth new
compounds which can selectively attack novel targets in dif-
ferent microorganisms. One possible way to reach such re-
sults is the modification of the structure of pre-established
molecules active against the said targets. In this context,
framing of two or more bioactive pharmacpohore in a single
molecular scaffold may furnish better results.
During last few decades, 1,3,4-oxadiazole derivatives are
implicated in a variety of biological applications as antimi-
crobial [5-10] and antituberculosis [11-13] agents, whereas,
1,3,4-thiadiazole nucleus is established as a core scaffold
having important bioprofiles as antimicrobial [14-16], anti-
tuberculosis [17] and anticancer [18,19] agents. In addition,
Literature survey ascribed that oxadiazolo condensed
piperazine derivatives based on aromatic or heterocyclic core
displayed good antimicrobial activity against various human
*Address correspondence to this author at the Department of Applied
Chemistry, S. V. National Institute of Technology, Surat–395007, Gujarat,
India; Tel: +91–9712755525; E-mail: rahul.svnit11@gmail.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

1,3,4-oxa/thiadiazoles as Potential Antimicrobials
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
479
N
X R
N N
O
O
N
N
N
N
R
S
Br
S
O
X
Y
N
N R
N
N
Improved Activity
S
O
O
S
R3
R1
X
= N-CH3 or O
Y = O or S
N N
R2
N
H
O
O
O
Scheme 1. Rationalization of the scaffold synthesized.
pathogenic microorganisms [36, 37]. Couramain nucleus is
recently employed to produce potential antimicrobial actitiv-
ities as presented in the present study (Scheme I) [38].
Prompted by these observations and in continuation of our
interest in 1,3,4-oxadiazole derivatives [39, 40], it was con-
templated to synthesize a novel series of fluoro/methoxy
piperazino-1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives
involving quinolone and coumarin moieties in order to estab-
lish newer molecules in a recent drug discovery process and
the results indicated that the biological activity is increased
significantly.
in 250 ml dry acetone and mixed with anhydrous potassium
carbonate (0.09 mol). This was treated with ethylchloroace-
tate (0.05 mol) and the mixture was refluxed for 7 h (for 1a)
and 9 h (for 1b). After the completion of reaction (monitored
by TLC), the reaction mixture was filtered and the filtrate
was distilled under reduced pressure. The solid thus obtained
was subjected to column chromatography using 5% ethyl
acetate: petroleum ether to furnish the final products 2a and
2b [41].
Ethyl 2-(1-methyl-2-oxo-1,2-dihydroquinolin-4-
yloxy)acetate (2a)
Yield 88 %, m.p. 130-132°C. IR (KBr, cm-1): 1732 (ester,
C=O), H NMR (400 MHz, Me2SO- d6): ꢀ 8.03 (d, J = 7.4
Hz, 1H, C8 proton of quinoline), 7.70 (t, J = 7.5 Hz, 1H, C7
proton of quinoline), 7.57 (d, J = 7.9 Hz, 1H, C5 proton of
quinoline), 7.42 (t, J = 7.6 Hz, 1H, C6 proton of quinoline),
7.41 (s, 1H, C3 proton of quinoline), 5.02(2H, s, O-CH2),
4.14 (2H, q, J = 5.9 Hz, OCH2CH3), 3.61 (s, 3H, N-CH3),
1.33 (3H, t, J = 6.0 Hz, CH2CH3).
EXPERIMENTAL
Chemistry
1
Solvents of HPLC grade were purchased from Rankem,
Surat, India. The TLC plates (silica gel 60 F254) were ob-
tained from Merck, Germany. Melting points were deter-
mined in open capillaries on a Veego electronic apparatus
VMP-D (Veego Instrument Corporation, Mumbai, India) and
are uncorrected. IR spectra (4000-400 cm-1) of synthesized
compounds were recorded on a Shimadzu 8400-S FT-IR
spectrophotometer (Shimadzu India Pvt. Ltd., Mumbai, In-
dia) using KBr pellets. Thin layer chromatography was per-
formed on object glass slides (2 x 7.5 cm) coated with silica
gel-G and spots were visualized under UV irradiation. H
NMR spectra were recorded on a Varian 400 MHz model
spectrometer (Varian India Pvt. Ltd., Mumbai, India) using
DMSO as a solvent and TMS as internal standard with H
resonant frequency of 400 MHz. The H NMR Chemical
Shifts were reported as parts per million (ppm) downfield
from TMS (Me4Si) and were performed at center for excel-
lence, Vapi, India. The splitting patterns are designated as
follows; s, singlet; d, doublet; dd, doublet of doublets; q,
quartet, m, multiplet. Elemental analyses (C, H, N) were
performed using a Heraeus Carlo Erba 1180 CHN analyzer
(Hanau, Germany).
Ethyl 2-(2-oxo-2H-chromen-4-yloxy)acetate (2b)
Yield 82 %, m.p. 98-99 °C (Lit. m.p. 97 °C). IR (KBr,
cm-1): 1728 (ester, C=O), 1H NMR (400 MHz, Me2SO- d6): ꢀ
7.96 (dd, J = 1.6, 1.3 Hz, 1H, C5 proton of coumarin), 7.55-
7.62 (m, 1H, coumarin), 7.50 (t, J = 8.7 Hz, 1H, C6 proton of
coumarin), 7.33-7.48 (m, 1H, coumarin), 5.02(2H, s, O-
CH2), 4.14 (2H, q, J = 5.9 Hz, OCH2CH3), 1.33 (3H, t, J =
6.0 Hz, CH2CH3).
1
1
1
General procedure for the preparation of hydrazide de-
rivatives (3a, 3b)
A
mixture of ethyl 2-(1-methyl-2-oxo-1,2-dihydro-
quinolin-4-yloxy)acetate (2a) or ethyl 2-(2-oxo-2H-
chromen-4-yloxy)acetate (2b) (0.03 mol) and hydrazine hy-
drate (0.03 mol) in ethanol (60 ml) was heated under reflux
for 8 h (for 2a) and 6 h (for 2b). The reaction mixture was
cooled to room temperature and the solid separated was col-
lected by filtration. It was washed with ethanol and recrystal-
lized in methanol. The products 3a and 3b were obtained as
light yellow solid [38].
General procedure for the preparation of ester deriva-
tives (2a, 2b)
4-hydroxy-1-methylquinolin-2(1H)-one (1a) and 4-
hydroxy-2H-chromen-2-one (1b) (0.05 mol) was dissolved

480 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Patel et al.
2-(1-Methyl-2-oxo-1,2-dihydroquinolin-4-
yloxy)acetohydrazide (3a)
(t, J = 7.8 Hz, 1H, C6 proton of quinoline), 7.42 (s, 1H, C3
proton of quinoline), 7.31-6.84 (4H, m, Ar-H), 4.89 (2H, s,
O-CH2), 3.73 (s, 3H, N-CH3).
Yield 86 %, m.p. 173-175 °C. IR (KBr, cm-1): 1653 (am-
1
ide, C=O), 3310, 3203 (NH-NH2), H NMR (400 MHz,
Me2SO- d6): ꢀ 9.83 (1H, br s, -CO-NH), 8.03 (d, J = 7.4 Hz,
1H, C8 proton of quinoline), 7.70 (t, J = 7.5 Hz, 1H, C7 pro-
ton of quinoline), 7.57 (d, J = 7.9 Hz, 1H, C5 proton of qui-
noline), 7.42 (t, J = 7.6 Hz, 1H, C6 proton of quinoline), 7.41
(s, 1H, C3 proton of quinoline), 5.02(2H, s, O-CH2), 4.58
(2H, br s,–NH2), 3.67 (s, 3H, N-CH3).
4-((5-Thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy)-
2H-chromen-2-one (5b)
73 % yield, m.p. 225-226 °C. IR (KBr, cm-1): v 3078 (-
CH Str.), 1680 (C=O, coumarin), 1635 (C=N of oxadiazole),
1218 (C=S), 1141 (N-N, oxadiazole), 1070 (Ph-O-CH2),
1041 (C-O-C-, oxadiazole) 1H NMR (400 MHz, Me2SO- d6):
ꢀ 10.55 (bs, 1H, NH), 8.07 (dd, J = 1.2, 1.3 Hz, 1H, C5 pro-
ton of coumarin), 7.61-7.69 (m, 1H, coumarin), 7.50 (t, J =
8.4 Hz, 1H, C6 proton of coumarin), 7.35-7.42 (m, 1H, cou-
marin), 7.23-6.84 (5H, m, Ar-H), 4.85 (2H, s, O-CH2).
2-(2-Oxo-2H-chromen-4-yloxy)acetohydrazide (3b)
Yield 80 %, m.p. 194-195 °C (Lit. m.p. 192 °C). IR
1
(KBr, cm-1): 1657 (amide, C=O), 3303, 3221 (NH-NH2), H
NMR (400 MHz, Me2SO- d6): ꢀ 9.83 (1H, br s, -CO-NH),
7.96 (dd, J = 1.6, 1.3 Hz, 1H, C5 proton of coumarin), 7.55-
7.62 (m, 1H, coumarin), 7.50 (t, J = 8.7 Hz, 1H, C6 proton of
coumarin), 7.33-7.48 (m, 1H, coumarin), 5.02 (2H, s, O-
CH2), 4.58 (2H, br s,–NH2).
General procedure for the preparation of 1,3,4-
thiadiazole derivatives (6a, 6b)
The above dried potassium 2-(2-(1-methyl-2-oxo-1,2-
dihydroquinolin-4-yloxy)acetyl)hydrazinecarbodithioate (4a)
and potassium 2-(2-(2-oxo-2H-chromen-4-yloxy)acetyl)
hydrazinecarbodithioate (4b) was added in very small por-
tions to a cooled sulfuric acid (10 mL, 0-5 oC) and stirred till
the solution became homogenous. The homogenous mixture
was poured in crushed ice. The separated precipitates were
filtered, washed with water, and dried in vacuum oven to
obtain 6a and 6b.
General procedure for the preparation of hydrazinecar-
bodithioate salts (4a, 4b)
2-(1-methyl-2-oxo-1,2-dihydroquinolin-4-yloxy)acetohy-
drazide (3a) and 2-(2-oxo-2H-chromen-4-yloxy)aceto-
hydrazide (3b) (0.01 mol) were added to a solution of potas-
sium hydroxide (0.01 mol) in absolute ethanol (70 mL)
placed in a 100 mL round bottomed flask mounted over a
magnetic stirrer. The reaction mixture was stirred for 1 h in
an ice bath. Carbon disulfide (0.015 mol) was added drop
wise to the above pre-cooled reaction mixture, which re-
sulted in the formation of a pale yellow precipitate. The pale
yellow precipitate was filtered and repeatedly washed with
cold acetone (2 x 10 mL) and dried in vacuum oven to obtain
4a and 4b.
1-Methyl-4-((5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-
yl)methoxy)quinolin-2(1H)-one (6a)
Yield 72 %, m.p. 209-211 °C. IR (KBr, cm-1): 3061 (-CH
Str.), 1637 (C=O, quinoline), 1611 (C=N of thiadiazole),
1232 (C=S), 1151 (N-N, thiadiazole), 1076 (Ph-O-CH2), 697
1
(C-S-C, thiadiazole). H NMR (400 MHz, Me2SO- d6): ꢀ
10.54 (bs, 1H, NH), 8.09 (d, J = 7.4 Hz, 1H, C8 proton of
quinoline), 7.60 (d, J = 8.2 Hz, 1H, C5 proton of quinoline),
7.54 (t, J = 7.5 Hz, 1H, C7 proton of quinoline), 7.47 (t, J =
7.6 Hz, 1H, C6 proton of quinoline), 7.38 (s, 1H, C3 proton of
quinoline), 7.31-6.89 (4H, m, Ar-H), 4.86 (2H, s, O-CH2),
3.71 (s, 3H, N-CH3).
General procedure for the preparation of 1,3,4-
oxadiazoles derivatives (5a, 5b)
The above dried potassium 2-(2-(1-methyl-2-oxo-1,2-
dihydroquinolin-4-yloxy)acetyl)hydrazinecarbodithioate (4a)
and potassium 2-(2-(2-oxo-2H-chromen-4-yloxy)acetyl)
hydrazinecarbodithioate (4b) were added in very small por-
4-((5-Thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy)-
2H-chromen-2-one (6b)
o
tions to a cooled hydrochloric acid (10 mL, 0-5 C) taken in
a round-bottomed flask and stirred till the solution became
homogenous. The homogenous mixture was poured in
crushed ice. The separated precipitates were filtered at pump,
washed with water, and dried in vacuum oven to obtain 5a
and 5b.
Yield 69 %, m.p. 218-219 °C. IR (KBr, cm-1): 3073 (-CH
Str.), 1681 (C=O, coumarin), 1624 (C=N of thiadiazole),
1238 (C=S), 1161 (N-N, thiadiazole), 1087 (Ph-O-CH2), 702
1
(C-S-C, thiadiazole). H NMR (400 MHz, Me2SO- d6): ꢀ
10.47 (bs, 1H, NH), 8.03 (dd, J = 1.3, 1.3 Hz, 1H, C5 proton
of coumarin), 7.49-7.64 (m, 1H, coumarin), 7.46 (t, J = 8.3
Hz, 1H, C6 proton of coumarin), 7.30-7.39 (m, 1H, cou-
marin), 7.27-6.77 (5H, m, Ar-H), 4.88 (2H, s, O-CH2).
Methyl-4-((5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-
yl)methoxy)quinolin-2(1H)-one (5a)
78 % yield, m.p. 233-235 °C. IR (KBr, cm-1): 3054 (-CH
Str.), 1651 (C=O, quinoline), 1632 (C=N of oxadiazole),
1232 (C=S), 1140 (N-N, oxadiazole), 1074 (Ph-O-CH2),
General procedure for the preparation of final deriva-
tives (7i-10vi)
1
1055 (C-O-C-, oxadiazole). H NMR (400 MHz, Me2SO-
To a 0.005 mol stirred solution of 1-methyl-4-((5-thioxo-
4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy)quinolin-2(1H)-
d6): ꢀ10.52 (bs, 1H, NH), 7.98 (d, J = 7.1 Hz, 1H, C8 proton
of quinoline), 7.68 (t, J = 7.5 Hz, 1H, C7 proton of quino-
line), 7.59 (d, J = 8.5 Hz, 1H, C5 proton of quinoline), 7.47
one
(5a),
4-((5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-
(5b), 1-methyl-4-((5-
yl)methoxy)-2H-chromen-2-one

1,3,4-oxa/thiadiazoles as Potential Antimicrobials
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
481
thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy)quinolin-
quinoline), 7.28-6.86 (4H, m, Ar-H), 5.19 (s, 2H, NCH2N),
4.92 (2H, s, O-CH2), 3.88 (4H, br s, piperazine), 3.72 (s, 3H,
N-CH3), 3.48 (4H, br s, piperazine). Anal Calcd for
C24H24FN5O2S2: C, 57.93; H, 4.86; N, 14.07. Found: C,
57.99; H, 4.80; N, 14.14.
2(1H)-one
(6a)
and
4-((5-thioxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)methoxy)-2H-chromen-2-one (6b) in ethanol,
0.006 mol of 40% formalin was added and the reaction mix-
ture was allowed to stir for half an hour. After that, appropri-
ate piperazine bases were dissolved in ethanol and added
drop wise to the above stirred mixture and allowed to reflux
for 3-8 h. The progress of the reaction was monitored by
Thin Layer Chromatography using ethyl acetate: n-hexane
(7: 3) as the mobile phase. After the completion of the reac-
tion, mixture was allowed to cool and poured onto crushed
ice. The precipitate formed was collected by filtration,
washed with water and dried in vacuum oven to furnish 7i-
10vi [27].
4-((4-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-5-
thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy)-2H-
chromen-2-one (10i)
o
Yield 71%, m.p. 280-282 C. IR (KBr, cm-1): 3068 (-CH
Str.), 1679 (C=O, coumarin), 1618 (C=N of thiadiazole),
1240 (C=S), 1152 (N-N, thiadiazole), 1086 (Ph-O-CH2), 753
(C-F), 687 (C-S-C, thiadiazole). 1H NMR (400 MHz,
Me2SO- d6): ꢀ 8.07 (dd, J = 1.5, 1.3 Hz, 1H, C5 proton of
coumarin), 7.54-7.61 (m, 1H, coumarin), 7.49 (t, J = 8.3 Hz,
1H, C6 proton of coumarin), 7.32-7.37 (m, 1H, coumarin),
7.30-6.85 (5H, m, Ar-H), 5.26 (s, 2H, NCH2N), 4.94 (2H, s,
O-CH2), 3.82 (4H, br s, piperazine), 3.53 (4H, br s, piperazi-
ne). Anal Calcd for C23H21FN4O3S2: C, 57.01; H, 4.37; N,
11.56. Found: C, 57.07; H, 4.42; N, 11.59.
4-((4-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-5-
thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy)-1-
methylquinolin-2(1H)-one (7i)
o
Yield 66%, m.p. 248-250 C. IR (KBr, cm-1): 3068 (-CH
Str.), 1650 (C=O, quinoline), 1620 (C=N of oxadiazole),
1241 (C=S), 1135 (N-N, oxadiazole), 1085 (Ph-O-CH2),
1
1048 (C-O-C-, oxadiazole), 753 (C-F). H NMR (400 MHz,
Biological Assay
Me2SO- d6): ꢀ 8.02 (d, J = 7.0 Hz, 1H, C8 proton of quino-
line), 7.70 (t, J = 7.7 Hz, 1H, C7 proton of quinoline), 7.62
(d, J = 8.3 Hz, 1H, C5 proton of quinoline), 7.49 (t, J = 7.7
Hz, 1H, C6 proton of quinoline), 7.39 (s, 1H, C3 proton of
quinoline), 7.28-6.80 (4H, m, Ar-H), 5.19 (s, 2H, NCH2N),
4.95 (2H, s, O-CH2), 3.87 (4H, br s, piperazine), 3.75 (s, 3H,
N-CH3), 3.47 (4H, br s, piperazine). Anal Calcd for
C24H24FN5O3S: C, 59.86; H, 5.02; N, 14.54. Found: C,
59.74; H, 5.06; N, 14.57.
In vitro Evaluation of Antimicrobial Activity
Antimicrobial activity for the final analogs carried out as
described by Clause [42] with minor modifications against
two Gram-positive bacteria (Staphylococcus aureus MTCC
96, Bacillus cereus MTCC 430), three Gram-negative bacte-
ria (Escherichia coli MTCC 739, Pseudomonas aeruginosa
MTCC 741, Klebsiella pneumoniae MTCC 109) and against
two fungal species (Aspergillus niger MTCC 282, Candida
albicans MTCC 183). Ampicillin and Gentamicina as well
as Fluconazole were used as standard antibacterial and anti-
fungal agents, respectively. Solutions of the test compounds
and reference drugs were dissolved in DMSO at a concentra-
tion of 500 ꢁg/mL. The dilution of the compounds and refer-
ence drugs was prepared (500, 250, 200, 100, 62.5, 50, 25,
12.5, 6.25, 3.13) ꢁg/mL. Antibacterial activities of the bacte-
rial strains were carried out in Muller–Hinton broth (Difco)
medium, at pH 6.9, with an inoculum of (1–2) x 103
cells/mL by the spectrophotometric method and an aliquot of
100 ꢁL was added to each tube of the serial dilution. The
chemical compounds-broth medium serial tube dilutions
inoculated with each bacterium were incubated on a rotary
shaker at 37 oC for 24 h at 150 rpm. The minimum inhibitory
concentrations of the chemical compounds were recorded as
the lowest concentration of each chemical compounds in the
tubes with no growth (i.e., no turbidity) of inoculated bacte-
ria. All fungi were cultivated in Sabouraud Dextrose Agar
(Merck). The fungi inoculums were prepared in Sabouraud
4-((4-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-5-
thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methoxy)-2H-
chromen-2-one (8i)
o
Yield 73%, m.p. 264-266 C. IR (KBr, cm-1): 3075 (-CH
Str.), 1692 (C=O, coumarin), 1628 (C=N of oxadiazole),
1228 (C=S), 1146 (N-N, oxadiazole), 1084 (Ph-O-CH2),
1
1048 (C-O-C-, oxadiazole), 753 (C-F). H NMR (400 MHz,
Me2SO- d6): ꢀ 8.06 (dd, J = 1.3, 1.3 Hz, 1H, C5 proton of
coumarin), 7.58-7.61 (m, 1H, coumarin), 7.45 (t, J = 8.6 Hz,
1H, C6 proton of coumarin), 7.32-7.39 (m, 1H, coumarin),
7.25-6.87 (5H, m, Ar-H), 5.20 (s, 2H, NCH2N), 4.89 (2H, s,
O-CH2), 3.83 (4H, br s, piperazine), 3.43 (4H, br s, piperazi-
ne). Anal Calcd for C23H21FN4O4S: C, 58.96; H, 4.52; N,
11.96. Found: C, 58.85; H, 4.58; N, 11.93.
4-((4-((4-(2-Fluorophenyl)piperazin-1-yl)methyl)-5-
thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methoxy)-1-
methylquinolin-2(1H)-one (9i)
o
liquid medium (Oxoid) which had been kept at 36 C over-
night and diluted with RPMI-1640 medium with L-
glutamine buffered with 3-[N-morpholino]-propansulfonic
acid (MOPS) at pH 7 to give a final concentration of 2.5 x
o
Yield 69%, m.p. 285-287 C. IR (KBr, cm-1): 3068 (-CH
Str.), 1647 (C=O, quinoline), 1614 (C=N of thiadiazole),
1229 (C=S), 1149 (N-N, thiadiazole), 1085 (Ph-O-CH2), 750
(C-F), 685 (C-S-C, thiadiazole). 1H NMR (400 MHz,
Me2SO- d6): ꢀ 8.04 (d, J = 7.2 Hz, 1H, C8 proton of quino-
line), 7.66 (t, J = 7.7 Hz, 1H, C7 proton of quinoline), 7.62
(d, J = 8.0 Hz, 1H, C5 proton of quinoline), 7.53 (t, J = 7.8
Hz, 1H, C6 proton of quinoline), 7.41 (s, 1H, C3 proton of
o
103 cfu/mL. The microplates were incubated at 36 C and
read visually after 24 h, except for Candida species when it
was at 48 h. The incubation chamber was kept humid. At the
end of the incubation period, MIC values were recorded as
the lowest concentrations of the substances that gave no
visible turbidity.

482 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Patel et al.
O
C
O
C
H
N
C H
O
3
NH
O
X
O
X
2
OH
a
b
O
O
3
X
O
3 a: X=N-C H
2a : X=N-CH
2b: X=O
1a: X=N-C H
1b: X=O
3
3
3 b: X=O
S
O
C
H
N
C
O
X
N
H
S
K
c
O
4a : X=N-C H
4b: X=O
3
e
d
N
NH
N
NH
O
X
S
S
O
X
O
S
O
O
5a: X=N-C H
5b: X=O
6 a: X=N-CH
6 b: X=O
3
3
f
f
HN
N
R
i- vi
N
N
N
N
R
N
N
N
N
R
S
S
O
X
S
O
O
9i-9v i: X=N- CH
3
10i-1 0vi
O
O
X
7i-7v i: X=N- CH
8i-8v i: X=O
3
: X=O
R =
C F
F
3
v
iii
iv
OCH
3
i
H C O
OC H
3
3
H
2
C
ii
CF
OCH
3
F
3
v i
Scheme 2. Synthetic protocol for the final analogs 7i-10vi.
Reagents and conditions: (a) ClCH2COOC2H5, Anhyd. K2CO3, Acetone, Reflux; (b) 90% NHNH2.H2O, EtOH, Reflux; (c) CS2/KOH, EtOH,
Reflux; (d/e) H2SO4/HCl, 0-5 oC; (f) HCHO, piperazines, EtOH, Reflux.
reagents were used as received or were dried prior to use as
needed. 4-hydroxy-1-methylquinolin-2(1H)-one (1a) and 4-
hydroxy-2H-chromen-2-one (1b) was treated with ethyl-
chloroacetate to yield the corresponding ester derivatives
(2a, 2b). IR spectra of the ester compounds revealed an ab-
RESULTS AND DISCUSSION
Chemistry
Scheme 2 outlines the synthetic pathway followed for the
synthesis of the title compounds 7i-10vi. The solvents and

1,3,4-oxa/thiadiazoles as Potential Antimicrobials
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
483
sorption band of an ester functional group at 1728-1732 cm–
1. The resulting ester derivative was then treated with 99%
hydrazine hydrate in ethanol to give the corresponding hy-
drazide derivatives (3a, 3b) in good yield and its correct syn-
thesis was confirmed by a broad band at 1653-1657 cm–1 due
to –C=O of amide and disappearance of an ester frequency
(1728-1732 cm–1) in the IR spectra. The resulted hydrazide
derivatives (3a, 3b) were then cyclized using carbon disul-
fide in ethanolic potassium hydroxide to furnish the hydrazi-
necarbodithioate salts (4a, 4b). The said hydrazinecar-
bodithioate salts (4a, 4b) were further treated with sulfuric
acid and hydrochloric acid at cooled temperature to furnish
the corresponding 1,3,4-thiadiazole derivatives (5a, 5b) and
1,3,4-oxadiazoles derivatives (6a, 6b), respectively. IR spec-
tra of the thiadiazole derivatives revealed a band at 697-702
cm–1 due to C-S-C group and IR spectra of the oxadiazoles
derivatives revealed a band at 1041-1057 cm–1 due to C-O-
C- group. 1H NMR spectra clearly evidenced the presence of
an –NH group in the ring of cyclized derivatives appearing
broad as singlet peak at around 10.50 ppm. The said 1,3,4-
oxadiazole and 1,3,4-thiadiazole derivatives were then
treated with different fluoro or methoxy substituted
piperazine moieties in the presence of formalin in methanol
drugs (12.5-25 ꢀg/mL) against Gram-negative P. aerugi-
nosa, while similar thiadiazoles with quinolone ring system
and either trifluoro (9iii) or trimethoxy (9vi) functional
groups exerted higher potency at 6.25 ꢀg/mL of MIC than
the standards (25 ꢀg/mL). All the final 1,3,4-oxa/thiadizoles
having substitution of para-methoxy group at the phenyl ring
of piperazine base indicated good activity at 12.5 ꢀg/mL of
MIC against A. niger fungi; these derivative were found half
fold active against the mentioned fungi when compared to
standard drug fluconazole (6.25 ꢀg/mL). 1,3,4-Oxadiazole
derivative with meta-trimethoxy functional group at qui-
nolone (7vi) and coumarin (8vi) ring systems indicated good
antifungal properties at 25 ꢀg/mL of MIC, i.e., half fold ac-
tive than the standard drug fluconazole. Majority of the re-
maining derivatives were found to exhibit good antimicro-
bial profiles either similarly active or half fold active to the
standard drug, while some of them were moderately active.
Hence, from the studied bioassay it can be stated that
1,3,4-thiadiazole derivatives were more active than the de-
rivative involving 1,3,4-oxadiazole ring system. In addition,
all the final derivatives with quinolone ring system as a core
scaffold showed good inhibition of all the microorganisms
studied when compared to those with coumarin as a core
scaffold. However, with an exception, it will suffice to men-
tion here that coumarin derivatives with 1,3,4-thiadiazole
ring system were more or equally active than the quinolone
derivatives having 1,3,4-oxadiazole ring. Analogs with sin-
gle fluorine or trifluoromehthyl functional group were found
to be good antibacterial agents, while those involving
methoxy or trimethoxy functionality indicated good antifun-
gal properties.
1
to furnish the final Mannich bases 7i-10vi. All the IR, H
NMR spectral data of compounds 7i-10vi were in accor-
dance with assumed structures. The purity of the synthesized
compounds was monitored by TLC and ascertained by ele-
mental analysis.
Pharmacology
Several novel heterocyclic scaffolds were synthesized
and examined for their in vitro antimicrobial activities. The
bioassay results presented in Table 1 demonstrated that the
majority of the final analogs succeeded to indicate remark-
able activity against the mentioned microorganisms. From
the activity results it can be stated that 1,3,4-thiadiazole de-
rivatives were more active against majority of the microor-
ganism studied when compared to those of 1,3,4-oxadiazole
derivatives. Final analogs with trimethoxy benzyl piperazine
substituents either linked through quinolone (9vi) or cou-
marin (10vi) nucleus displayed excellent activity against
Gram-positive S. aureus at 3.12 ꢀg/mL of MIC. These ana-
logs were found more potent against the said bacteria than
the standard drugs ampicillin and gentamicina. In addition,
quinolone based 1,3,4-oxadiaazole analogs with highly elec-
tronegative terifluoromehtyl functional group linked to the
meta (7iii) or para-position (7iv) of the phenyl ring of
piperazine substituent indicated higher anti Gram-positive
activity against B. cereus at 6.25 ꢀg/mL of MIC, i.e. equipo-
tent to the standard drugs. 1,3,4-Oxadiazole (8i, 8ii) and
1,3,4-thiadizole (10i, 10ii) derivatives involving coumarin
nucleus and substitution of single fluorine atom at ortho and
para-position showed good inhibitory effects against Gram-
negative E. coli strain at 12.5 ꢀg/mL of MIC, the concentra-
tion was comparable to the standards. Final 1,3,4-thiadiazole
derivatives with trifluoromethyl functionality either at qui-
nolone (9ii, 9iv) or coumarin (10iii) ring system displayed
higher antibacterial activity (6.25 ꢀg/mL) than the standard
CONCLUSION
Novel 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives
involving condensation of different fluoro/methoxy
piperazines based on quinolone or coumarin nucleus have
been synthesized. Investigation of antimicrobial properties
showed that many compounds exhibited higher potency than
the standard drugs. In fact, some analogs were more active
against Gram-positive S. aureus and Gram-negative P. aeru-
ginosa at excellent MICs of 3.12-6.25 ꢀg/mL than the stan-
dard drugs ampicillin and gentamicina (6.25-25 ꢀg/mL),
however, many derivatives demonstrated equipotency to the
standard drugs. 1,3,4-thiadiazole analogs were found re-
markably potent when compared to 1,3,4-oxadiazoles, and
the activity may be due to the presence of sulphur atom in
the ring system. Many final analogs showed half fold activity
(MIC: 12.5-25 ꢀg/mL) in the antifungal bioassay. From the
results it can be stated that a combination of quinolone ring
with 1,3,4-thiadiazole ring system may lead to the improved
antimicrobial agents (variety of human pathogenic microor-
ganisms), however, other derivatives may also be optimized
to derive fruitful results. Hence, the mentioned scaffolds
provide a good starting point for further antimicrobial drug
discovery process. Other experiments on the optimization of
structural features of the presented analogs are underway in
our laboratory and the results will be derived soon.

484 Letters in Organic Chemistry, 2012, Vol. 9, No. 7
Table 1. In–vitro Antimicrobial Activity of 7i-10vi
Patel et al.
N N
S
N
N R
N N
N
N R
S
S
O
X
O
X
O
7i-vi, 8i-vi
9i-vi, 10i-vi
O
O
MIC in ꢀg/mL
Entry
7i
X
R
S.a
B.c
E.c
P.a
K.p
A.n
C.a
F
N-CH3
100
62.5
62.5
50
50
200
100
7ii
N-CH3
N-CH3
100
50
50
50
62.5
25
62.5
12.5
250
200
100
F
CF3
7iii
62.5
6.25
62.5
7iv
7v
N-CH3
N-CH3
25
50
6.25
25
12.5
100
25
50
50
CF3
100
100
250
12.5
62.5
OCH3
OCH3
OCH3
H3CO
H2
C
7vi
N-CH3
25
50
62.5
100
100
25
25
F
8i
8ii
8iii
O
O
O
200
100
50
200
100
62.5
12.5
12.5
62.5
50
25
50
100
62.5
100
250
200
100
250
250
500
F
CF3
8iv
8v
O
O
50
50
100
100
50
50
200
62.5
100
CF3
100
200
250
100
12.5
OCH3
H3CO
OCH3
H2
C
8vi
O
12.5
50
100
200
50
50
25
OCH3
F
9i
9ii
9iii
N-CH3
N-CH3
N-CH3
100
62.5
12.5
62.5
100
25
50
25
25
50
100
200
50
200
100
100
6.25
12.5
F
CF3
12..5
62.5
6.25
9iv
9v
N-CH3
N-CH3
6.25
25
25
50
50
6.25
6.25
50
62.5
CF3
100
50
100
12.5
25
OCH3

1,3,4-oxa/thiadiazoles as Potential Antimicrobials
Letters in Organic Chemistry, 2012, Vol. 9, No. 7
485
Table 1. contd….
MIC in ꢀg/mL
Entry
9vi
X
R
S.a
B.c
E.c
P.a
K.p
A.n
C.a
H3CO
OCH3
OCH3
H2
C
N-CH3
3.12
25
100
50
62.5
25
50
F
10i
10ii
10iii
O
O
O
50
50
200
200
25
12.5
12.5
50
25
25
62.5
62.5
25
200
250
100
100
100
50
F
CF3
12.5
6.25
10iv
10v
O
O
25
50
62.5
200
12.5
62.5
25
62.5
62.5
50
CF3
62.5
100
200
12.5
OCH3
H3CO
OCH3
H2
C
10vi
O
3.12
62.5
100
50
100
25
50
OCH3
Amp.
Gen.
12.5
6.25
12.5
6.25
6.25
12.5
25
25
25
-
-
12.5
-
6.25
-
-
12.5
-
Flu.
DMSO
-
-
-
-
-
Amp.: Ampicillin, Gen.:- Gentamicina, Flu.: Fluconazole
S.a - Staphylococcu aureus, B.c - Bacillus cereus, E.c - Escherichia coli, P.a - Pseudomonas aeruginosa, K.p - Klebsiella pneumoniae, A.n - Aspergillus niger, C.a - Candida albi-
cans.
United States, 1999–2005. Emerg. Infect. Dis., 2007, 13(12), 1840–
1846.
ACKNOWLEDGEMENTS
The authors are thankful to the Applied Chemistry
Department of S. V. National Institute of Technology, Surat
for the scholarship, encouragement and facilities. The
authors wish to offer their deep gratitude to Microcare
Laboratory, Surat, India for carrying out the biological
screenings. We are also thankful to the Center of Excellence,
Vapi, India for recording 1H NMR spectra.
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CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
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SUPPLEMENTARY INFORMATION
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