Synthesis and Antimicrobial Activity of 1,3,4-Oxadiazole-2(3H)-thione and Azidomethanone Derivatives Based on Quinoline-4-carbohydrazide Derivatives

Article abstract of DOI:10.1002/jhet.2529

A new series compounds of quinoline derivatives were synthesized by reaction of 3-(carboxymethyl)-2-arylquinoline-4-carboxylic acids 1a, 1b, 1c with different nucleophiles. The structures of the new compounds were elucidated on the basis of FTIR,¹

Full text of DOI:10.1002/jhet.2529

Month 2015
Synthesis and Antimicrobial Activity of 1,3,4-Oxadiazole-2(3H)-thione
and Azidomethanone Derivatives Based on Quinoline-
4-carbohydrazide Derivatives
*
Mansoura I. Mohamed, Nadia G. Kandile, and Howida T. Zaky
Department of Chemistry, Faculty of Women, Ain Shams University, Heliopolis, 11757 Cairo, Egypt
*
E-mail: mansouraismail@yahoo.com
Received May 28, 2015
DOI 10.1002/jhet.2529
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
A new series compounds of quinoline derivatives were synthesized by reaction of 3-(carboxymethyl)-2-
arylquinoline-4-carboxylic acids 1a–c with different nucleophiles. The structures of the new compounds
were elucidated on the basis of FTIR, 1H-NMR, 13C-NMR spectral data, GC/MS, and chemical analysis. In-
vestigation of antimicrobial activity of all new compounds was evaluated using a broth dilution technique in
terms of minimal inhibitory concentration count against four pathogenic bacteria and two pathogenic fungi.
Most of the new compounds were significantly active against bacteria and fungi.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
chlorobenzoylamino)-3-[2-(1H)-quinolinon-4-yl] propio-
nic acid) (1, Fig. 1) is a quinoline-derived compound act-
ing as efficient anti-gastric ulcer agent, the protective
effect of rebamipide is not only because of stimulating en-
dogenous prostaglandin in gastric mucosa but also because
of inhibiting oxygen-derived free radicals production. The
quinoline derivative 4-(arylamino)quinoline (2, Fig. 1)
inhibited the gastric (Hþ/Kþ)-ATPase, the enzyme respon-
sible for the secretion of acid into the gastric lumen.
Consequently, several research groups have synthesized
quinoline-based derivatives [including AU-461 (3, Fig. 1)
and AS-2646] as potential anti-ulcer agents [30].
The Pfitzinger reaction of isatins with α-methylidene
carbonyl compounds is used widely for the synthesis
of physiologically active derivatives of substituted
quinoline-4-carboxylic acids [25,26,31–34]. Herein, we re-
port a simple one-pot synthesis of quinoline-4-carboxylic
acid derivatives by an improved Pfitzinger reaction of
isatins with β-aroylpropionic acid and catalysts in aqueous
medium [35].
The quinoline nucleus is an important heterocyclic struc-
ture found in many synthetic and natural occurring products
with a wide range of pharmacological activities, such as
antiviral, anticancer, antibacterial, antifungal, anti-obesity,
and anti-inflammatory [1–8], which can be well illustrated
by the large number of commercially available drugs
containing the quinoline nucleus.
Recently, a number of new quinoline derivatives with
excellent antitumor activity have been reported [9–21].
Among them, 6,7-disubstituted-4-phenoxyquinoline deriva-
tives, which inhibit c-Met kinase, have attracted our attention.
In particular, the acridine family includes derivatives of
many pharmacologically significant compounds such as
actinomycin-D, daunomycin, adriamycin, and some of which
show the significant bioactivity of inhibiting topoisomerase
enzyme [22–24]. As one type of acridine compound, the
6,7-dihydrodibenzo[b,j] phenanthroline derivatives may be
of interesting biomedical use. The Pfitzinger reaction
[25,26] is probably a shortcut to obtain these derivatives,
yet there are few successful examples synthesized using
1,3-diketones and isatins via this reaction up to date, during
our investigation of synthetic methodologies [27–29].
Quinoline derivatives are versatile biodynamic agents
both from synthetic and natural origin. Rebamipide (2-(4-
RESULTS AND DISCUSSION
The synthesis of the target compounds was carried out as
outlined in Schemes 1 and 2. The versatile Pfitzinger
© 2015 HeteroCorporation

M. I. Mohamed, N. G. Kandile, and H. T. Zaky
Vol 000
Figure 1. Quinoline derivatives showing anti-ulcer activity.
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Antimicrobial Activity of 1,3,4-Oxadiazole-2(3H)-thione and
Azidomethanone Derivatives
reaction [25,35] was utilized to synthesize the
3-(carboxymethyl)-2-arylquinoline-4-carboxylic acids 1a–c
by reaction of isatin (indolin-2,3-dione) with β-aroylpropionic
acids under basic conditions as described in Scheme 1.
Treatment of compounds 1a–c with different nucleophilic
reagents such as acetyl chloride and methyl alcohol afforded
3-(carboxymethyl)-2-arylquinoline-4-carboxylic acid anhy-
drides 2a–c and half esters 2-[(4-methoxycarbonyl)-2-
arylquinolin-3-yl] acetic acids 6a–c, respectively. These
bands at δ 10.00 (t, 1H, NH of NHNH2), 8.89 (d, 2H, NH2
of NHNH2), 7.54–6.87 (m, 8H, 2Ar-H), 2.87 (s, 3H, CH3
of CH3-Ar), and 2.53 (s, 3H, CH3) ppm. As indicated in
Scheme 2, the title compounds named 5-(3-methyl-2-
phenylquinolin-4-yl)-1,3,4-oxadiazole-2(3H)-thione 11a,
5-[3-methyl-2-(p-tolyl)quinolin-4-yl]-1,3,4-oxadiazole-2(3H)-
thione 11b, (3-methyl-2-phenylquinolin-4-yl)azidomethanone
12a, and [3-methyl-2-(p-tolyl)quinolin-4-yl]azidomethanone
12b were prepared via reaction of 10a,b with carbon
disulfide and sodium azide, respectively. The 1H-NMR spec-
trum of 5-(3-methyl-2-phenylquinolin-4-yl)-1,3,4-oxadiazole-
2(3H)-thione 11a showed bands at δ 10.12 (s, 1H, NH),
7.21–6.99 (m, 9H, 2Ar-H), and 2.55 (s, 3H, CH3)ppm. The
structure of 11b was supported by its analytical and spectral
data. The IR spectrum shows disappearance of absorption of
NH2 group of the hydrazide. The structure of 12a was sup-
ported by its analytical and spectral data. The IR spectrum
shows disappearance of absorption of NH2 group of hydra-
zide, and the appearance of absorption peaks for N3 group
1
structures were established by FTIR, H-NMR, 13C-NMR,
1
mass spectral, and analytical data. The H-NMR spectrum
of compound 2[(4-methoxycarbonyl)-2-(4-methylphenyl)
quinolin-3-yl] acetic acid 6b showed bands at δ 11.12 (s,
1H, OH of COOH), 8.95–7.15 (m, 8H, 2Ar-H), 3.88 (s,
3H, COOCH3), 3.49 (s, 2H, CH2 of CH2COOH), and 2.35
(s, 3H, CH3 of CH3-Ar)ppm. The 13C-NMR spectrum of
compound 6b showed bands at δ 174.3, 166.2, 166.0,
151.4, 145.6, 136.3, 133.4, 129.3, 129.2, 128.7, 127.6,
127.4, 125.9, 123.8, 51.5, 35.2.
1
for azide. The H-NMR spectrum of [3-methyl-2-(p-tolyl)
Cyclization of 2-[(4-methoxycarbonyl)-2-phenylquino-
lin-3-yl] acetic acid 6a with fused sodium acetate in the
presence of acetic anhydride gave 5-acetoxymethylbenzo
[c] acridine-7-carboxylic acid 7. However, 3-
(carboxymethyl)-2-arylquinoline-4-carboxylic acids 1a–c
were reacted with fused sodium acetate in the presence of
acetic anhydride and yielded 3-alkylbenzo[c]acridin-5-yl
acetates 3a–c. These structures were confirmed by FTIR,
1H-NMR, mass spectral, and analytical data. The 1H-
NMR spectrum of compound 3-methoxybenzo[c]acridin-
5-yl acetate 3c showed bands at δ 7.82–7.12 (m, 8H,
3Ar-H), 5.78 (s, 1H, CH), 3.73 (s, 3H, OCH3 of CH3O-
Ar), and 2.08 (s, 3H, CH3 of COCH3)ppm. Accordingly,
the products 3-methyl-2-arylquinoline-4-carboxylic acids
4a–c were obtained by the reaction of 1a–c with nitroben-
zene. Moreover, the reaction of 1a with methyl alcohol
(2mole) gave the corresponding methyl-3-(2-methoxy-2-
oxoethyl)-2- phenylquinoline-4-carboxylate 5. This structure
was assigned by FTIR, 1H-NMR, mass spectral, and analyti-
quinolin-4-yl]azidomethanone 12b showed bands at δ 8.12–
7.15 (m, 8H, 2Ar-H), 2.75 (s, 3H, CH3 of CH3-Ar), and
2.32 (s, 3H, CH3) ppm. The synthetic route used to synthe-
size these compounds is outlined in Scheme 2.
CONCLUSION
A number of 2-arylquinoline derivatives were synthe-
sized and evaluated for antimicrobial activities against four
antibacterial such as E. coli (ATCC-25922) and K.
pneumoniae; Gram-positive S. aureus (ATCC-25923)
and S. epidermidis; and two antifungal such as C. albicans
and A. fumigatus. The investigation of the antimicrobial
revealed that all the synthesized compounds showed
strong in vitro antibacterial and moderate in vitro antifun-
gal activities. The susceptibility of the microorganisms to
the compounds on the basis of measuring the inhibition
zone diameters varied according to the stains used, but
globally, the highest inhibition zone diameters were re-
corded for compounds 6b, 10b, and 11b. Compounds
1c, 4c, and 8 had no antifungal effect, while compounds
1a, 1c, 2a, 2c, 3c, 4c, 6a, and 8 were completely inactive
against A. fumigatus only.
1
cal data. H-NMR spectrum of compound 5 showed bands
at δ 7.86–7.11 (m, 9H, 2Ar-H), 3.88 (s, 3H, CH3 of
COOCH3), 3.79 (s, 2H, CH2 of CH2COOCH3), and 3.27
(s, 3H, CH3 of CH2COOCH3) ppm as described in Scheme 1.
Fusion of 3-methyl-2-(p-tolyl)quinoline-4-carboxylic acid
4b with 3,5-dimethoxy-4-hydroxybenzaldehyde above their
melting point afforded 3-(4-hydroxy-3,5-dimethoxystyryl)-
2-(4-methylphenyl)quinolin-4-carboxylic acid 8. Esterifi-
cation of 4a,b by their reaction with ethyl alcohol in the
presence of a few drops of conc. H2SO4 gave ethyl-3-
methyl-2-arylquinoline-4-carboxylates 9a,b. The structures
3-methyl-2-phenylquinoline-4-carbohydrazide 10a and 3-
methyl-2-(4-methylphenyl)quinoline-4-carbohydrazide 10b
were confirmed by reaction of 9a,b with hydrazine hydrate
EXPERIMENTAL
All melting points are uncorrected and were determined
on a Gallenkamp instrument (General Scientific Instrument
Services Inc., London).
Infrared spectra were measured on a Perkin-Elmer spec-
trophotometer model 1430 (Perkin Elmer, Waltham , MA)
using potassium bromide pellets, and frequencies are
reported in cmꢀ1. The 1H-NMR and 13C-NMR were
measured on Varian Gemini-300 MHz spectrophotometer,
1
in ethyl alcohol. The H-NMR spectrum of 3-methyl-2-(4-
methylphenyl)quinoline-4-carbohydrazide 10b showed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. I. Mohamed, N. G. Kandile, and H. T. Zaky
Vol 000
and chemical shifts (δ) are in ppm. The mass spectra (m/z)
values were measured on mass spectrophotometer HP
model GC MS-QPL000EX (Shimadzu) at 70 eV. Elemen-
tal analyses were carried out at the Microanalytical Centre,
Cairo University. Antimicrobial activity evaluations were
carried out at the Basic Science Department, Faculty of
Applied Medical Science, October 6 University, October
City, Egypt.
2Ar-H) and 3.55 (s, 2H, CH2)ppm. Anal. Calcd for
C18H11NO3 (289.28): N, 4.84. Found: N, 5.10. MS (m/z):
288M+ ꢀ1.
3-(Carboxymethyl)-2-(4-methylphenyl)quinoline-4-carboxylic
acid anhydride 2b. Yellow solid, yield 94%, mp 170–171°C;
IR (KBr pellet): 1798, 1729 for (C¼O) and 1605 for (C¼N)
cmꢀ1.1H-NMR (DMSO, 300MHz) δ 8.00–6.99 (m, 8H,
2Ar-H), 3.43 (s, 2H, CH2), and 2.45 (s, 3H, CH3 of CH3-
Ar)ppm. Anal. Calcd for C19H13NO3 (303.31): C, 75.23;
H, 4.32; N, 4.62. Found: C, 75.60; H, 4.30; N, 4.80. MS
Preparation of 3-(carboxymethyl)-2-arylquinoline-4-carbo
xylic acids 1a,b [35],c.
β-aroylpropionic acid (0.04mole)
(m/z): 303M+.
was added to a solution of isatin (0.04mole) in 33%
ethanolic potassium hydroxide solution (100 mL) and
refluxed for about 12 h. The solution after cooling was
acidified by dilute hydrochloric acid then made just alkaline
with potassium hydroxide solution and finally acidified with
aqueous acetic acid.
The precipitate was collected and crystallized from ethyl
alcohol to give 1a–c.
3-(Carboxymethyl)-2-phenylquinoline-4-carboxylic acid 1a.
3-(Carboxymethyl)-2-(4-methoxyphenyl)quinoline-4-carboxy
lic acid anhydride 2c. Yellow solid, yield 85%, mp 198°C;
IR (KBr pellet): 1797, 1732 for (C¼O) and 1607 for
(C¼N) cmꢀ1.1H-NMR (DMSO, 300 MHz) δ 7.89–7.11
(m, 8H, 2Ar-H), 3.29 (s, 2H, CH2), and 3.04 (s, 3H,
OCH3 of CH3O-Ar) ppm. 13C-NMR (DMSO, 300 MHz)
δ 166.0, 165.0, 159.3, 150.8, 149.5, 145.9, 132.5, 128.6,
128.0, 127.9, 127.4, 124.5, 122.5, 114.8, 55.9, 32.0.
Anal. Calcd for C19H13NO4 (319.31): C, 71.46; H, 4.10;
N, 4.39. Found: C, 71.70; H, 4.30; N, 4.60. MS (m/z):
319 M+.
Pale yellow solid, yield 65%, mp 277°C; IR (KBr pellet):
3424, 3398 for (OH of COOH) group; 1670, 1664 for
(C¼O); and 1580 for (C¼N) cmꢀ1
.
1H-NMR (DMSO,
300MHz) δ 11.32–11.21 (s, 2H, 2OH of 2COOH), 8.08–
7.18 (m, 9H, 2Ar-H), and 3.49 (s, 2H, CH2)ppm. Anal.
Calcd for C18H13NO4 (307.29): C, 70.35; H, 4.26; N, 4.56.
Preparation of 3-alkylbenzo [c]acridin-5-yl acetates 3a,b
[35],c.
A mixture of 1a–c (0.02mole), fused sodium
acetate (2 g) and acetic anhydride (25 mL) was refluxed
for 5 h. The excess acetic anhydride was evaporated
under reduced pressure, and water was added. The solid
formed was treated with ether. The ether insoluble
fraction was crystallized from benzene to give 3a–c.
Benzo[c]acridin-5-yl acetate 3a. Pale yellow solid, yield
47%, mp 300°C; IR (KBr pellet): 1729 for (C¼O) and
Found: C, 70.80; H, 4.40; N, 4.50. MS (m/z): 307 M+.
3-(Carboxymethyl)-2-(4-methylphenyl)quinoline-4-carboxylic
acid 1b. Pale yellow solid, yield 62%, mp 264°C; IR (KBr
pellet): 3446, 3434 for (OH of COOH) group, 1668, 1658 for
C¼O, and 1579 for C¼Ncmꢀ1
.
1H-NMR (DMSO,
300 MHz) δ 11.05–10.86 (s, 2H, 2OH of 2COOH), 7.88–
7.08 (m, 8H, 2Ar-H), 3.29 (s, 2H, CH2), and 2.67 (s, 3H,
CH3 of CH3-Ar)ppm. 13C-NMR (DMSO, 300 MHz) δ
174.3, 169.4, 165.0, 150.8, 145.9, 137.0, 133.3, 132.5,
129.6, 127.9, 127.5, 127.4, 124.5, 122.5, 35.2, 24.3. Anal.
Calcd for C19H15NO4 (321.32): C, 71.02; H, 4.71; N, 4.36.
1554 for (C¼N)cmꢀ1
.
1H-NMR (DMSO, 300MHz) δ
7.87–7.12 (m, 9H, 3Ar-H), 5.99 (s, 1H, CH), and 2.34 (s,
3H, CH3 of COCH3) ppm. Anal. Calcd for C19H13NO2
(287.30): C, 79.43; H, 4.56; N, 4.88. Found: C, 79.90; H,
4.10; N, 4.50. MS (m/z): 287M+.
Found: C, 71.12; H, 5.30; N, 4.40. MS (m/z): 321 M+.
3-(Carboxymethyl)-2-(4-methoxyphenyl)quinoline-4-carbo
xylic acid 1c. Pale yellow solid, yield 60%, mp 260–261°C;
3-Methylbenzo[c]acridin-5-yl acetate 3b. Pale yellow solid,
yield 48%, mp 312°C; IR (KBr pellet): 1727 for (C¼O) and
1555 for (C¼N)cmꢀ1
.
1H-NMR (DMSO, 300 MHz) δ
7.86–7.02 (m, 8H, 3Ar-H), 6.00 (s, 1H, CH), 3.08 (s, 3H,
CH3 of COCH3), and 2.46 (s, 3H, CH3 of CH3-Ar) ppm.
13C-NMR (DMSO, 300 MHz) δ 169.0, 150.3, 148.8,
146.9, 136.4, 135.3, 134.5, 129.9, 129.0, 128.5, 128.3,
128.0, 127.3, 127.2, 127.0, 121.3, 118.5, 24.7, 20.3.
Anal. Calcd for C20H15NO2 (301.33): C, 79.71; H, 5.02;
N, 4.65. Found: C, 79.70; H, 5.00; N, 4.90. MS (m/z):
301 M+.
IR (KBr pellet): 3434, 3386 for (OH of COOH) group; 1663,
1652 for (C¼O); and 1608 for (C¼N)cmꢀ1
.
1H-NMR
(DMSO, 300MHz) δ 10.99-10.52 (s, 2H, 2OH of
2COOH), 8.00-6.99 (m, 8H, 2Ar-H), 3.55 (s, 2H, CH2), and
3.21 (s, 3H, OCH3 of CH3O-Ar)ppm. Anal. Calcd for
C19H15NO5 (337.32): C, 67.65; H, 4.48; N, 4.15. Found: C,
67.40; H, 4.30; N, 4.50. MS (m/z): 340M++2.
Preparation of 3-(carboxymethyl)-2-arylquinoline-4-car
boxylic acid anhydrides 2a,b [35],c. A mixture of 1a–c
(0.01 mole) and acetyl chloride (10 mL) was heated under
reflux for 3h. The reaction mixture after cooling was
filtered and crystallized from benzene to give 2a–c.
3-(Carboxymethyl)-2-phenylquinoline-4-carboxylic acid
3-Methoxybenzo[c]acridin-5-yl acetate 3c.
Pale yellow
solid, yield 48%, mp >312°C; IR (KBr pellet): 1726 for
(C¼O) and 1605 for (C¼N)cmꢀ1
.
1H-NMR (DMSO,
300 MHz) δ 7.82–7.12 (m, 8H, 3Ar-H), 5.78 (s, 1H, CH),
3.73 (s, 3H, OCH3 of CH3O-Ar), and 2.08 (s, 3H, CH3
of COCH3) ppm. Anal. Calcd for C20H15NO3 (317.33):
C, 75.69; H, 4.76; N, 4.41. Found: C, 75.70; H, 4.76; N,
4.70. MS (m/z): 316M+ ꢀ 1.
anhydride 2a.
Yellow solid, yield 66%, mp 170°C; IR
(KBr pellet):1807, 1750 for (C¼O) and 1629 for (C¼N)
cmꢀ1.1H-NMR (DMSO, 300MHz) δ 7.99–7.00 (m, 9H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Antimicrobial Activity of 1,3,4-Oxadiazole-2(3H)-thione and
Azidomethanone Derivatives
Preparation of 3-methyl-2-arylquinoline-4-carboxylic acids
4a,b [35],c.
2[(4-Methoxycarbonyl)-2-phenylquinolin-3-yl] acetic acid
6a. Pale yellow solid, yield 70%, mp 150–152°C; IR
A mixture of 1a–c (1 g) was refluxed in
nitrobenzene (20 mL) for 1 h. The solid product separated
on cooling at room temperature was filtered off and
crystallized from benzene to give 4a–c.
(KBr pellet): 3426 for (OH of carboxylic acid), 1730 for
(C¼O of ester), 1692 for (C¼O of acid), and 1651 for
(C¼N)cmꢀ1
.
1H-NMR (DMSO, 300MHz) δ 11.00 (s,
3-Methyl-2-phenylquinoline-4-carboxylic acid 4a.
Pale
1H, OH of COOH), 7.99–7.27 (m, 9H, 2Ar-H), 3.88 (s,
3H, CH3 of COOCH3), and 3.49 (s, 2H, CH2 of
CH2COOCH) ppm. Anal. Calcd for C19H15NO4 (321.32):
C, 71.02; H, 4.71; N, 4.36. Found: C, 70.92; H, 4.58; N,
green solid, yield 50%, mp 299°C; IR (KBr pellet): 3425
for (OH of carboxylic acid), 1675 for (C¼O), and 1617
1
for (C¼N) cmꢀ1. H-NMR (DMSO, 300MHz) δ 11.00
4.54. MS (m/z): 323M+ + 2.
(s, 1H, OH of COOH), 7.78–7.02 (m, 9H, 2Ar-H), and
2.32 (s, 3H, CH3)ppm. Anal. Calcd for C17H13NO2
(263.28): C, 77.55; H, 4.98; N, 5.32. Found: C, 77.90; H,
2[(4-Methoxycarbonyl)-2-(4-methylphenyl)quinolin-3-yl]
acetic acid 6b. Pale yellow solid, yield 65%, mp 135–
137°C; IR (KBr pellet): 3389 for (OH of carboxylic acid),
5.40; N, 5.00. MS (m/z): 264M+ +1.
3-Methyl-2-(4-methylphenyl)quinoline-4-carboxylic acid 4b.
Pale green solid, yield 62%, mp 295–296°C; IR (KBr
pellet): 3425 for (OH of carboxylic acid), 1680 for
1726 for (C¼O of ester), 1686 for (C¼O of acid), and
1632 for (C¼N)cmꢀ1
.
1H-NMR (DMSO, 300MHz) δ
11.12 (s, 1H, OH of COOH), 8.95–7.15 (m, 8H, 2Ar-H),
3.88 (s, 3H, COOCH3), 3.49 (s, 2H, CH2 of CH2COOH),
and 2.35 (s, 3H, CH3 of CH3-Ar)ppm. 13C-NMR (DMSO,
300MHz) δ 174.3, 166.2, 166.0, 151.4, 145.6, 136.3,
133.4, 129.3, 129.2, 128.7, 127.6, 127.4, 125.9, 123.8,
51.5, 35.2. Anal. Calcd for C20H17NO4 (335.35): C, 71.63;
H, 5.11; N, 4.18. Found: C, 71.42; H, 4.88; N, 4.54. MS
(C¼O), and 1614 for (C¼N) cmꢀ1
.
1H-NMR (DMSO,
300 MHz) δ 10.98 (s, 1H, OH of COOH), 7.89–7.22
(m, 8H, 2Ar-H), 3.35 (s, 3H, CH3 of CH3-Ar), and
2.32 (s, 3H, CH3) ppm. Anal. Calcd for C18H15NO2
(277.31): C, 77.96; H, 5.45; N, 5.05. Found: C, 77.90;
H, 5.40; N, 5.00. MS (m/z): 278 M+ + 1.
3-Methyl-2-(4-methoxyphenyl) quinoline-4-carboxylic acid
(m/z): 336M+ +1.
4c.
Pale green solid, yield 50%, mp 290–291°C; IR
2[(4-Methoxycarbonyl)-2-(4-methoxyphenyl)quinolin-3-yl]
acetic acid 6c. Pale yellow solid, yield 65%, mp 143–
145°C; IR (KBr pellet): 3377 for (OH of carboxylic
(KBr pellet): 3426 for (OH of carboxylic acid), 1662 for
(C¼O), and 1607 for (C¼N) cmꢀ1
.
1H-NMR (DMSO,
300 MHz) δ 11.02 (s, 1H, OH of COOH), 8.21–7.12
(m, 8H, 2Ar-H), 3.75 (s, 3H, OCH3 of CH3O-Ar), and
2.33 (s, 3H, CH3) ppm. 13C-NMR (DMSO, 300 MHz) δ
169.4, 165.0, 159.3, 150.8, 145.9, 132.0, 128.6, 128.0,
127.9, 127.4, 124.5, 122.5, 114.8, 55.9, 11.3. Anal.
Calcd for C18H15NO3 (293.31): C, 73.70; H, 5.15; N,
4.77. Found: C, 73.90; H, 5.40; N, 5.00. MS (m/z):
293 M+.
acid), 1716 for (C¼O of ester), 1686 for (C¼O of
acid), and 1620 for (C¼N) cmꢀ1
.
1H-NMR (DMSO,
300 MHz) δ 11.6 (s, 1H, OH of COOH), 8.15–7.01 (m,
8H, 2Ar-H), 3.67 (s, 3H, COOCH3), 3.59 (s, 2H, CH2
of CH2COOH), and 3.43 (s, 3H, OCH3 of CH3O-Ar)
ppm. Anal. Calcd for C20H17NO5 (351.35): C, 68.36;
H, 4.88; N, 3.99. Found: C, 68.42; H, 4.86; N, 4.14.
MS (m/z): 351 M+.
Preparation of methyl-3-(2-methoxy-2-oxoethyl)-2-phe
nylquinoline-4-carboxylate 5. A mixture of 1a (0.01mole)
was refluxed in methyl alcohol (0.02mole) for 3h. The
reaction mixture was evaporated under reduced pressure,
and the solid product was filtered off and crystallized from
benzene to give 5.
Preparation of 5-acetoxymethylbenzo[c]acridine-7-carbo-
xylic acid 7. A mixture of 6a (0.02 mole), fused sodium
acetate (2 g) and acetic anhydride (25 mL) was refluxed
for 5 h. The excess acetic anhydride was evaporated
under reduced pressure, and water was added. The solid
formed was crystallized from benzene to give 7.
Methyl-3-(2-methoxy-2-oxoethyl)-2-phenylquinoline-4-carbo
5-Acetoxymethylbenzo[c]acridine-7-carboxylic acid 7. Yellow
xylate 5.
Pale yellow solid, yield 55%, mp 102°C; IR
solid, yield 45%, mp 135–137°C; IR (KBr pellet):
1
1730–1689 for (C¼O) and 1620 for (C¼N) cmꢀ1. H-
(KBr pellet): 1736–1720 for (C¼O) and 1617 for (C¼N)
cmꢀ1.1H-NMR (DMSO, 300MHz) δ 7.86–7.11 (m, 9H,
2Ar-H), 3.88 (s, 3H, CH3 of COOCH3), 3.79 (s, 2H, CH2
of CH2COOCH3), and 3.67 (s, 3H, CH3 of CH2COOCH3)
ppm. Anal. Calcd for C20H17NO4 (335.35): C, 71.63; H,
5.11; N, 4.18. Found: C, 71.90; H, 5.40; N, 4.52. MS (m/z):
336M+.
Preparation of 2-[(4-methoxycarbonyl)-2-arylquinolin-3-
yl] acetic acids 6a–c. A mixture of 2a–c (0.01 mole) was
refluxed in methyl alcohol (0.01 mole) for 3 h. The
reaction mixture was evaporated under reduced pressure,
and the solid product was filtered off and crystallized
from benzene to give 6a-c.
NMR (DMSO, 300 MHz) δ 8.05–7.21 (m, 9H, 3Ar-H),
3.51 (s, 3H, CH3 of COOCH3), and 2.49 (s, 3H, CH3
of OCOCH3) ppm. Anal. Calcd for C21H15NO4
(345.34): C, 73.03; H, 4.38; N, 4.06. Found: C, 73.23;
H, 4.58; N, 4.23. MS (m/z): 345 M+.
Preparation of 3-(4-hydroxy-3,5-dimethoxystyryl)-2-(4-
methylphenyl)quinolin-4-carboxylic acid 8. Fusion of 4b
(0.01 mole) with 3, 5-dimethoxy-4-hydroxybenzaldehyde
(0.01 mole) for 2h above their melting point. The solid
product obtained was crystallized from benzene to give 8.
3-(4-Hydroxy-3,5-dimethoxystyryl)-2-(4-methylphenyl)quino
lin-4-carboxylic acid 8. Pale yellow solid, yield 56%, mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. I. Mohamed, N. G. Kandile, and H. T. Zaky
Vol 000
Ethyl-3-methyl-2-(4-methylphenyl)quinoline-4-carboxylate
9b. Pale yellow solid, yield 80%, mp 150–152°C; IR
270–272°C; IR (KBr pellet): 3440 for (OH of carboxylic
acid), 3133 for (OH of phenol), 1675 for (C¼O), and
1602 for (C¼N) cmꢀ1
.
1H-NMR (DMSO, 300 MHz) δ
(KBr pellet): 1725 for (C¼O of ester) and 1600 for
1
(C¼N) cmꢀ1. H-NMR (DMSO, 300 MHz) δ 7.75– 6.98
11.00 (s, 1H, OH of COOH), 8.13–7.02 (m, 10H, 3Ar-
H), 5.99–5.67 (d, 2H, CH¼CH), 5.21 (s, 1H, OH), 3.78–
3.53 (s, 6H, 2OCH3 of 2CH3O-Ar), and 2.35 (s, 3H, CH3
of CH3-Ar) ppm. Anal. Calcd for C27H23NO5 (441.46): C,
73.45; H, 5.25; N, 3.17. Found: C, 73.65; H, 5.03; N,
(m, 8H, 2Ar-H), 3.76 (q, 2H, CH2 of –CH2CH3), 2.88
(t, 3H, CH3 of –CH2CH3), 2.52 (s, 3H, CH3), and 2.26
(s, 3H, CH3 of CH3-Ar) ppm. 13C-NMR (DMSO,
300 MHz) δ 166.2, 166.0, 151.4, 145.6, 137.0, 133.4,
133.3, 129.6, 129.3, 129.2, 128.7, 127.5, 125.9, 123.8,
60.9, 24.3, 14.1, 11.3. Anal. Calcd for C20H19NO2
(305.37): C, 78.66; H, 6.27; N, 4.59. Found: C, 78.54;
H, 6.78; N, 4.83. MS (m/z): 305 M+.
3.42. MS (m/z): 439 M+ ꢀ2.
Preparation of ethyl-3-methyl-2-arylquinoline-4-carboxy
lates 9a,b. A mixture of 4a,b (0.01mole) was refluxed in
ethyl alcohol in the presence of a few drops of conc.
sulfuric acid for 3h. The reaction mixture was evaporated
under reduced pressure, and the solid product was washed
with water, filtered off, and crystallized from benzene to
give 9a,b.
Preparation of 3-methyl-2-arylquinoline-4-carbohydrazides
10a,b.
A mixture of 9a,b (0.01mole) and hydrazine
hydrate (0.02mole) was refluxed in ethyl alcohol (20mL)
for 3h. The reaction mixture was evaporated under reduced
pressure. After cooling, the resulting solid was filtered,
dried, and recrystallized from benzene to give 10a,b.
Ethyl-3-methyl-2-phenylquinoline-4-carboxylate 9a.
Pale
yellow solid, yield 78%, mp 176–178°C; IR (KBr pellet):
1
1712 for (C¼O of ester) and 1607 for (C¼N)cmꢀ1. H-
3-Methyl-2-phenylquinoline-4-carbohydrazide 10a.
Pale
NMR (DMSO, 300 MHz) δ 7.99–7.05 (m, 9H, 2Ar-H), 3.53
(q, 2H, CH2 of –CH2CH3), 2.76 (t, 3H, CH3 of –CH2CH3),
and 2.35 (s, 3H, CH3)ppm. Anal. Calcd for C19H17NO2
(291.34): C, 78.32; H, 5.88; N, 4.81. Found: C, 78.62; H,
5.91; N, 5.00. MS (m/z): 291 M+.
brown solid, yield 56%, mp 302°C; IR (KBr pellet): 3360
for (NH), 3215–3198 for (NH2), 1665 for (C¼O), and
1607 for (C¼N)cmꢀ1
.
1H-NMR (DMSO, 300MHz) δ
10.43 (t, 1H, NH of NHNH2), 9.10 (d, 2H, NH2 of
NHNH2), 7.22–6.69 (m, 9H, 2Ar-H), and 2.35 (s, 3H,
Table 1
Antimicrobial activity of compounds 1a to 12b.
Inhibition zone diameter (mm)
Escherichia
coli
Klebsiella
pneumoniae
Staphylococcus
aureus
Staphylococcus
epidermidis
Aspergillus
fumigatus
Candida
albicans
Compounds (50 μg/mL)
1a
1b
1c
2a
2b
2c
3a
3b
3c
4b
4c
5
6a
6b
7
8
9a
9b
10b
11a
11b
12a
12b
19
21
21
20
23
19
18
21
20
20
20
17
18
24
21
21
19
21
28
21
25
21
21
27
—
14
15
13
15
14
13
13
13
14
13
14
13
15
16
13
13
13
14
16
15
16
15
16
22
—
16
18
18
18
19
16
14
18
17
19
18
14
15
20
16
18
17
19
21
19
20
18
20
25
—
15
16
15
16
16
16
13
15
16
14
14
13
13
15
16
14
16
14
19
17
16
16
14
25
—
Negative
13
14
Negative
12
11
Negative
Negative
12
Negative
11
12
Negative
10
Negative
10
Negative
12
11
Negative
11
15
11
14
14
14
12
Negative
15
12
15
12
Negative
13
12
15
10
14
11
10
—
21
15
17
12
16
12
14
—
24
Tetracycline (30 μg/mL)
Fluconazole (10 μg/mL)
Negative, no inhibition up to 100 μg/well.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Antimicrobial Activity of 1,3,4-Oxadiazole-2(3H)-thione and
Azidomethanone Derivatives
5-(3-Methyl-2-(4-methylphenyl)quinolin-4-yl)-1,3,4-oxadiazole-
2(3H)-thione 11b. Pale yellow solid, yield 56%, mp 282–
CH3)ppm. Anal. Calcd C17H15N3O (277.32): C, 73.62; H,
5.45; N, 15.16; Found: C, 73.99; H, 5.45; N, 14.98. MS
(m/z): 277M+.
284°C; IR (KBr pellet): 3396 for NH, 1647 for (C–O),
1
1600–1594 for (2C¼N), and 1252 for (C¼S)cmꢀ1. H-
3-Methyl-2-(4-methylphenyl)quinoline-4-carbohydrazide 10b.
Pale brown solid, yield 60%, mp 220°C; IR (KBr pellet)
NMR (DMSO, 300MHz) δ 9.87 (s, 1H, NH), 7.57–6.83
(m, 8H, 2Ar-H), 2.72 (s, 3H, CH3 of CH3-Ar), and 2.47 (s,
3H, CH3)ppm. Anal. Calcd for C19H15N3OS (333.34): N,
3343 for (NH), 3210–3185 for (NH2), 1676 for (C¼O),
1
and 1602 for (C¼N) cmꢀ1. H-NMR (DMSO, 300MHz)
12.61; S, 9.60. Found: N, 13.00; S, 9.31. MS (m/z): 333M+.
Preparation of (3-methyl-2-arylquinolin-4-yl)azidomethanone
12a,b. To a cooled solution of 3-methyl-2-arylquinoline
δ 10.00 (t, 1H, NH of NHNH2), 8.89 (d, 2H, NH2 of
NHNH2), 7.54–6.87 (m, 8H, 2Ar-H), 2.87 (s, 3H, CH3 of
CH3-Ar), and 2.53 (s, 3H, CH3) ppm. Anal. Calcd for
C18H17N3O (291.35): C, 74.20; H, 5.88; N, 14.43. Found:
C, 73.85; H, 5.92; N, 14.76. MS (m/z): 291M+.
carbohydrazides 10a,b (0.01 mole) in 1.25 N HCl (20 mL)
was added sodium nitrite solution (0.01mole) at 0–5°C
for 30min with stirring. The reaction mixture was kept for
2 h at room temperature, diluted with water, and filtered.
The solid product obtained was dried and crystallized
from benzene to give 12a,b.
Preparation of 5-(3-methyl-2-arylquinolin-4-yl)-1,3,4-oxa
diazole-2(3H)-thione 11a,b.
A mixture of 10a,b with
carbon disulfide was refluxing in dry pyridine for 5 h, the
reaction mixture was evaporated under reduced pressure,
treated with dil. HCl and was washed with water. The
solid product formed was crystallized with benzene to
(3-Methyl-2-phenylquinolin-4-yl)azidomethanone 12a. Yellow
solid, yield 60%, mp 320°C; IR (KBr pellet): 2053 for
(N3), 1675 for (C¼O) and 1603 for (C¼N) cmꢀ1. Anal.
Calcd for C17H12N4O (288.31): C, 70.82; H, 4.20; N,
19.44. Found: C, 71.02; H, 4.26; N, 19.85. MS (m/z):
give 11a,b.
5-(3-Methyl-2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2(3H)-
thione 11a. Yellow solid, yield 55%, mp 278°C; IR (KBr
287 M+ ꢀ1.
pellet): 3356 for NH, 1659 for (C–O), 1613–1604 for
1
(2C¼N), and 1252 for (C¼S) cmꢀ1. H-NMR (DMSO,
(3-Methyl-2-(4-methylphenyl)quinolin-4-yl)azidomethanone
12b. Yellow solid, yield 60%, mp 308–309°C; IR (KBr
300 MHz) δ 10.12 (s, 1H, NH), 7.21–6.99 (m, 9H, 2Ar-
H), and 2.55 (s, 3H, CH3) ppm. Anal. Calcd for
C18H13N3OS (319.31): C, 67.70; H, 4.10; N, 13.16.
Found: C, 67.65; H, 4.53; N, 13.42. MS (m/z): 318 M+ ꢀ1.
pellet): 2038 for (N3 azide), 1653 for (C¼O), and 1607
1
for (C¼N) cmꢀ1. H-NMR (DMSO, 300 MHz) δ 8.12–
7.15 (m, 8H, 2Ar-H), 2.75 (s, 3H, CH3 of CH3-Ar), and
Table 2
MIC (μg/mL) results of compounds 1a to 12b.
MIC values (μg/mL)
Escherichia
coli
Klebsiella
pneumoniae
Staphylococcus
aureus
Staphylococcus
epidermidis
Aspergillus
fumigatus
Candida
albicans
Compounds
1a
1b
1c
2a
2b
2c
3a
3b
3c
4b
4c
10
15
10
10
5
15
15
20
15
15
20
20
15
20
15
15
20
15
10
10
10
15
10
5
15
15
10
10
15
15
15
15
15
15
10
15
15
10
10
10
15
10
5
15
15
10
10
15
15
15
15
15
15
15
15
15
10
10
10
15
10
5
—
20
—
—
15
—
15
15
—
20
—
20
—
15
20
—
20
15
10
20
10
20
15
15
15
—
15
15
10
15
15
10
20
—
15
20
15
20
—
20
15
10
20
10
20
15
15
15
15
15
15
15
15
15
10
10
10
15
10
5
5
6a
6b
7
8
9a
9b
10b
11a
11b
12a
12b
15
5
15
10
15
10
15
10
15
5
15
10
15
10
15
10
MIC, minimum inhibitory concentration.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. I. Mohamed, N. G. Kandile, and H. T. Zaky
Vol 000
2.32 (s, 3H, CH3) ppm. Anal. Calcd for C18H14N4O
(302.34): C, 71.50; H, 4.67; N, 18.54. Found: C, 71.75;
H, 4.89; N, 18.82. MS (m/z): 302 M+.
Minimum inhibitory concentration is defined as the low-
est concentration of an antimicrobial that will inhibit visi-
ble growth after definite period of incubation [39]. It is
considered a standard for determining the susceptibility
of microorganisms to different compounds.
The microdilution assay gave MIC values ranging from
5 to 25 μg/mL. From Table 2, it was found that MICs for
the bacterial strains were ranging from 5 to 20 μg/mL,
while that for the fungal strains were ranging from 10 to
20 μg/mL. Compound 10b was found to have a broad anti-
microbial spectrum with MIC 5 μg/mL for bacteria and
10 μg/mL for fungi.
Biological activity evaluation.
The synthesized
compounds were screened for their antibacterial and
antifungal activities using the agar well diffusion technique
[36]. The microorganisms (reference and clinical isolates)
used include Gram-negative Escherichia coli (ATCC-25922)
and Klebsiella pneumoniae; Gram-positive Staphylococcus
aureus (ATCC-25923) and Staphylococcus epidermidis;
and Candida albicans and Aspergillus fumigatus.
For the antibacterial assay, a standard inoculum
(105CFU/mL) was distributed on the surface of sterile nu-
trient agar plates by a sterile glass spreader. While for the
antifungal assay, a loopful of a particular fungal strain
was transferred to a 3-mL saline to obtain a suspension of
the corresponding species, 0.1 mL of the spore suspension
was distributed on the surface of sterile Sabouraud dex-
trose agar plats.
Acknowledgments. The authors are indebted to Dr. Nashwa A.
Ahmed, Basic Science Department, Faculty of Applied Medical
Science, October City, Egypt, for his help with antimicrobial
activity measurements. The authors alone are responsible for the
content and writing of the article.
DECLARATION OF INTEREST
A 6-mm diameter well was punched in the agar media
and filled with 100 μL of (500 μg/mL in DMSO) the tested
chemical compounds previously sterilized through 0.45
sterile membrane filter [37]. The plates were kept at room
temperature for 1 h and then incubated at 37°C for 24h
for bacteria and 30°C for 4 days for fungi. The antimicro-
bial activities were evaluated by measuring the inhibition
zone diameters. Commercial antibiotic discs were used as
positive reference standard to determine the sensitivity of
the strains; see Table 1.
The authors confirm that this article contents has no con-
flict of interest.
REFERENCES AND NOTES
[1] De Souza, M. V.; Pais, K. C.; Kaiser, C. R.; Peralta, M. A.; de
Ferreira, M. L.; Louren o, M. C. Bioorg Med Chem 2009, 17, 1474.
[2] Font, M.; Monge, A.; Ruiz, I.; Heras, B. Drug Des Discovery
1997, 14, 259.
[3] Nakamura, T.; Oka, M.; Aizawa, K.; Soda, H.; Fukuda, M.;
Terashi, K.; Ikeda, K.; Mizuta, Y.; Noguchi, Y.; Kimura, Y.; Tsuruo, T.;
Kohno, S. Biochem Biophys Res Commun 1999, 255, 618.
[4] Kaminsky, D.; Meltzer, R. I. J Med Chem 1968, 11, 160.
[5] Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.; Niedbala, H.;
Podeszwa, B.; Palka, A.; Majerz-Maniecka, K.; Oleksyn, B.; Polanski, J.
Bioorg Med Chem 2006, 14, 3592.
[6] Warshakoon, N. C.; Sheville, J.; Bhatt, R. T.; Ji, W.; Mendez-
Andino, J. L.; Meyers, K. M.; Kim, N.; Wos, J. A.; Mitchell, C.; Paris, J. L.;
Pinney, B. B.; Reizes, O.; Hu, X. E. Bioorg Med Chem Lett 2006, 16, 5207.
[7] Sloboda, A. E.; Powell, D.; Poletto, J. F.; Pickett, W. C.;
Gibbons, J. J.; Bell, D. H.; Oronsky, A. L.; Kerwar, S. S. J Rheumatol
1991, 18, 855.
[8] Insuasty, B.; Montoya, A.; Becerra, D.; Quiroga, J.; Abonia, R.;
Robledo, S.; Vélez, I. D.; Upegui, Y.; Nogueras, M.; Cobo, J. Eur J Med
Chem 2013, 67, 252.
[9] Zillhardt, M.; Park, S. M.; Romero, I. L.; Sawada, K.; Montag, A.;
Krausz, T.; Yamada, S. D.; Peter, M. E.; Lengyel, E. Clin Cancer Res
2011, 17, 4042.
[10] Yakes, F. M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y. C.; Yu,
P. W.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird,
A. D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y. C.; Joly, A. H. Mol Cancer
Ther 2011, 10, 2298.
[11] Mannion, M.; Raeppel, S.; Claridge, S.; Zhou, N.; Saavedra, O.;
Isakovic, L.; Zhan, L. J.; Gaudette, F.; Raeppel, F.; Déziel, R.; Beaulieu, N.;
Nguyen, H.; Chute, I.; Beaulieu, C.; Dupont, I.; Robert, M. F.; Lefebvre, S.;
Dubay, M.; Rahil, J.; Wang, J.; Croix, H. S.; Macleod, A. R.; Besterman, J. M.;
Vaisburg, A. Bioorg Med Chem Lett 2009, 19, 6552.
[12] Norman, M. H.; Liu, L. B.; Lee, M.; Xi, N.; Fellows, I.;
D’Angelo, N. D.; Dominguez, C.; Rex, K.; Bellon, S. F.; Kim, T. S.;
Dussault, I. J Med Chem 2012, 55, 1858.
Determination of minimum inhibitory concentration of the
synthesized compounds. Compounds inhibiting the growth
of one or more of the aforementioned microorganisms were
further tested for their minimum inhibitory concentration
(MIC) and were determined by the broth dilution
technique [38]. The nutrient broth and the yeast extract
broth media, which contained 1 mL of different
concentrations of the tested compounds (5, 10, 15, 20,
25 μg/mL), were inoculated with the microbial strains,
the bacterial cultures were incubated for 24 h at 37°C,
while the fungal ones were incubated at 30°C for 48 h.
The growth was monitored spectrophotometrically. The
lowest concentration required to arrest the microbial
growth was regarded as MICs and is given in Table 2.
The investigation of the antimicrobial screening data
in Table 1 revealed that all the synthesized compounds
showed strong in vitro antibacterial and moderate
in vitro antifungal activities. The susceptibility of the
microorganisms to the compounds on the basis of
measuring the inhibition zone diameters varied according
to the stains used, but globally, the greatest inhibition
zone diameters were recorded for compounds 6b, 10b,
and 11b. Compounds 1c, 4c, and 8 have no antifungal
effect, while compounds 1a, 1c, 2a, 2c, 3c, 4c, 6a, and 8
were completely inactive against A. fumigatus only.
[13] D’Angelo, N. D.; Bellon, S. F.; Booker, S. K.; Cheng, Y.;
Coxon, A.; Dominguez, C.; Fellows, I.; Hoffman, D.; Hungate, R.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Antimicrobial Activity of 1,3,4-Oxadiazole-2(3H)-thione and
Azidomethanone Derivatives
[25] Pfitzinger, W. J Prakt Chem 1886, 33, 100.
[26] Shvekhgeimer, M. G. A. Chem Heterocycl Compd 2004,
40, 257.
[27] Lv, Q. H.; Fang, L. Z.; Wang, P. F.; Lu, C. J.; Yan, F. L. Het-
erocycles 2012, 85, 1457.
[28] Lv, Q. H.; Fang, L. Z.; Wang, P. F.; Lu, C. J.; Yan, F. L.
Monatsh Chem 2013, 144, 391.
[29] Fang, L. Z.; Ma, J. S.; Lu, C. J.; Li, H. H.; Yang, X. O. Hetero-
cycles 2014, 89, 209.
[30] Sashidhara, K. V.; Avula, S. R.; Mishra, V.; Palnati, G. R.;
Singh, L. R.; Singh, N.; Chhonker, Y. S.; Swami, P.; Bhatta, R. S.;
Palit, G. Eur J Med Chem 2015, 89, 638.
[31] Eastland, G.; Prous, J.; Castacer, J. Drugs Future 1988, 13, 13.
[32] Dejmek, L. Drugs Future 1990, 15, 126.
[33] Giardina, G. A. M.; Raveglia, L. F.; Grugni, M.; Sarau, H. M.;
Farina, C.; Medhurst, A. D.; Graziani, D.; Schmidt, D. B.; Rigolio, R.;
Luttmann, M.; Cavagnera, S.; Foley, J. J.; Vecchietti, V.; Hay, D. W. P.
J Med Chem 1999, 42, 1053.
[34] Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.;
Baguley, B. C.; Denny, W. A. Bioorg Med Chem 2000, 8, 977.
[35] El-Abbady, A. M.; Omara, M. A.; Kandil, N. G. Rev Roum
Chim 1973, 18, 899.
[36] Ahmad, S.; Rathish, I. G.; Bano, S.; Alam, M. S.; Javed, K.
J Enzyme Inhib Med Chem 2010, 25, 266.
[37] Tadeg, H.; Mohammed, E.; Asres, K.; Gebre-Mariam, T. J.
Ethnopharmacol 2005, 100, 168.
[38] Karthikeyan, S. M.; Prasad, J. D.; Mahalinga, M.; Holla, S. B.;
Kumari, S. B. Eur J Med Chem 2008, 43, 25.
Lefko, P. K.; Lee, M. R.; Li, C.; Liu, L. B.; Rainbeau, E.; Reider, P. J.;
Rex, K.; Siegmund, A.; Sun, Y. X.; Tasker, A. S.; Xi, N.; Xu, S. M.;
Yang, Y. J.; Zhang, Y. H.; Burgess, T. L.; Dussault, I.; Kim, T. S. J
Med Chem 2008, 51, 5766.
[14] Kung, P. P.; Funk, L.; Meng, J.; Alton, G.; Padrique, E.;
Mroczkowski, B. Eur J Med Chem 2008, 43, 1321.
[15] Liu, X. D.; Newton, R. C.; Scherle, P. A. Trends Mol Med
2009, 16, 1471.
[16] Kataoka, Y.; Mukohara, T.; Tomioka, H.; Funakoshi, Y.;
Kiyota, N.; Fujiwara, Y.; Yashiro, M.; Hirakawa, K.; Hirai, M.;
Minami, H. Invest New Drugs 2012, 30, 1352.
[17] Cecchi, F.; Rabe, D. C.; Bottaro, D. P. Eur J Cancer 2010, 46, 1260.
[18] Qian, F.; Engst, S.; Yamaguchi, K.; Yu, P.; Won, K. A.;
Mock, L.; Lou, T.; Tan, J.; Li, C.; Tam, D.; Lougheed, J.; Yakes, F. M.;
Bentzien, F.; Xu, W.; Zaks, T.; Wooster, R.; Greshock, J.; Joly, A. H. Cancer
Res 2009, 69, 8009.
[19] González-Sánchez, I.; Solano, J. D.; Loza-Mejía, M. A.;
Olvera-Vázquez, S.; Rodríguez-Sotres, R.; Morán, J.; Lira-Rocha, A.;
Cerbón, M. A. Eur J Med Chem 2011, 46, 2102.
[20] Abonia, R.; Insuasty, D.; Castillo, J.; Insuasty, B.; Quiroga, J.;
Nogueras, M.; Cobo, J. Eur J Med Chem 2012, 57, 29.
[21] Ai, Y.; Liang, Y. J.; Liu, J. C.; He, H. W.; Chen, Y.; Tang, C.;
Yang, G. Z.; Fu, L. W. Eur J Med Chem 2012, 47, 206.
[22] Dzierzbicka, K.; Kolodziejczyk, A. M. L.; Wysocka-Skrzela, B.;
Mysliwski, A.; Sosnowska, D. J Med Chem 2001, 44, 3606.
[23] Dzierzbicka, K.; Kolodziejczyk, A. M. J Med Chem 2003, 46, 183.
[24] Ravi, H.; Padma, T.; Mayur, C. Y.; Gowdahalli, K.;
Kuntebommanahalli, N. T.; Peter, J. H.; Yerigeri, M. Eur J Med Chem
2004, 39, 161.
[39] Andrews, J. M. J Antimicrob Chemother 2001, 48, 5.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet