Microwave activated solid support synthesis of new antibacterial quinolones

Article abstract of DOI:10.1007/s007060070029

A novel synthesis of 6-fluoro-7-(5-aryl-1,3,4-thiadiazol/oxadiazol-2-yl-sulfanyl)-4-quinolone-3- carboxylic acids from 7-chloro-6-fluoro-4-quinolone-3-carboxylic acid and 5-substituted 1,3,4-thiadiazoles/oxadiazoles on basic alumina under microwave activation is described. All compounds were screened for their in vitro antibacterial activity against B. lichenformis, 2689, K. aerogens 2281, S. typhimurium 2501, E. herbicola 2491, and P. vulgaris 2027 and found to possess activities comparable to that of the standard drug norfloxacin.

Full text of DOI:10.1007/s007060070029

Monatshefte fuÈr Chemie 131, 1207±1212 (2000)
Microwave Activated Solid Support Synthesis
of New Antibacterial Quinolones
Mazaahir Kidwai1;Ã, Preeti Misra1, Bhavesh Dave1, Kumar R. Bhushan1,
Rajendra K. Saxena2, and Meena Singh2
1
Department of Chemistry, University of Delhi, Delhi-110007, India
2
Deparment of Microbiology, University of Delhi, South Campus, New Delhi-110021, India
Summary. A novel synthesis of 6-¯uoro-7-(5-aryl-1,3,4-thiadiazol/oxadiazol-2-yl-sulfanyl)-4-
quinolone-3-carboxylic acids from 7-chloro-6-¯uoro-4-quinolone-3-carboxylic acid and 5-substi-
tuted 1,3,4-thiadiazoles/oxadiazoles on basic alumina under microwave activation is described. All
compounds were screened for their in vitro antibacterial activity against B. lichenformis, 2689, K.
aerogens 2281, S. typhimurium 2501, E. herbicola 2491, and P. vulgaris 2027 and found to possess
activities comparable to that of the standard drug nor¯oxacin.
Keywords. Quinolones; Solid support; Microwave irradiation; Antibacterial activity.
Introduction
Microwave heating techniques for solventless organic reactions have been
developed very recently by Villemin [1] and Mingos [2] who have used inorganic
oxides (alumina, silica) and acidic clays (montmorillonite K10 or KSF) as carriers
[3]. The strategy of microwave activated synthesis on solid inorganic supports
[4±5] seems to be the most ef®cient technology. Acidic or basic solid mineral
oxides such as silica gel, alumina, etc. act both as catalysts and supports [6].
Moreover, we have coupled this technique with microwave activation, thus
achieving more effective reactions than by the use of conventional methods for dry
organic reactions [4±6] combined with the advantages of clean products and short
reaction times [7±8].
The broad application spectrum and in vivo ef®ciency of quinolone
antibacterials [9], thiadiazoles [10], and oxadiazoles [11] have generated much
enthusiasm in the medical community and prompted extensive research in the
pharmaceutical industry as well. Substituted quinolones have been prepared by
nucleophilic substitution reactions using heterocyclic groups like piperazinyl,
pyrrole, etc. under basic conditions [12]. These methods are very expensive, require
long reaction times, and are characterized by dif®cult work-up procedures resulting
in low yields.
Ã
Corresponding author

1208
M. Kidwai et al.
Keeping in view the importance of quinolones and the advantages of solvent-
free microwave induced reactions [13, 14], it was thought worthwhile to synthesize
the thiadiazolyl/oxadiazolyl substituted quinolones 3a±j using the above technique.
Results and Discussion
Syntheses
Diethyl-3-chloro-4-¯uoro anilinomethylene malonate (1) was synthesized from the
corresponding chloro¯uoroaniline and methylene malonate within 6±7 h using
conventional heating [15], whereas under microwave irradiation (MWI) the reaction
was completed within 40 s. Cyclization of 1 to the quinolone 2 was carried out using
acidic alumina, thus circumventing the use of polyphosphoric acid as has been
reported earlier [15]. The reaction of 2 with mercapto substituted 1,3,4-thiadiazoles/
oxadiazoles 3a±j [16] on basic alumina under MWI for 60±90 s furnished the
substituted carboxylic acids 4a±j within 60±90 s, without the need to use bases like
NaOH or K2CO3. The yields were signi®cantly better than for the conventional
methods [17] (Table 1).
The formation of compounds 4a±j was evidenced by the disappearance of the
1
band due to the -SH moiety of the thiadiazoles/oxadiazoles at 2550 cm and the
1
appearance of the C=N band of the thiadiazole ring at 1575 cm in the IR spectra.
In the 1H NMR spectra, the signal for the -SH protons at ꢀ ˆ 11:1 ppm was missing
and thus con®rmed the condensation of two moieties.
Pharmacological results
B. lichenformis, K. aerogenes, S. typhimurium, E. herbicola, and P. vulgaries were
used to determine the antibacterial activity by the cup diffusion method [18].
Compounds were dissolved in DMF at a concentration of 50 mg/cm3. All
compounds were found to be active; however, only compounds 4f, 4h, and 4i
showed promising antibacterial activity. Nor¯oxacin was used as the standard drug
(Table 2).
Table 1. Comparison of reaction times and yields for the transformation 3a±j!4a±j
Solution phase (conv.)
yield/% / time/h
Solution Phase (MWI)
yield/% / time/min
Solid Phase (MWI)
yield/% / time/s
4a
4b
4c
4d
4e
4f
60/12
62/13
59/10
60/14
65/16
62/13
63/11
63/9
72/4
70/4
73/5
72/3
73/5
74/4
72/4
76/4
78/5
73/5
90/60
94/70
92/65
90/90
93/80
96/60
90/80
94/85
92/90
96/75
4g
4h
4i
63/15
65/10
4j

Microwave Assisted Quinolone Synthesis
1209
X
R
X
R
4a
4b
4c
4d
4e
S
S
S
S
S
H
4f
4g
4h
4i
O
O
O
O
O
H
4-Cl
2-Cl
4-NO2
4-CN
4Cl
2-Cl
4-NO2
4-CN
4j
Scheme 1
Table 2. In vitro antibacterial activity of compounds 4a±j; ‡: 3±9 mm, ‡‡: 10±12 mm, ‡‡‡:
13±16 mm, ‡‡‡‡: 17±21 mm
B. lichenformis
K. aerogenes S. typhimurium
E. herbicola
P. vulgaris
2689
2281
2501
2490
2027
4a
4b
‡
‡‡
‡
‡
‡
‡‡
‡
‡‡
‡
‡‡
‡‡
‡
‡
4c
4d
‡
‡
‡
‡‡
‡‡
‡‡
‡
‡‡
‡
‡‡
‡
‡
4e
‡
‡
4f
4g
‡‡
‡
‡‡
‡
‡‡
‡
‡‡
‡
4h
4i
‡‡
‡‡
‡‡
‡‡‡
‡‡
‡‡
‡
‡‡
‡‡
‡
‡‡
‡‡
‡‡
‡‡‡
‡‡
‡‡
‡
4j
Nor¯oxacin
‡‡‡‡
‡‡‡
‡‡‡
Experimental
Melting points were determined by means of a Thomas Hoover melting point apparatus and are
uncorrected. IR spectra (KBr pellets) were recorded on a Perkin-Elmer spectrophotometer model
1
599. H NMR were recorded on a Perkin-Elmer R-32 (90 MHz) instrument using TMS as internal
standard. Elemental analyses were performed by means of a Heraeus CHN rapid analyser; their
results agreed satisfactorily with the calculated values. A Padmini Essentia Microwave oven (Model

1210
M. Kidwai et al.
Brownie; 2450 MHz, 560 W) was used. For TLC analysis, silica gel coated Al plates (Merck) were
employed.
Diethyl-3-chloro-4-¯uoroanilino-methylene malonate (1)
A mixture of 0.01 mol 3-chloro-4-¯uoro-aniline and 0.01 mol diethyl ethoxy methylenemalonate was
mixed in an 250 cm3 Erlenmeyer ¯ask and subjected to MWI for 40 s. The formation of the product
was con®rmed by TLC. The crude product (oil) was pure enough for the next step. A yield of 96%
was obtained.
Ethyl-7-chloro-6-¯uoro-4-quinolone-3-carboxylic acid (2)
Acidic alumina [19] (18 g) was added to a solution of 0.01 mol 1 in 10 cm3 CH2Cl2 at room
temperature. The reactants were thoroughly mixed, and the material was dried on air and placed in an
alumina bath [20] inside the domestic microwave oven at 560W for 60±90 s. Progress of the reaction
was monitored by TLC at an interval of 30 s. After cooling the mixture to room temperature, the solid
was extracted with 4Â10 cm2 CH2Cl2, and the solvent was recovered under vacuum to yield 82% 2.
6-Fluoro-7-(5-aryl-1,3,4-thiadiazol/oxadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic
acids (4a±j); general procedure
5-Aryl-1,3,4-thiadiazole/oxadiazole-2-thiols 3a±j (0.01 mol) and 0.01 mol ethyl carboxylate (2) were
adsorbed separately on basic alumina [21]. Both adsorbed materials were mixed intimately and
irradiated in the microwave oven for 60±90 s. After completion of the reaction the mixture was
cooled, and the product was extracted with 4Â10 cm3 CH2Cl2. Recovering the solvent under reduced
pressure afforded the products 4a±j which were recrystallized from EtOH/CH2Cl2. For details on
yields, see Table 1.
6-Fluoro-7-(5-phenyl-1,3,4-thiadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4a; C18H10N3O3S2F)
1
M.p.: 230±232ꢀC. H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.4±7.8 (m, 5H, Ar-H), 8.65 (d, 1H,
J ˆ 9 Hz, C5-H), 9.15 (d, 1H, J ˆ 9 Hz, C8-H), 9.28 (brs, 1H, NH), 9.70 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(40-chlorophenyl)-1,3,4-thiadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4b; C18H9N3O3S2FCl)
1
M.p.: 225±227ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.6±7.8 (m, 4H, Ar-H), 8.73 (d, 1H,
J ˆ 9 Hz, C5-H), 9.10 (d, 1H, J ˆ 5 Hz, C8-H), 9.25 (brs, 1H, NH), 9.69 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(20-chlorophenyl)-1,3,4-thiadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4c; C18H9N3O3S2FCl)
1
M.p.: 232±233ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.5±7.8 (m, 4H, Ar-H), 8.66 (d, 1H,
J ˆ 9 Hz, C5-H), 9.12 (d, 1H, J ˆ 5 Hz, C8-H), 9.25 (brs, 1H, NH), 9.69 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(30-nitrophenyl)-1,3,4-thiadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4d; C18H9N3O3S2FCl)
1
M.p.: 225±227ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.5±7.9 (m, 4H, Ar-H), 8.72 (d, 1H,
J ˆ 9 Hz, C5-H), 9.13 (d, 1H, J ˆ 9 Hz, C8-H), 9.25 (brs, 1H, NH), 9.72 (s, 1H, C2-H) ppm.

Microwave Assisted Quinolone Synthesis
1211
6-Fluoro-7-(5-(40-cyanophenyl)-1,3,4-thiadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4e; C19H9N4O3S2F)
1
M.p.: 280±282ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.7±8.0 (m, 4H, Ar-H), 8.75 (d, 1H,
J ˆ 9 Hz, C5-H), 9.12 (d, 1H, J ˆ 5 Hz, C8-H), 9.25 (brs, 1H, NH), 9.69 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-phenyl-1,3,4-oxadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4f; C18H10N3O4SF)
1
M.p.: 225±227ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.6±7.9 (m, 4H, Ar-H), 8.67 (d, 1H,
J ˆ 9 Hz, C5-H), 9.15 (d, 1H, J ˆ 5 Hz, C8-H), 9.25 (brs, 1H, NH), 9.65 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(40-chlorophenyl)-1,3,4-oxadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4g; C18H10N3O4SF)
1
M.p.: 280±282ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.7±8.0 (m, 4H, Ar-H), 8.75 (d, 1H,
J ˆ 9 Hz, C5-H), 9.12 (d, 1H, J ˆ 5 Hz, C8-H), 9.27 (brs, 1H, NH), 9.66 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(20-chlorophenyl)-1,3,4-oxadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4h; C18H10N3O4SF)
1
M.p.: 285±287ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.6±7.9 (m, 4H, Ar-H), 8.69 (d, 1H,
J ˆ 9 Hz, C5-H), 9.15 (d, 1H, J ˆ 9 Hz, C8-H), 9.27 (brs, 1H, NH), 9.69 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(30-nitrophenyl)-1,3,4-oxadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4i; C18H9N4O6SF)
1
M.p.: 220±222ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.7±8.1 (m, 4H, Ar-H), 8.69 (d, 1H,
J ˆ 9 Hz, C5-H), 9.15 (d, 1H, J ˆ 9 Hz, C8-H), 9.30 (brs, 1H, NH), 9.80 (s, 1H, C2-H) ppm.
6-Fluoro-7-(5-(40-cyanophenyl)-1,3,4-oxadiazol-2-yl-sulfanyl)-4-quinolone-3-carboxylic acid
(4j; C18H9N4O6SF)
1
M.p.: 289±291ꢀC; H NMR (CDCl3‡DMSO-d6, ꢀ, 90 MHz): 7.7±8.2 (m, 4H, Ar-H), 8.70 (d, 1H,
J ˆ 9 Hz, C5-H), 9.16 (d, 1H, J ˆ 9 Hz, C8-H), 9.25 (brs, 1H, NH), 9.65 (s, 1H, C2-H) ppm.
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M. Kidwai et al.: Microwave Assisted Quinolone Synthesis
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Ê
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Ê
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Received May 2, 2000. Accepted (revised) June 13, 2000