Microwave assisted synthesis and antibacterial activity of new quinolone derivatives

Article abstract of DOI:10.1007/PL00013504

A series of novel 6-fluoro-7-(5-alkyl-1,3,4-thiadiazol/oxadiazol-2-ylsulfanyl)-4-quino-lone-3- carboxylic acids were synthesized using microwave irradiation. The compounds were tested for their in vitro antibacterial activity. All compounds containing the 1,3,4-thiadiazole/oxadiazole moiety at position 7 showed promising antibacterial activity.

Full text of DOI:10.1007/PL00013504

Monatshefte f uÈ r Chemie 129, 961±965 (1998)
Microwave Assisted Synthesis and Antibacterial
Activity of New Quinolone Derivatives
Mazaahir Kidwai1 , Preeti Misra , Rajesh Kumar , Rajendra K. Saxena ,
Rani Gupta , and Sapna Bradoo
;Ã
1
1
2
2
2
1
Department of Chemistry, University of Delhi, Delhi 110007, India
2
Department of Microbiology, University of Delhi, South Campus, Delhi 110021, India
Summary. A series of novel 6-¯uoro-7-(5-alkyl-1,3,4-thiadiazol/oxadiazol-2-ylsulfanyl)-4-quino-
lone-3-carboxylic acids were synthesized using microwave irradiation. The compounds were tested
for their in vitro antibacterial activity. All compounds containing the 1,3,4-thiadiazole/oxadiazole
moiety at position 7 showed promising antibacterial activity.
Keywords. Microwave irradiation; Quinolones; Antibacterial activity.
Mikrowellenunterst uÈ tzte Synthese und antibakterielle Aktivit aÈ t von neuen Chinolonderivaten
Zusammenfassung. Einige neue 6-Fluoro-7-(5-alkyl-1,3,4-thiadiazol/oxadiazol-2-sulfanyl)-4-chi-
nolon-3-carbons aÈ uren wurden unter Bestrahlung mit Mikrowellen synthetisiert. Die Verbindungen
wurden hinsichtlich ihrer antibakteriellen Aktivit aÈ t in vitro untersucht. S aÈ mtliche Verbindungen mit
7
-st aÈ ndigen 1,3,4-Thiadiazol/Oxadiazol-Einheiten zeigten vielversprechende Aktivit aÈ t.
Introduction
In recent years, three quinolones [1] (cipro¯oxacin [2], o¯oxacin [3], and
nor¯oxacin [4]) have become commercially available. Quinolones inhibit the
replication of DNA [5] by inhibition of the DNA gyrase. The latter is probably a
metalloenzyme and interacts with the DNA molecule via an intermediate (iron
complex) that carries the quinolone drug. It has been reported that quinolone anti-
bacterial agents do not bind to the gyrase subunit, but rather to DNA, and the
mechanism of action is based on drug DNA complex formation [6±7]. Quinolones
act as bidentate chelating agents.
Quinolone derivatives have been associated with antibacterial [8], antimicrobial
[
9], and antistaphylococcal [10] activities. Thiadiazoles and oxadiazoles are
pharmacologically important [11]. Keeping in view the importance of MORE
Microwave induced Organic Reaction Enhancement [12±17] chemistry and the
(
biological importance of the above mentioned moieties, it was thought worthwhile
to develop a method for the rapid synthesis of 6-¯uoro-7-(5-alkyl-1,3,4-thiadiazol/
oxadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acids and to screen them for
bactericidal activity.
à Corresponding author

962
M. Kidwai et al.
Results and Discussion
To our knowledge, this is the ®rst report on quinolone synthesis in which micro-
wave technique has been used and thiadiazole/oxadiazole rings are incorporated.
Diethyl-3-chloro-4-¯uoroanilinomethylene malonate (1) was synthesized by
condensation of 3-chloro-4-¯uoroaniline with diethylethoxymethylene malonate.
Cyclization of 1 in PPA under microwave irradiation for 3 min yielded the cyclized
ester which upon alkaline hydrolysis afforded 2 as evidenced by the disappearance
1
of the ester group signals in the H NMR spectrum at ꢀ ˆ 1.5 and 4.2 ppm. Formal
nucleophilic substitution of the chlorine in 2 with mercapto substituted 1,3,4-
thiadiazoles/oxadiazoles was achieved under microwave irradiation for 4±5 min
furnishing 3a±f (Scheme 1). The structures of the compounds were con®rmed by
their analytical and spectroscopic data given in the experimental part.
Table 1. Antibacterial activity of compounds 3a±f
Organism
3a
3b
3c
3d
3e
3f
Nor¯oxacin
2
2
2
2
2
253-Corynebacterium
rubrum NCL
‡‡‡
‡
‡‡‡
‡‡‡‡ ‡‡‡
‡‡‡
‡‡‡‡
281-Klebsiella
aerogens NCL
491-Erwinia
‡
�
�
‡‡‡
‡‡‡
‡‡
‡‡
‡‡‡
‡
‡
‡‡‡‡
‡‡‡
‡‡
‡
‡
‡
�
‡‡
‡‡
‡
‡‡‡
�
herbicola NCL
715-Bacillus
‡‡‡‡
‡‡‡
lichenformis NCL
323-Bacillus
‡
‡
‡‡
‡‡
coagulans NCL
K12-E. coli
‡‡
‡
‡
‡
�
‡‡‡
‡‡
‡‡
‡‡
‡‡
‡‡‡‡
‡‡‡
2689-Bacillus
‡‡‡
‡‡‡
lichenformis NCL
�
: No measurable activity; ‡: 3±9 mm; ‡‡: 10±12 mm; ‡‡‡: 13±16 mm; ‡‡‡‡: 17±21 mm

Microwave Assisted Synthesis of Quinolone Derivatives
963
Compounds 3a±f were tested (Table 1) for their in vitro antibacterial activity
against 6 bacterial strains by the cup-plate agar diffusion method [18]. They were
dissolved in DMF at a concentration of 50 mg/ml. All compounds were found active
against Corynebacterium rubrum, Escherichia coli, and Erwinia herbicola.
Compounds with a 1,3,4-oxadiazole ring at position 7 possess better antibacterial
activity than those with a 1,3,4-thiadiazole ring. Among all synthesized quinolones,
3d provided the best antibacterial activity and compared well with the activities of
nor¯oxacin. 3a, 3e, and 3f also possess promising antibacterial activity.
Experimental
Melting points were taken on an electrothermal apparatus and are uncorrected. IR spectra were
1
recorded on a 1710 Perkin Elmer FTIR spectrophotometer using KBr discs. H NMR spectra were
recorded on a FTNMR Hitachi R-600 spectrometer operating at 90 MHz using TMS as internal
standard (ꢀ in ppm). Elemental analysis data agreed satisfactorily with the calculated ones. A
Padmini Essentia microwave oven, Model Brownie, at 2450 MHz was used. For TLC analysis, silica
gel coated Al plates (Merck) were used.
Diethyl-3-chloro-4-¯uoroanilinomethylene malonate (1; C14H15O4 NClF)
A stirred mixture containing an equimolar ratio of 3-chloro-4-¯uoro aniline and diethylethox-
ꢀ
ymethylene malonate was heated at 120±140 C until the evolution of ethanol ceased. The
disappearance of aniline was con®rmed by TLC using petrol ether:CHCl3:acetone (80:15:5) as
eluent. The yield was almost quantitative, and the crude product (oil) was pure enough for the next
step.
Yield: 91%; IR (KBr): 3320 (N-H), 1725 (C=O) cm 1; 1H NMR (CDCl3, ꢀ): 1.3 (t, 6H,
�
2
CH2CH3), 4.1 (q, 4H, 2CH2CH3), 7.0±7.3 (m, 3H, Ar-H), 9.1 (br, 1H, NH), 9.4 (s, 1H, C2-H) ppm;
‡
MS: m/z calculated for C14H15O4 NClF (M ) 315.18, found 315.03.
7-Chloro-6-¯uoro-4-quinolone-3-carboxylic acid (2; C10H5O3 NClF)
A mixture containing 1.5 g 1 and 7 ml polyphosphoric acid (PPA) was subjected to microwave
irradiation (MWI) for 3 min. The reaction was monitored by TLC using petrol ether:ethylacetate
(
9:1) as eluent. The resulting mixture was alkalized with an excess of NaOH and subjected to MWI
for 4±5 min. The resulting solution was neutralized with 10% HCl to adjust the pH value to 4 and
extracted with ethyl acetate. After drying over Na2SO4, the extract was evaporated to dryness. 2 was
isolated as slightly yellow crystalline product.
Yield: 78%; m.p.: >300 C; IR (KBr): 3400 (N±H), 1700 (C=O) cm ; 1H NMR (CDCl3, ꢀ): 8.7
ꢀ
� 1
(
d, 1H, J ˆ 9 Hz, C5-H), 9.0 (d, 1H, J ˆ 5 Hz, C8-H), 9.6 (s, 1H, C2-H), 9.2 (br, 1H, NH) ppm; MS:
‡
m/z calculated for C10H5O3 NClF (M ) 241.51, found 241.43.
General procedure for the preparation of 6-¯uoro-7-(5-alkyl-1,3,4-thiadiazol/oxadiazol-
2-ylsulfanyl)-4-quinolone-3-carboxylic acids (3a±f)
A mixture of 2 (0.05 mol), 1, 3, 4-thiadiazole/oxadiazole (0.05 mol), and 4 g K2CO3 in 5 ml DMF
was subjected to MWI for 4±5 min. The inorganic salt was ®ltered off, and the resulting ®ltrate was
poured into an excess of ice cold water (100 ml) and extracted with ethyl acetate. The organic layer
was washed with water (2Â50 ml), dried over Na2SO4, and evaporated to afford the corresponding
products which were recrystallized from DMF±EtOH.

964
M. Kidwai et al.
6-Fluoro-7-(5-methyl-1,3,4-thiadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acid
(
3a; C13H8O3N3FS2)
Yield: 50%; m.p.: >300 C; IR (KBr): 1680 (C=O), 1580 (C=N) cm ; 1H NMR (CDCl3, ꢀ): 2.7 (s,
ꢀ
� 1
3
H, CH3), 8.65 (d, 1H, J ˆ 9 Hz, C5-H), 9.13 (d, 1H, J ˆ 5 Hz, C8-H), 9.62 (s, 1H, C2-H), 9.27 (br,
‡
1
H, NH) ppm; MS: m/z calculated for C13H8O3N3FS2 (M ) 337.12, found 337.02.
6-Fluoro-7-(5-nonyl-1,3,4-thiadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acid
(
3b; C21H24O3N3FS2)
Yield: 72%; m.p.: 278 C; IR (KBr): 1685 (C=O), 1575 (C=N) cm ; 1H NMR (CDCl3, ꢀ): 0.88 (t,
ꢀ
� 1
0
0
0
3
H, 9 CH3), 1.27 (m, 12H, 6CH2), 1.6 (m, 2H, 2 CH2), 2.34 (t, 2H, 1 CH2), 8.67 (d, 1H, J ˆ 9 Hz,
C5-H), 9.15 (d, 1H, J ˆ 5 Hz, C8-H), 9.65 (s, 1H, C2-H), 9.25 (br, 1H, NH) ppm; MS: m/z calculated
‡
for C21H24O3N3FS2 (M ) 449.29, found 449.14.
6-Fluoro-7-(5-undecyl-1,3,4-thiadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acid
(
3c; C23H28O3N3FS2)
Yield: 67%; m.p.: 290 C; IR (KBr): 1680 (C=O), 1575 (C=N) cm ; 1H NMR (CDCl3, ꢀ): 0.88 (t,
ꢀ
� 1
0
0
0
3
H, 11 CH3), 1.26 (m, 16H, 8CH2), 1.62 (m, 2H, 2 CH2), 2.34 (t, 2H, 1 CH2), 8.63 (d, 1H, J ˆ 9 Hz,
C5-H), 9.10 (d, 1H, J ˆ 5 Hz, C8-H), 9.58 (s, 1H, C2-H), 9.20 (br, 1H, NH) ppm; MS: m/z calculated
‡
for C23H28O3N3FS2 (M ) 477.31, found 477.18.
6-Fluoro-7-(5-methyl-1,3,4-oxadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acid
(
3d; C13H8O4N3FS)
Yield: 58%; m.p.: >300 C; IR (KBr): 1675 (C=O), 1530 (C=N) cm ; 1H NMR (CDCl3, ꢀ): 2.76
ꢀ
� 1
(
s, 3H, CH3), 8.70 (d, 1H, J ˆ 9 Hz, C5-H), 9.10 (d, 1H, J ˆ 5 Hz, C8-H), 9.76 (s, 1H, C2-H), 9.32
‡
(
br, 1H, NH) ppm; MS: m/z calculated for C13H8O4N3FS (M ) 321.14, found 321.03.
6-Fluoro-7-(5-nonyl-1,3,4-oxadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acid
(
3e; C21H24O4N3FS)
Yield: 69%; m.p.: 280 C; IR (KBr): 1680 (C=O), 1525 (C=N) cm ; 1H NMR (CDCl3, ꢀ): 0.89 (t,
ꢀ
� 1
0
0
0
3
H, 9 CH3), 1.26 (m, 12H, 6CH2), 1.62 (m, 2H, 2 CH2), 2.34 (t, 2H, 1 CH2), 8.67 (d, 1H, J ˆ 9 Hz,
C5-H), 9.15 (d, 1H, J ˆ 5 Hz, C8-H), 9.65 (s, 1H, C2-H), 9.27 (br, 1H, NH) ppm; MS: m/z calculated
‡
for C21H24O4N3FS (M ) 433.22, found 433.20.
6-Fluoro-7-(5-undecyl-1,3,4-oxadiazol-2-ylsulfanyl)-4-quinolone-3-carboxylic acid
(
3f; C23H28O4N3FS)
Yield: 63%; m.p.: 286 C; IR (KBr): 1685 (C=O), 1520 (C=N) cm ; 1H NMR (CDCl3, ꢀ): 0.88 (t,
ꢀ
� 1
0
0
0
3
H, 11 -CH3), 1.25 (m, 16H, 8CH2), 1.6 (m, 2H, 2 -CH2), 2.34 (t, 2H, 1 -CH2), 8.65 (d, 1H, J ˆ 9 Hz,
C5-H), 9.15 (d, 1H, J ˆ 5 Hz, C8-H), 9.60 (s, 1H, C2-H), 9.27 (br, 1H, NH) ppm; MS: m/z calculated
‡
for C23H28O4N3FS (M ) 461.24, found 461.10.
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Microwave Assisted Synthesis of Quinolone Derivatives
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Received January 19, 1998. Accepted (revised) February 10, 1998