Indian Journal of Chemistry

Vol. 44B, October 2005, pp. 2114-2119

Synthesis, characterization and antibacterial activity studies on some fluorine

containing quinoline-4-carboxylic acids and their derivatives
d
B Shivarama Hollaa*, K Narayana Poojarya,b, Boja Poojarya, K Subrahmanya Bhata,c & N Suchetha Kumari
a
Department of Post-Graduate Studies and Research in Chemistry, Mangalore University,
Mangalagangothri, Mangalore 574 199, India.
b
Department of Chemistry, Sri Bhuvanendra Collge, Karkala 574104.
c
Chemistry and Catalysis, GE India Technology Centre, 122, EPIP, Whitefield Road, Bangalore 560066, India.
d
Department of Biochemistry, KSHEMA, Deralakatte, Mangalore 574 162.
*E-mail: hollabs@yahoo.com
Received 19 October 2004; accepted (revised) 22 February 2005

A series of 3-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-6-yl-2-(2,4-dichloro-5-fluorophenyl)quinolines 5 have

been synthesized by the condensation of hitherto unreported quinoline-4-carboxylic acids 3 with various 3-substituted-4-
amino-5-mercapto-1,2,4-triazoles 4. The structures of newly synthesized compounds have been confirmed on the basis of
elemental analysis, IR, 1H NMR and mass spectral data. The newly synthesized compounds are evaluated for their
antibacterial activities.

Keywords: Quinoline-4-carboxylic acids; Fluoroheterocycles; 1,2,4-triazoles; 1,3,4-thiadiazoles; antibacterial activity

IPC: Int.Cl.7 C 07 D 215/00 // A 61 P 31/04

Quinoline and its derivatives are known for their anti- quinoline-4-carboxylic acid 3 (R=Br) was prepared
malarial and therapeutic properties1. A number of from 5-bromoisatin (Scheme I). The condensation of
quinoline derivatives are known to possess anti- quinoline-4-carboxylic acids 3 with various 3-
tumor, anti-bacterial, anti-fungal, hypotensive, anti- substituted-4-amino-5-mercapto-1,2,4-triazoles in the
leishmanial, anti-HIV, analgesic and anti-inflam- presence of phosphorus oxychloride afforded 3-
matory activities2-7. Applications of quinoline deri- substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazol-6-yl-
vatives are fast spreading from antimalarial drugs to 2-(2,4-dichloro-5-fluorophenyl)quinolines 5 (Table I,
almost every branch of medicinal chemistry8,9. A Scheme II). The quinoline-4-carboxylic acids 3 and
fluorine atom located at a suitable position of a bio- their triazolothiadiazole derivatives 5 were characteri-
active molecule is found to exert a profound zed by elemental analysis and spectral (IR, 1H NMR
pharmacological effect10,11. and mass) data.
Prompted by recent literature observations12a and as In the 1H NMR spectrum of quinoline-4-carboxylic
a part of our search for bio-active quinoline acids 3a, the signals due to two protons of 2,4-
derivatives12b, we undertook the synthesis of fluorine dichloro-5-fluorophenyl ring appeared as two
containing quinoline-4-carboxylic acids and their doublets at δ 8.79 (J = 9 Hz) and 8.69 (J = 6 Hz),
heterocyclic derivatives. The results of these studies respectively. The remaining aromatic protons ap-
along with the antibacterial activities of these peared as multiplet in the region δ 6.7-8.2. The mass
compounds are reported in this paper. 2-(2,4- spectrum of this compound showed an intense
Dichloro-5-fluorophenyl)quinoline-4-carboxylic acid molecular ion peak at m/z 334 consistent with its
3 (R=H) was prepared by heating isatin 1 with 2,4- molecular formula, C16H7Cl2FNO2 with its isotopic
dichloro-5-fluoroacetophenone 2 in the presence of peaks at m/z 336 and 338. The loss of chlorine radical
sodium hydroxide followed by acidification. from the molecular ion resulted in the formation of a
Similarly, 6-bromo-2-(2,4-dichloro-5-fluorophenyl)- peak at m/z 299. The loss of CO2 from the molecular
 HOLLA et al.: FLUORINE CONTAINING QUINOLINE-4-CARBOXYLIC ACIDS 2115

O F
R
O
O
+ Cl
N
CH3
H
Cl
11 OH-/H2O
22
CO2 H

R
Cl

33 Cl

R = H, Br
Scheme I

Mechanism for Scheme I

O
OH O
O
O
R R R
O
-H2O O
O + OH
N NH
NH 2
H
F
F
O
O
Cl
-H2O Cl
CH2 H + OH CH2
Cl
Cl

O
O O
O
Cl OH
O OH
O
O
R R Cl H Cl
O H2 C R
+ Cl H2O
NH 2 O Cl
NH2 O
..
NH 2 O
Cl

F
F
-H2O F

O OH O O O O

R R R
Cl Cl Cl
+ H+ -H2O

N
..
N N
OH
H
Cl Cl Cl
OH
F F F
2116 INDIAN J. CHEM., SEC B, OCTOBER 2005

Table I — Physicochemical data of triazolothiadiazole derivatives 5a-t

Compd R R1 Mol. formula m.p. Yield

(°C) (%)
5a H H C18H8Cl2FN5S 248-50 82
5b H CH3 C19H10Cl2FN5S 185-86 74
5c H CH3CH2CH2 C21H14Cl2FN5S 204-06 70
5d H C6H5CH2 C25H14Cl2FN5S 86-88 75
5e H C6H5NHCH2 C25H15Cl2FN6S 128-30 68
5f H 2-ClC6H4OCH2 C25H13Cl3FN5OS 168-69 73
5g H 4-ClC6H4OCH2 C25H13Cl3FN5OS 178-80 72
5h H 2,4-Cl2C6H3OCH2 C25H12Cl4FN5OS 195-97 69
5i H 3,4-(CH3)2C6H3OCH2 C27H18Cl2FN5OS 138-40 72
5j H 4-Cl-3-CH3C6H3OCH2 C26H15Cl3FN5OS 230-32 78
5k Br H C18H7BrCl2FN5S 164-66 70
5l Br CH3 C19H9BrCl2FN5S 192-93 68
5m Br CH3CH2CH2 C21H13BrCl2FN5S 160-62 82
5n Br C6H5CH2 C25H13BrCl2FN5S 158-60 71
5o Br C6H5NHCH2 C25H14BrCl2FN6S 128-30 70
5p Br 2-ClC6H4OCH2 C25H12BrCl3FN5OS 148-50 73
5q Br 4-ClC6H4OCH2 C25H12BrCl3FN5OS 208-10 69
5r Br 2,4-Cl2C6H3OCH2 C25H11BrCl4FN5OS 225-26 74
5s Br 3,4-(CH3)2C6H3OCH2 C27H17BrCl2FN5OS 160-62 69
5t Br 4-Cl-3-CH3C6H3OCH2 C26H14BrCl3FN5OS 118-20 75
All the compounds analyzed satisfactorily for their N content. They agree to the theoretical values
within ± 0.4%. Solvent of crystallization: Ethanol + DMF mixture.
IR (KBr, cm-1): 3a: 3400(O-H), 3090(Ar-H), 1700(C=O), 1630(C=N), 1580(C=C), 1088(C-F), 908(C-
H), 729(C-Cl), 720(C-Cl); 3b: 3421(O-H), 3099(Ar-H), 1705(C=O), 1630(C=N), 1578(C=C), 1090(C-
F), 910(C-H), 750(C-Cl), 725(C-Cl), 653(C-Br); 5e: 3402(N-H), 3060(Ar-H), 2931(C-H), 1625(C=N),
1593(C=C), 1087(C-F), 732(C-Cl); 5m: 3015(Ar-H), 2992(C-H), 2900(C-H), 1643(C=N), 1603(C=C),
1490(C-H), 1090(C-F), 900(C-H), 740(C-Cl); 5p: 3097(Ar-H), 2997(C-H), 1630(C=N), 1093(C-F),
900(C-H), 731(C-Cl).
1
H NMR(DMSO-d6, δ): 3a: 6.7-8.2(2H, m, ArH), 8.69(1H, d, J=6.0Hz, ArH); 8.79(1H, d, J=9.0Hz,
ArH); 5b: 2.5(s, 3H, CH3), 7.3-8.3(m, 7H, ArH); 5d: 2.9(s, 2H, CH2), 6.63-8.32(m,12H, ArH); 5e:
4.92(s, 1H, NH), 5.30(s, 2H, NCH2), 8.69(d, 1H, Ar-H, J=6.02Hz), 8.79(d, 1H, Ar-H, J=9.04Hz), 6.65-
8.26(m, 10H, Ar-H); 5m: 0.9-1.1(t, 3H, J=3.0Hz, CH3), 1.7-1.85(sextet, 2H, J=4.5Hz, CH2), 2.65-
2.90(t, 2H, J=6.0Hz, CH2), 6.92-8.26(m, 6H, ArH); 5o: 4.85(s, 1H, NH), 5.27(s, 2H, NCH2), 6.68-
8.30(m, 9H, Ar-H), 8.65(d, 1H, Ar-H, J=6.1Hz), 8.80(d, 1H, Ar-H, J=9.1Hz).
MS (m/z, % abundance): 3a: 334(M+, 52), 336(M+2, 32), 38(M+4, 5), 299(M-Cl, 27), 290(M-CO2,
25), 189(M+ of 2,4-dichloro-5-flourobenzonitrile cation, 100), 191(M+2 of 2,4-dichloro-5-
flourobenzonitrile cation, 69), 193(M+4 of 2,4-dichloro-5-flourobenzonitrile cation, 10), 163(2,4-
dichloro-5-flourophenyl cation, 32), 165(2,4-dichloro-5-flourophenyl cation, 22), 167(2,4-dichloro-5-
flourophenyl cation, 7); 5i: 549 (M+, 5.9), 428(12.5), 163(4.5), 84(100); 5p: 507(M - p-chlorophenoxy
radical), 127(55.4), 84(100).

ion gave a peak at m/z 290. The base peak observed at compound 3a showed the characteristic absorption
m/z 189 was due to the formation of the 2,4-dichloro- bands at stretching frequencies - 3400 (O-H), 1700
5-fluorobenzonitrile cation. This further underwent (C=O), 1630 (C=N), 1586 (C=C), 1088 (C-F) and 729
fragmentation to give 2,4-dichloro-5-fluorophenyl cm-1 (C-Cl).
cation with m/z value of 163. In the 1H NMR spectrum of triazolothiadiazolyl
The absence of absorption band due to NH quinoline 5e, the NH protons appeared as a singlet at
stretching frequency in the IR spectra of compounds δ 4.92. The anilinomethyl protons appeared as a
3a and 3b clearly indicated the formation of singlet at δ 5.83. The signals due to the protons of 2,4-
quinoline-4-carboxylic acids. IR spectrum of dichloro-5-fluorophenyl moiety was seen as two
 HOLLA et al.: FLUORINE CONTAINING QUINOLINE-4-CARBOXYLIC ACIDS 2117

N N R
N N
POCl3, 110-200C, 6h R1 S
+ 3a or b N

N
R1 SH
N
N
H2N
4 Cl

Cl
5
R1 = H , CH3 , CH3 CH2 CH2 , C6 H5 CH2 , C6 H5 NHCH2 , 2-ClC6 H4 OCH2 , 4-ClC6 H4 OCH2 ,
2,4-Cl2 C6 H3 OCH2 , 3,4-(CH3 )2 C6 H3 OCH2 , 4-Cl-3-CH3 C6 H3 OCH2 .
Scheme II

Mechanism for Scheme II

O
..O H
Cl
O O O P O Cl
O

R + P R
Cl
R
Cl -HCl Cl
-PO2Cl Cl
Cl Cl
Cl
N N N

Cl Cl Cl

F F F
N N

O Cl
R1 S
N
N N
R
.. Cl -HCl ..NH2 C O
R1
N
S H +
R
NH2 N Cl

Cl N

F
N N Cl

F
R1 S N N
N

N C R1 S
N
-H2O
R H N C OH
Cl

R
N Cl

Cl N

F
Cl

F
2118 INDIAN J. CHEM., SEC B, OCTOBER 2005

doublets at δ 8.79 (J = 9Hz) and 8.69 (J = 6 Hz) Table II — Anti-bacterial activities of quinoline-4-carboxylic
respectively. The remaining aromatic protons acids 3 and their triazolothiadiazole derivatives 5
appeared as complex multiplet in the region δ 6.65-
Compd Minimum inhibitory concentration in μg/mL
8.26 integrating for ten protons.
S. aureus E. coli B. subtilis
The mass spectrum of triazolothiadiazolyl
3a 12.5 12.5 12.5
quinoline 5i showed the molecular ion peak at m/z
3b 6.0 6.0 12.5
549 consistent with the molecular formula,
C27H18Cl2FN5OS. The peak at m/z 163 could be 5a 12.5 6.0 12.5
assigned to the formation of 2,4-dichloro-5- 5b 12.5 6.0 6.0
fluorophenyl cation during fragmentation. A peak 5c 6.0 6.0 6.0
seen at m/z 84 confirmed the formation of 5d 6.0 12.5 12.5
CH2=C=N--C+=S ion during fragmentation. 5e 12.5 12.5 25.0
In the IR spectra of triazolothiadiazolylquinolines, 5f 6.0 3.0 6.0
the absorption bands corresponding to the NH 5g 25.0 12.5 12.5
stretching frequency of the starting triazole and the 5h 3.0 3.0 6.0
carboxyl group of quinoline-4-carboxylic acid were 5i 25.0 12.5 6.0
absent. This confirmed the involvement of these 5j 25.0 6.0 12.5
groups in the ring formation. The IR spectrum of 5k 12.5 6.0 12.5
compound 5e showed the prominent absorption bands 5l 6.0 6.0 12.5
at stretching frequencies-3402 (NH), 3060 (Ar-H), 5m 12.5 12.5 6.0
2939 (C-H), 1625 (C=N), 1593 (C=C), 1087 (C-F) 5n 6.0 6.0 12.5
and 737 cm-1 (C-Cl).
5o 12.5 12.5 12.5
5p 6.0 3.0 6.0
Biological activity
5q 12.5 6.0 12.5
Anti-bacterial activity
The quinoline-4-carboxylic acids and their 5r 3.0 6.0 6.0
triazolothiadiazole derivatives were screened for their 5s 6.0 12.5 12.5
in vitro anti-bacterial activity against S. aureus, 5t 6.0 6.0 3.0
E. coli and B. subtilis by serial dilution method13. Furacin 12.5 6.0 12.5
Solutions of the test compounds were kept in
dimethyl formamide. Nitrofurazone (furacin) was hydroxide (2 g, 0.05 mole) and isatin/5-bromoisatin 1
used as a standard drug for comparison and solvent (0.01 mole) in water (25 mL) was heated till a clear
control was kept. The minimum inhibitory solution was obtained. 2,4-Dichlor-5-fluorophenyl-
concentrations (MIC values) of the above compounds acetophenone 2 (0.05 mole) was added to it in small
are given in Table II. It is interesting to note that the portions with occasional shaking and heating was
compounds 5f, 5h, 5p, 5r and 5t showed very good continued for 2 hr. The reaction mixture was chilled
anti-bacterial activity. in an ice-bath. The solid mass formed was collected
by filtering through a sintered glass crucible (G-4).
Experimental Section The sodium salt of quinoline-4-carboxylic acid
Melting points were determined by capillary obtained was dissolved in water (100 mL). Quinoline-
method and are uncorrected. IR spectra in KBr pellets 4-carboxylic acid was precipitated by neutralizing this
were recorded on a Shimadzu FTIR 8700 spectro- solution with glacial acetic acid. It was collected by
photometer; 1H NMR spectra in CDCl3/CDCl3- filtration, washed with water, dried and re-crystallized
DMSO-d6 mixture on a Bruker AC 300F 300 MHz from dimethyl formamide. 3a (R=H): yield 78%, m.p.
NMR spectrometer using TMS as an internal 224-26°C; 3b (R=Br): yield 76%, m.p. 245-47°C.
standard; and mass spectra on a JEOL JMS 300 mass Preparation of 4-(3-substituted-1,2,4-triazolo-
spectrometer operating at 70 eV. The required [3,4-b]-1,3,4-thiadiazol-6-yl)-2-(2,4-dichloro-5-fluo-
aminomercaptotriazoles and 5-bromoisatin were rophenyl)quinolines 5a-t. A mixture of 3-substi-
prepared according to the literature methods14-16. tuted-4-amino-5-mercapto-1,2,4-triazole 4 (0.01 mole),
Preparation of 2-(2,4-dichloro-5-fluorophenyl)quino- quinoline-4-carboxylic acid 3 (0.01 mole) and
line-4-carboxylic acids 3a, b. A solution of sodium phosphorus oxychloride (10 mL) was heated under
 HOLLA et al.: FLUORINE CONTAINING QUINOLINE-4-CARBOXYLIC ACIDS 2119

reflux for 6 hr. The reaction mixture was cooled and Bret M L & D’Angelo J, Bioorg Med Chem Lett, 14, 2004,
allowed to stand at room temperature for 2 hr. It was 2473.
6 Quraishi M A, Thakur V R & Dhawan S N, Indian J Chem,
then poured onto crushed ice. The solid mass formed 28B, 1989, 891.
was collected by filtration, washed with sodium 7 Bala M, Naparzewska A & Chojnacka W, Pol J Pharmacol
bicarbonate solution (5%), then with water and dried. Pharm, 38, 1986, 222; Chem Abstr, 105, 1986, 164770.
Recrystallized from a mixture of ethanol and dimethyl 8 Norwich Pharmaceutical Co, US Pat, 3,272,806, 1966; Chem Abstr, 65,
formamide (2:1) to get compounds 5 in 68-82% 1966, 18567.
yields. 9 Pfizer and Co Inc Neth Pat 6,601,980, 1966; Chem Abstr, 66,
1967, 115616.
10 Filler R, Chem Technology, 9, 1974, 752.
Acknowledgement 11 (a) Filler R & Kobayashi Y, Biomedical Aspects of Fluorine
The authors thank the Director, RSIC, Punjab Chemistry, (Elsevier, New York) 1982.
University, Chandigarh and the Head, CDRI, (b) Bhat K S, Prasad D J, Poojary B & Holla B S,
Lucknow for providing the spectral data. One of the Phosphorus, Sulfur and Silicon, 179, 2004, 1595.
authors (KSB) is thankful to the CSIR, New Delhi for (c) Holla B S, Bhat K S & Shetty N S, Phosphorus, Sulfur and
Silicon, 178, 2003, 2193.
the award of SRF. Author (KNP) is grateful to UGC,
(d) Bhat K S, Karthikeyan M S, Holla B S & Shetty N S,
New Delhi for financial assistance. Indian J Chem, 43B, 2004,1765.
(e) Zheng X, Li Z, Wang Y, Chen W, Huan Q, Liu C & Song
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