Synthesis and characterization of some novel quinolinothiazines of biological interest

Article abstract of DOI:10.1080/10426500701792933

A series of 3-aryl-4H-5-(61/81-substituted-31-formyl-21-quinolinyl) thia-1,2,4-triazoles were prepared by the reaction of 2-chloro-3-formyl-6/8- substituted quinoline with 3-substituted 4H-5-mercapto-1,2,4-triazole. These thia-triazoles 5 on reaction with substituted acetophenone gave a novel series of 2-substituted-s-triazolo[5,1-b]-6/8-substituted quinolino-9-arylacetyl[1,3] thiazines 8 rather than the expected 1-aryl-3-[21-(5-substituted-4H-1,2,4- triazole-5-thia)-61/81-substituted quinoline-31-yl]-2-propen-1-ones 7. The new compounds were screened for their antibacterial activity against Gram-positive and Gram-negative bacteria and antifungal activity against Candida albicans. Most of the tested compounds showed significant antibacterial activity much higher than that of the standard drug Nitrofurazone. The structures of the new compounds were established based on analytical and spectral data. In a typical example, the structure of thiazine 8e was further confirmed by single crystal x-ray data. Copyright Taylor & Francis Group, LLC.

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Synthesis and Characterization
of Some Novel
Quinolinothiazines of Biological
Interest
Balakrishna Kalluraya a , Janardhana Nayak a
,
Adithya Adhikari a , Sujith K. V. a , N Sucheta Shetty
b & Manuela Winter c
a Department of Studies in Chemistry, Mangalore
University, Mangalagangothri, Karnataka, India
b Department of Biochemistry, K.S. Hegde Medical
Academy, Deralakatte, Mangalore, Karnataka, India
c Anoranische Chemie II, Ruhr University, Bochum,
Germany
Version of record first published: 28 Jul 2008.
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K. V., N Sucheta Shetty & Manuela Winter (2008): Synthesis and Characterization of
Some Novel Quinolinothiazines of Biological Interest, Phosphorus, Sulfur, and Silicon
and the Related Elements, 183:8, 1870-1883
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Phosphorus, Sulfur, and Silicon, 183:1870–1883, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701792933
Synthesis and Characterization of Some Novel
Quinolinothiazines of Biological Interest
Balakrishna Kalluraya,1 Janardhana Nayak,1
Adithya Adhikari,1 Sujith K.V.,1 N Sucheta Shetty,2
and Manuela Winter3
1Department of Studies in Chemistry, Mangalore University,
Mangalagangothri, Karnataka, India
2Department of Biochemistry, K.S. Hegde Medical Academy,
Deralakatte, Mangalore, Karnataka, India
3Anoranische Chemie II, Ruhr University, Bochum, Germany
A series of 3-aryl-4H-5-(61 /81 -substituted-31 -formyl-21 -quinolinyl) thia-1,2,4-
triazoles were prepared by the reaction of 2-chloro-3-formyl-6/8-substituted
quinoline with 3-substituted 4H-5-mercapto-1,2,4-triazole. These thia-triazoles
5
on reaction with substituted acetophenone gave a novel series of 2-
substituted-s-triazolo[5,1-b]-6/8-substituted quinolino-9-arylacetyl[1,3]thiazines 8
rather than the expected 1-aryl-3-[21 -(5-substituted-4H-1,2,4-triazole-5-thia)-
61 /81 -substituted quinoline-31 -yl]-2-propen-1-ones 7. The new compounds were
screened for their antibacterial activity against Gram-positive and Gram-negative
bacteria and antifungal activity against Candida albicans. Most of the tested com-
pounds showed significant antibacterial activity much higher than that of the stan-
dard drug Nitrofurazone. The structures of the new compounds were established
based on analytical and spectral data. In a typical example, the structure of thiazine
8e was further confirmed by single crystal x-ray data.
Keywords Biological activity; quinoline; thiazines; triazole
INTRODUCTION
Heterocycles bearing symmetrical triazole ring are reported to
show a broad spectrum of biological activities.1,2 Likewise, quinoline
Received July 31, 2007; accepted September 6, 2007.
The authors are thankful to The Head, Department of Chemistry, Mangalore Uni-
versity, for the microanalysis and The Head, Regional Sophisticated Instrumentation
Centre, Indian Institute of Sciences, Bangalore, for spectral data.
Address correspondence to Balakrishna Kalluraya, Department of Studies in Chem-
istry, Mangalore University, Mangalagangothri 574 199, Karnataka, India. E-mail:
bkalluraya 2001@yahoo.com
1870

Quinolinothiazines of Biological Interest
1871
derivatives exhibit a variety of biological activities like antimalarial,
anti-inflammatory, antimicrobial, HIV receptors, anticonvulsant, an-
tipyretic, and so on.3–6
In our earlier communications,7,8 we have reported the one-pot
synthesis of quinolino thiadiazepines by the reaction of 3-substituted-
4-amino-5-mercapto-1,2,4-triazole with 6/8- substituted -2-chloro-3-
formyl quinoline. Keeping in view of these observations, we studied
the mode of reaction between 6/8-substituted -2-chloro-3-formyl
quinoline 4 with the 3-substituted- 4H-5-mercapto-1,2,4-triazole 3
in ethanol medium employing pyridine as catalyst and such reac-
tions resulted in the formation of novel series of 3-aryl -4H-5-(61/81-
substituted-31-formyl-21-quinolinyl) thia-1,2,4-triazoles 5 (Scheme 1).
Reaction of 3-aryl-4H-5-(61/81-substituted-31-formyl-21-quinolinyl)
thia-1,2,4-triazoles 5 with substituted acetophenone 6 in ethanol
medium in the presence of sodium hydroxide as catalyst gave novel
series of 2-substituted-s-triazolo[5,1-b]-6/8-substituted quinolino-9-
arylacetyl[1,3]thiazines 8 instead of 1-aryl-3-[21-(5-substituted-4H-
1,2,4-triazole-5-thia)-61/81-substitutedquinoline-31-yl]-2-propene-1-
ones 7 (Scheme 2). 3- Substituted -4H-5-mercapto-1,2,4-triazoles 3
were prepared by the cyclization of appropriate aroyl thiosemicarbazide
2 with potassium hydroxide. These thiosemicarbazide 2 were obtained
by the reaction of aroyl hydrazide 1 with potassium thiocyanate, as per
the literature method.9 6/8-Substituted-2-chloro-3-formylquinolines 4
were prepared according to the literature method.10 The structures of
new compounds were characterized by analytical, spectral data, and
X-ray diffraction studies (Tables I, II, III & VI).
RESULTS AND DISCUSSION
The structures of the newly synthesized compounds were established
based on analytical and spectral data. In the IR spectra of compounds
5, the aldehyde carbonyl absorption band was observed in the region
1
of 1687-1690 cm−1. Further, the H NMR spectra of compound 5c the
methyl protons of the quinoline moiety came into resonance as a singlet
at δ 2.75 integrating for three protons. The aldehyde proton appeared
as a singlet at δ 10.35 integrating for one proton. The N-H proton ap-
peared as a singlet at δ 7.11, while the signal due to quinoline 4-H
appeared as singlet at δ 8.43, integrating for one proton. The signal
due to the remaining quinoline protons (5H, 7H, and 8H) and aro-
matic protons overlapped with each other and appeared as multiplets
in the region of δ 7.40–8.12 integrating for eight protons. Similarly, 1H
NMR spectra for compounds 5d, 5e, and 5j were also recorded and the
chemical shift values observed are presented in Table I. When

1872
B. Kalluraya et al.
SCHEME 1

Quinolinothiazines of Biological Interest
1873
SCHEME 2
these 3-aryl-5-(6/8-substituted-3-formyl quinoline-2-yl)thia-4H-1,2,4-
triazole 5 were condensed with appropriately substituted ace-
tophenones in the presence of sodium hydroxide, we expected
the formation of 1-aryl-3-[21-(5-substituted-4H-1,2,4-triazole-5-thia)-
61/81-substituted quinoline-31-yl]-2-propen-1-ones 7. However, surpris-
ingly this one pot reaction resulted in the formation of a novel
series of 2-substituted-s-triazolo[5,1-b]-6/8-substituted quinolino-9-
arylacetyl[1,3]thiazines 8 (Scheme 2). A probable mechanistic pathway
for the formation of these compounds is suggested in Scheme 3. Fur-
ther evidence for the proposed structure was obtained by Mass spectral

1874
B. Kalluraya et al.
TABLE I Selected1 H NMR (δ, ppm) Spectra of the Compounds
5d. 1H NMR (CDCl3+ DMSO-d6)δ 3.96 (s,3H,OCH3) 10.5 (s,1H, CHO), 7.03 (s, 1H,
triazole-NH), 8.36 (s, 1H, quinoline-4H ), 7.89 (d, 1H, quinoline-8H), 7.13–8.15 (m,
7H, Ar-H & quinoline-5H , 7H).
5e. 1H NMR (CDCl3+ DMSO-d6)δ 10.5 (s, 1H, CHO), 9.33 (s, 1H, OH), 8.45 (s, 1H,
quinoline-4H), 6.91 (d, 2H, ortho-protons of p-hydroxyphenyl), 7.96 (d, 2H, meta-
protons of p-hydroxyphenyl ), 7.48–8.02 (m, 5H, quinoline-5H, 6H, 7H, 8H and
triazole-NH protons).
5j. 1H NMR (CDCl3)δ 2.57 (s, 1H, CH3), 10.55 (s, 1H, CHO), 8.39 (s, 1H, quinoline-4H),
7.44 (d, 2H, ortho protons of p-chlorophenyl), 8.09 (d, 2H, meta protons of
p-chlorophenyl), 7.07–7.92 (m, 4H, quinoline-5H, 6H, 8H and triazole-NH protons).
8d. 1H NMR (CDCl3+ DMSO-d6)δ 3.87 (dd, 1H, CH), 3.65 (dd, 2H, CH2), 8.43 (s, 1H,
quinoline-4H), 6.88 (d, 2H, ortho-protons of p-hydroxyphenyl), 7.78 (d, 2H,
meta-protons of p-hydroxyphenyl), 7.37 (d, 2H, ortho-protons of p-chlorophenyl),
7.88 (d, 2H, meta-protons of p-chlorophenyl), 7.54–7.99 (m, 5H, OH, quinoline-5H,
6H, 7H and 8H).
8e. 1H NMR (CDCl3)δ 2.73 (s, 3H, CH3), 3.87 (dd, 1H, CH), 3.61 (dd, 2H, CH2), 8.35 (s,
1H, quinoline-4H ), 7.34–8.09 (m, 13H, Ar-H and quinoline-5H, 6H and 7H).
8j. 1H NMR (CDCl3)δ 3.92 (s, 3H, OCH3), 3.65 (dd, 1H, CH), 3.55 (dd, 2H, CH2),
7.28–8.15 (m, 13H, Ar-H and quinoline-4H, 5H, 6H and 7H).
data. In the Mass spectra of 5d, the molecular ion peak is observed
at m/z 362 (Molecular Formula C19H14N4O2S) in agreement with the
proposed structure. Similarly the Mass spectrum of compounds 5g m/z
363 (M++1 peak) (Molecular Formula C19H14N4O2S) and 5h m/z 378
(Molecular Formula C19H14N4O3S) are in agreement with the proposed
structure.
In the IR spectra of compounds 8, the carbonyl absorption band was
1
observed in the region of 1670–1681 cm−1. In the H NMR spectra of
compound 8a, the thiazine 4H (i.e., CH) proton came into resonance as
doublet of a doublet centered at δ 3.89 integrating for one proton. The
signal due to CH2 protons appeared as two doublets centered at δ 3.62
integrating for two protons, which indicated that the two protons are
magnetically non-equivalent since they are adjacent to a chiral carbon.
The quinoline-4H proton appeared as a singlet at δ 8.43 integrating for
one proton, while the signal due to remaining quinoline protons (5H,
6H, 7H, and 8H) and two phenyl ring protons overlapped with each
other and appeared as multiplets in the region of δ 7.26–8.10 integrat-
ing for 14 protons. Similarly, the 1H NMR spectra of thiazines 8d, 8e,
and 8j were also recorded and the chemical shift assignments are given
in Table I. Further evidence for the proposed structure was obtained
by Mass-spectral data. The mass spectrum of compound 8a showed the
molecular ion peak at m/z 435, which is M++1 peak and is in agree-
ment with the molecular formula C26H18N4OS. The other prominent

1875

1876

Quinolinothiazines of Biological Interest
1877
TABLE IV Antibacterial Activities of 3-Aryl-5-(6/8
substituted-3-formyl-2-yl) thia-4H-1,2,4-triazoles 5a–l
Minimum inhibitory concentration (MIC) (µg/ml)
Compound no.
E. coli
K. pneu.
P. aer.
S. aur.
5a
5b
10
25
12.5
25
25
25
25
25
5c
5d
25
25
12.5
25
25
25
12.5
25
5e
5f
5g
5h
12.5
12.5
25
12.5
25
12.5
25
25
25
25
25
12.5
25
12.5
25
25
5i
25
25
25
25
5j
5k
5l
12.5
12.5
25
12.5
12.5
25
25
12.5
25
12.5
12.5
25
Nitrofurazone
DMF (control)
12.5
—
12.5
—
12.5
—
12.5
—
E. coli = Escherichia coli; K. pneu = Klebsiella pneumonia; P. aer =
pseudomonas aeruginosa; and S. aur = Staphylococcus aureus
peak at m/z 329 is due to loss of benzoyl cation from the molecular ion.
Similarly, the peak at m/z 105 is due to benzoyl cation. The mass spec-
trum of compound 8d showed molecular ion peak at m/z 485 (M++1)
in agreement with molecular formula C26H17ClN4O2S. The peak at m/z
345 is due to the loss of benzoyl cation. Similarly, for the mass spectrum
of the compound 8e, the molecular ion peak was observed at m/z 448 in
agreement with the molecular formula C27H20N4OS. The base peak at
m/z 343 is due to the loss of benzoyl cation. The formation of thiazine
rather than the expected chalcone is confirmed by recording single crys-
tal X-ray for the compound 8e (Figure 1). The crystallographic data are
summarized in Table VI.
EXPERIMENTAL
The melting points of the newly synthesized compounds were de-
termined in open capillaries and were uncorrected. The IR spectra
were recorded on a Perkin Elmer 983 spectrophotometer or NICOLET
1
AVATAR 330 FT IR spectrophotometer in KBr pellets. The H-NMR
spectra were recorded on a Bruker AC 300F (300MHz) NMR spectrome-
ter using DMSO-d6 or CDCl3 as solvent and TMS as internal standard.
All chemical shift values are expressed in δ scale. Mass spectra was
recorded on a Jeol-JMS-D300 mass spectrometer operating at 70eV or

1878
B. Kalluraya et al.
TABLE V Antibacterial and Antifungal Activity Data of Compounds
8a–l
Antifungal activity
(MIC in µg/ml)
Antibacterial activity (MIC in µg/ml)
Compd. no.
E. coli S. aureus P. aeruginosa B. subtilis
C. albicans
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
6.25
6.25
6.25
6.25
6.25
12.5
12.5
6.25
50
6.25
6.25
6.25
12.5
—
6.25
6.25
12.5
6.25
6.25
25
12.5
6.25
25
6.25
12.5
6.25
6.25
—
6.25
6.25
6.25
6.25
6.25
12.5
6.25
6.25
25
6.25
6.25
6.25
12.5
—
6.25
6.25
6.25
6.25
12.5
25
6.25
6.25
25
6.25
12.5
6.25
12.5
—
6.25
6.25
6.25
3.125
6.25
6.25
6.25
6.25
6.25
6.25
6.25
3.125
—
Nitrofurazone
Fluconazole
DMF (Control)
6.25
—
—
—
—
—
Disc size = 5.5 mm; Duration = 24 h; E. coli = Escherichia coli; S. aur =
Staphylococcus aureu; P. aer = pseudomonas aeruginosa; B. subtilis = Bacillus
subtilis; and C. albicans = Candida albicans.
JEOL SX 102/DA-6000 mass spectrometer using Argon/Xenon (6 kV,
10 mA) as the FAB gas operating at 10 kV. CHN analysis was car-
ried out on a Vairo-EL(Elementa) model. The purity of all compounds
was confirmed by TLC. The single crystal X-ray was measured on an
Oxford Excalibur 2 Diffractometer [R(int) = 0.0515]. The structural
solution and refinement was done using SHELXS-9711 and SHELXL-
9712 programs. The yield, melting point and other characterization data
of compounds 8 are given in Table III.
3-Aryl-5-mercapto-4H-1,2,4-triazoles 3
A mixture of aroyl hydrazine 1 (0.01 mol), potassium thiocyanate
(1.9 g, 0.02 mol), conc. HCl (10 mL) and water (20 mL) was refluxed
for 3 h. After cooling, the resulting aroyl thiosemicarbazide 2 was
collected by filtration, washed with water, dried, and recrystallized
from ethanol. A mixture of aroyl thiosemicarbazide 2 (0.05 mol)
and 10% KOH (50 mL) was refluxed for 3 h. The mixture was then
cooled to room temperature and filtered. The filtrate was neutralized
by the gradual addition of glacial acetic acid. The resulting solid
3-aryl-5-mercapto-4H-1,2,4-triazole 3 was collected by filtration, dried
and recrystallized from ethanol.

Quinolinothiazines of Biological Interest
1879
TABLE VI Crystal Data and Structure Refinement for C27H20N4OS
(8e)
Identification code
Empirical formula
Formula weight
cvd113
C27H20N4OS
448.54
Temperature
106(2) K
Wavelength
0.71073 A
Crystal system, space group
Unit cell dimensions
Triclinic, P-1
a = 10.2601(6) A alpha = 61.041(9) deg.
b = 11.1491(10) A beta = 69.497(8) deg.
c = 11.2440(10) A gamma = 76.479(7) deg.
1050.86(15) A∧3
Volume
Z, Calculated density
Absorption coefficient
F(000)
2, 1.421 Mg/m∧3
0.184 mm∧-1
470
Crystal size
Theta range for data collection
Limiting indices
0.15 × 0.10 × 0.06 mm
2.57 to 25.00 deg.
-12<=h<=12, -13<=k<=13, -13<=l<=13
13756/3681 [R(int) = 0.0515]
2453 Fo > 4sig(Fo)
99.6%
Reflections collected / unique
Observed reflns[I>2sigma(I)]
Completeness to theta = 25.00
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F∧2
Final R indices [I>2sigma(I)]
R indices (all data)
None
Full-matrix least-squares on F∧2
3681/0/274
0.895
R1 = 0.0365, wR2 = 0.0836
R1 = 0.0598, wR2 = 0.0877
0.361 and -0.644 e.A∧-3
Largest diff. peak and hole
6/8-Substituted 2-chloro-3-formyl quinoline 4
Dimethyl formamide (9.13 g, 9.9 ml, 0.125 mol) was cooled to 0◦C in
a flask equipped with a drying tube; phosphorous oxychoride (53.7 g,
32.2 ml. 0.35 mol) was added drop wise with stirring. To this solution,
acetanilide (6.55 g, 0.05 mol) was added and the solution was heated
under reflux for 16 h. The reaction mixture was poured into ice water
and stirred for 30 min at 0–10◦C until 6/8-substituted-2-chloro-3-formyl
quinoline 4 separated as yellow precipitate. It was filtered, washed with
water, and recrystallized from ethyl acetate.
3-Aryl-4H-5-(61/81-substituted-31-formyl-21-quinolinyl)
thia-1,2,4-triazole 5
A mixture of 3-aryl-5-mercapto-4H-1,2,4-triazole 3 (0.01 mol), 6/8- sub-
stituted -2-chloro-3-formyl quinoline 4 (0.01mol) were dissolved in
ethanol (20 mL). Pyridine (1 mL) was added as a catalyst to the above
mixture and the contents were refluxed on water bath for 4 to 5 h. After

1880
B. Kalluraya et al.
SCHEME 3
the completion of reaction, the excess solvent was removed by distil-
lation, and the contents were cooled to room temperature. The solid
product separated was collected by filtration, dried, and recrystallized
from a mixture of ethanol and dimethylformamide (Table II).
2-Substituted-s-triazolo[5,1-b]-6/8-substituted
quinolino-9-arylacetyl[1,3]thiazines 8
To
a
thoroughly stirred solution of 3-aryl-5-(61/81-substituted-
31-formyl-21-yl)thia-1,2,4-triazole 5 (0.01 mol) and p-substituted
acetophenone 6 (0.01 mol) in ethanol (25 mL) was added 40% NaOH
(3 mL). The reaction mixture was stirred for 24 h. It was poured into

Quinolinothiazines of Biological Interest
1881
FIGURE 1 Single crystal X-ray structure of the compound 8e. Selected bond
˚
angles (A) and angles (deg.): S(21)-C(22) 1.7287(19); S(21)-C(20) 1.7663(19);
C(22)-S(21)-C(20) 100.63(9); N(19)-C(20)-S(21) 110.56(14); N(23)-C(22)-S(21)
124.97(14); N(24)-C(22)-S(21) 124.26(14); C(10)-C(20)-S(21) 124.32(15); O(7)-
C(7) 1.218(2); N(24)-N(25) 1.372(2).
ice water, acidified with dil.HCl, filtered, and recrystallized from a mix-
ture of ethanol and dimethylformamide to give 8 (Table III).
BIOLOGICAL ACTIVITY
Antibacterial Activity
The antibacterial activity of the newly synthesized compounds 5 were
carried out against four different pathogenic organisms. They are

1882
B. Kalluraya et al.
Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, and
Staphylococcus aureus. The antibacterial activity of the newly synthe-
sized compounds in the present investigation was assessed by Minimum
Inhibitory Concentration (MIC) by serial dilution method13 (Table-IV).
Among the compounds tested compound 5k carrying p-chlorophenyl
group at the third position of the triazole and methyl group at the
eighth position of the quinoline showed highest activity among all the
organisms tested at 10µg/mL concentration comparable with that of
standard drug Nitrofurazone. Apart from these compounds, 5e carry-
ing p-hydroxyphenyl group at the third position of the triazole and 5j
carrying p-chlorophenyl group at the third position of the triazole and
methyl substituent at the sixth position of quinoline showed consider-
able activity against E. coli., K. pneumonia, and S. aureus. In addition,
compound 5a, carrying the phenyl group at the third position of the
triazole, showed activity against E. coli; 5c, carrying phenyl group at
the third position of the triazole and methyl substituent at the eighth
position of the quinoline moiety, showed activity against K. pneumo-
niae and S. aureus; and 5f, carrying p-hydroxy phenyl group at the
third position of the triazole and methyl group at the sixth position of
the quinoline moiety, showed activity against E. coli. Compound 5g,
carrying p-hydroxy phenyl group at the third position of the triazole
and methyl group at the eight position of the quinoline moiety, showed
activity against K. pneumoniae and S. aureus.
The antibacterial activity of the newly synthesized thiazines 8 were
carried out against four different pathogenic organisms—two each
of Gram-negative and Gram-positive. They are Staphylococcus au-
reus (Gram-positive), Bacillus subtilis (Gram-positive), Escherichia coli
(Gram-negative), and Pseudomonas aeruginosa (Gram-negative). The
concentration at which there is no turbidity was taken as Minimum In-
hibitory Concentration (MIC) and the results are tabulated in Table-V.
Among the compounds tested most of the compounds showed signif-
icant antibacterial activity comparable with that of standard drug
Nitrofurazone.14
Antifungal Activity
Antifungal activity of thiazines 8 was carried out on the fungus Candida
albicans. Fluconazole was employed as the standard. The results of
antifungal activity data are also given in Table V. Among the compounds
tested, the compounds 8d and 8l showed the highest antifungal activity
comparable with that of standard drug Fluconazole.

Quinolinothiazines of Biological Interest
1883
CONCLUSION
A novel series of thiazines 8 were obtained in the one-pot reaction of 3-
aryl-5-(6/8-substituted-3-formyl quinoline-2-yl)thia-4H-1,2,4-triazole
5 with various substituted acetophenones 6, instead of the expected
1-aryl-3-[21-(5-substituted-4H-1,2,4-triazole-5-thia)-61/81-substituted
quinoline-31-yl]-2-propen-1-ones 7. The biological activity studies of in-
termediate and final thiazines indicates that the thiazines are more po-
tent antibacterial agents and the activity is comparable with that of the
standard drug Nitrofurazone which is an effective antibacterial agent
against urinary infections, particularly against the bacteria E. coli.
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