Synthesis, identification and in vitro biological evaluation of some novel quinoline incorporated 1,3-thiazinan-4-one derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.06.038

The present study describes the synthesis of two new series of 3-hydroxy-N-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-8-(trifluoromethyl)quinoline-2-carboxamide derivatives (4a–j) and 3-((7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one derivatives (5a–7j). All the compounds were synthesized in moderate to good yield by one-pot three component cyclo-condensation reaction. The newly synthesized compounds were characterized by FT-IR,¹H,¹³C NMR and elemental analysis. The compounds were screened for their in vitro antibacterial activity against a panel of pathogenic bacterial strains, antitubercular activity against Mycobacterium tuberculosis H₃₇Rv and also for their in vitro antimalarial activity against Plasmodium falciparum. Among the synthesized compounds two of them (4f and 5f) showed excellent antibacterial activity against C. tetani at 15.6?μg/mL. Some of them exhibited excellent antitubercular (4f & 5f) and good antimalarial (4f, 5f & 6f) activity compared with the first line drugs.

Full text of DOI:10.1016/j.bmcl.2016.06.038

Accepted Manuscript
Synthesis, Identification and in vitro biological evaluation of some novel qui-
noline incorporated 1,3-thiazinan-4-one derivatives
S. Umamatheswari, C. Sankar
PII:
S0960-894X(16)30649-7
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.06.038
BMCL 23991
Reference:
Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
6 November 2015
31 May 2016
15 June 2016
Please cite this article as: Umamatheswari, S., Sankar, C., Synthesis, Identification and in vitro biological evaluation
of some novel quinoline incorporated 1,3-thiazinan-4-one derivatives, Bioorganic & Medicinal Chemistry Letters
(2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.06.038
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Synthesis, Identification and in vitro biological evaluation of some novel
quinoline incorporated 1,3-thiazinan-4-one derivatives
S. Umamatheswaria and C. Sankarb*
aDepartment of Chemistry, Govt. Arts College, Tiruchirappalli, Tamil Nadu, India – 620022.
bDepartment of Chemistry, TRP Engineering College, Irungalur, Tiruchirappalli, Tamil Nadu,
India - 621 105.
ABSTRACT
The present study describes the synthesis of two new series of 3-hydroxy-N-(4-
oxo-2-phenyl-1,3-thiazinan-3-yl)-8-(trifluoromethyl)quinoline-2-carboxamide derivatives
(4a-j)
and
3-((7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one
derivatives (5a-7j). All the compounds were synthesized in moderate to good yield by
one-pot three component cyclo-condensation reaction. The newly synthesized compounds
1
13
were characterized by FT-IR, H, C NMR and elemental analysis. The compounds were
screened for their in vitro antibacterial activity against a panel of pathogenic bacterial
strains, antitubercular activity against Mycobacterium Tuberculosis H37Rv and also for
their in vitro antimalarial activity against Plasmodium falciparum. Among the synthesized
compounds two of them (4f and 5f) showed excellent antibacterial activity against C.
Tetani at 15.6 µg/mL. Some of them exhibited excellent antitubercular (4f & 5f) and good
antimalarial (4f, 5f & 6f) activity compared with the first line drugs.
Keywords: Tuberculosis - Quinoline - Thiazinan-4-one - Antimalarial.
*Corresponding author, Tel.; +91-9944585257
E. mail address: sankschem@gmail.com (C.Sankar)
1

Malaria is a mosquito-borne infectious disease of human’s and other animals
caused by protists of the genus Plasmodium. The WHO estimates that the death rate due to
malaria is comparable to roughly 2000 deaths every day.1,2 Plasmodium falciparum is the
parasite responsible for most malaria cases (80%). The malaria burden is concentrated in
14 endemic countries, which account for an estimated 80% of malaria deaths.3 Likewise,
the occurrence of multidrug-resistant M. Tuberculosis strains is one of the chief causes of
the revival of tuberculosis observed during the world since the mid-1980s.4,5 Multidrug-
resistant TB and extensively drug-resistant TB are inflexible to handle with any of the
usually accessible drugs. This warrants the need for latest component of drugs to counter
successfully the danger posed by these strains.6 It is a disgusting revelation that MDR-TB
is present in almost all countries as per the recent survey by the WHO.7 The WHO has
declared tuberculosis to be a ‘global emergency’ and estimates that about 30 million
people will be infected by mycobacterium tuberculosis within the next 20 years.8
Heterocyclic compounds play an important role in designing new class of
structural entities for medicinal applications. Among pharmacologically important
heterocyclic compounds, substituted quinolines and its derivatives are significant because
of their wide spectrum of biological activities and their presence in naturally occurring
compounds. In particular, quinoline alkaloids are found in many different plants including
Berberidaceae, Fumariaceae, Papavaraceae and Rutaceae.9-12 A large variety of quinoline
derivatives have been used as antimalarial,13-15 antibiotic,16,17 anticancer,18 anti-
inflammatory,19 antihypertensive,20 tyrokinase PDGF-RTK inhibition21 and anti-HIV22,23
properties. To list a few quinoline derivatives quinine (antipyretic, antimalarial, analgesic,
and anti-inflammatory properties), chloroquine (antimalarial), amidiaquine (antimalarial
and anti-inflammatory agent) which are actively used in pharmacological field are given in
Fig. 1.
2

H
OH
N
N
HN
HO
N
HN
O
Cl
N
N
N
Chloroquine
Quinine
amidiaquine
Fig. 1. Chemical structures of quinoline derivatives as antimalarial drugs
Quinoline has been considered a pharmacophore for the design of anti-TB agents.
Ciprofloxacin and moxifloxacin (Fig. 2) are promising agents for the treatment of TB24
having quinoline moiety. Quinoline based mefloquine (Fig. 2) is known for anti-tubercular
activity25-28 and its analogs have displayed moderate29 to submicromolar30 level.
O
N
O
HO
O
N
O
N
H
F
OH
F
OH
N
HN
N
CF3
HN
OMe
CF3
Ciprofloxacin
Mefloquine
Moxifloxacin
Fig. 2. Chemical structures of quinoline derivatives as anti-TB drugs
It has been well established that fluorinated quinolines, inparticular, -CF3
substituted quinolines have got a significant place in modern medicinal chemistry.
Introduction of trifluoromethyl group provides better electronic effect at neighboring
carbon centers, as well as having a substantial effect on the molecule's dipole moment,
acidity and basicity of neighboring groups.31 Their biological studies clearly indicated that,
the presence of trifluoromethyl group in position seven and eight of the quinoline ring is
responsible for their enhanced biological activity32-34 and are the subject of considerable
growing interest. Further, various types of hydrazones have attracted continued interest
3

inthe field of medicine owing to their varied biological activities as antimicrobial,35
antimalarial,36 and antitubercular properties.37
Therefore, the syntheses of quinoline and its derivatives have received an
increasing attention to synthetic organic chemists and biologists.38,39 It is still a challenge
for the pharmaceutical chemist to develop more effective and less toxic agents to treat
signs and symptoms of TB, Malarial disorders.
All the above facts reveal that there is an urgent need for expansion of new drugs
with divergent and unique structure and with a mechanism of action possibly different
from that of existing drugs. In this regards, it was thought worth to synthesize various
novel compounds which may have combined applications as antimalarial, antituberculosis
and antimicrobial agents.
In continuation of our research on bioactive molecules, we designed and
synthesized a new series of (3-quinolin-2-yl)-2-aryl-1,3-thiazinan-4-one derivatives. We
emphasized the strategy of combining two chemically different, but pharmacologically
compatible moieties such as quinoline and thiazinan-4-one within one frame. In the
present study the quinoline moiety was incorporated in the 1,3-thiazinan scaffold and
evaluated for in vitro antimicrobial, antimalarial and MTB activity.
The synthetic route used to synthesize the unreported title compounds are
illustrated in Scheme 1. One of the starting material 4-hydroxy-8-
(trifluoromethyl)quinoline-3-carbohydrazide was prepared according to literature
method.16 The quinolone skeletons were built up by the Gould–Jacobs procedure starting
from 3-(trifluoromethyl) aniline.
4

HO
CF3
O
N
O
S
a
N
N
H
HN
NH2
n=2-4
R
O
O
4a-j
EDC, THF
HS
OH
Cl
N
O
2
or
Cl
+
H
OH
NH2
N
N
H
N
O
R
NH
Com. No. R
b
CF3
n=2-4
N
a
b
c
d
e
f
H
1
3
p-CH3
p-OCH3
p-Cl
p-F
p-Br
S
R
5a-5j; n = 2
6a-6j; n = 3
7a-7j; n = 4
g
h
i
p-OH
m-OCH3
m-Cl
m-F
j
Scheme 1. Synthesis protocol of quinolone antibiotic 1,3-thiazinan-4-ones (4a-7j). Reagents and conditions.
a) 4-hydroxy-8-(trifluoromethyl)quinoline-3-carbohydrazide, THF, -5 °C, aldehyde, 3-mercaptopropionic
acid, EDC, stirring 7-9 h. (b) 7-chloroquinoline-1,2-diamine, THF, -5 °C, aldehydes, 3-mercaptopropionic
acid, EDC, stirring 7-9 h
3-(Trifluoromethyl) aniline condensation with diethyl ethoxymethylene malonate and
following thermal cyclization in dowtherm (biphenyl: biphenyloxide (3:7)) yielded the 4-
hydroxyquinoline-3-carboxylic ester, which on condensation with hydrazine hydrate in
presences of alcoholic medium resulted 4-hydroxy-7-trifluoromethyl-quinoline-3-
carboxylic acid hydrazide. Quinoline hydrazide/ diamine was dissolved in THF and the
reaction mixture was cooled to -5 °C, the substituted benzaldehydes was then added drop
wise, followed by 3-mercaptopropionic acid and 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide, the reaction mixture was then slowly warmed to room temperature and
stirred at room temperature for another 7-9 h, it was then quenched with water and worked
5

up to give the desired meta thiazanones in quantitative yield. The purity of compounds 4a-
j and 5a-7j were checked by TLC and elemental analysis. Both analytical and spectral data
(1H &13C NMR) of all the synthesized compounds were in full agreement with the
proposed structures.40,41
The FT-IR spectrum of compounds 4a-7j showed two bands at 3410 cm-1 and 3138
cm-1, which are due to the hydroxyl and amide groups respectively. The strong absorption
band around 1668 - 1670 cm-1 which are attributed to the carbonyl group (C=O stretching).
1
In the H-NMR spectra reveal a signal corresponding to quinoline at 6.93-7.27 ppm as
multiplet. The proton H-2 appeared as a singlet at 6.5-6.85 ppm. The four diastereotopic
protons of H-5 and H-6 of thiazinanone ring are shown as multiplets due to the
superposition of signals in the range of 2.78-2.65 ppm. In the 13C NMR spectrum carbonyl
carbons of thiazinanones are assigned as 170-169 ppm. In fluorine substituted compounds,
two signals were observed around 163 and 161 ppm because of fluorine attached carbon.
The observed two signals were due to C-F coupling between carbon and the fluorine atom.
There are two signals around 44.8 and 58.3 ppm, which are conveniently assigned to C-7
and C-8 of ethylene carbons, whereas the thiazinan-4-one carbons C-6, C-5,and C-2
appeared at 21.5, 34.1 and 58.3 ppm respectively.
In vitro antibacterial activity of all the synthesized compounds were evaluated
against three Gram positive bacteria (Streptococcus pneumonia MTCC 1936, Bacillus
subtilis MTCC 441 and Clostridium tetani MTCC 449) and three Gram negative bacteria
(Escherichia coli MTCC 443, Salmonella typhi MTCC 98 and Vibrio cholera MTCC
3906) by using ampicillin, norfloxacin and ciprofloxacin as the standard antibacterial
drugs. The minimal inhibitory concentration (MIC) of all the synthesized compounds was
determined by the broth micro dilution method according to National Committee for
Clinical Laboratory Standards (NCCLS).42 All the synthesized compounds (4a-4j and 5a-
6

Table 1. In-vitro antibacterial activity of 4a-7j in µg/mL
S.No
S.
Pneumonia Subtilis Tetani E. Coli S.Typhi Cholera
B.
C.
V.
Comp.
4a
1
500
500
250
250
125
125
250
500
250
250
500
500
250
125
62.5
62.5
250
250
125
125
500
250
125
62.5
31.25
62.5
125
250
250
125
500
500
250
250
100
100
250
500
250
250
100
10
250
250
125
62.5
31.25
62.5
125
250
125
125
250
250
250
62.5
62.5
31.25
62.5
62.5
250
250
500
125
125
125
62.5
62.5
250
250
125
125
500
250
250
250
100
100
250
500
250
250
250
100
500
250
250
125
15.6
31.25
250
500
250
125
250
250
125
62.5
15.6
31.25
250
250
250
250
500
500
250
250
100
100
250
500
250
250
500
250
250
125
125
250
500
250
250
125
250
50
500
500
250
250
125
125
250
250
125
125
500
250
125
125
62.5
125
500
250
125
62.5
500
250
250
125
62.5
125
250
250
250
250
500
500
500
250
125
62.5
125
250
250
125
100
10
500
250
125
250
250
31.25
125
250
250
250
500
500
250
250
62.5
100
250
500
250
250
500
500
500
250
125
62.5
62.5
250
250
125
500
500
250
125
62.5
62.5
250
250
125
100
100
10
500
500
250
125
125
62.5
125
250
250
125
250
250
250
125
125
31.25
250
500
250
250
500
500
250
250
100
100
250
500
250
250
500
250
125
62.5
62.5
125
250
125
125
125
100
10
2
4b
4c
3
4
4d
4e
5
6
4f
7
4g
8
4h
9
4i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
4j
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
Ampicillin
Norfloxacin
7

Ciprofloxacin
43
25
50
100
25
25
25
The antibacterial screening of compounds 8-trifluoromethyl quinoline4a–j and 7-
chloro quinoline 5a–7j derivatives (Table 1) pointed out that compounds 4e and 5e
showed an outstanding inhibitory effect i.e.15.6 µg/mL against C. tetani as compared to
ampicillin and ciprofloxacin. The majority of the compounds showed excellent activity
against gram positive bacteria B. subtilis and C. tetani as that of the ampicillin. In the case
of inhibiting S. pneumoniae, compound 6e was found to be very good potent as ampicillin.
Whereas in the case of inhibiting Gram negative bacteria, compounds 4f and 5f showed
maximum activity against V. cholera and S. typhi as compared to ampicillin. Compounds
5e, 5j, 6e and7f showed similar activity against E. coli upon comparison with the standard
drug ampicillin. The antibacterial results revealed that most of the prepared compounds
showed improved activity against the Gram-positive bacteria rather than Gram-negative
bacteria.
In the present investigation, we also determined the antitubercular activity of the
lead molecules against the Mycobacterium tuberculosis H37Rv strain. Primary screening of
all the newly synthesized compounds was conducted at 6µg/mL by using Lowensteine–
Jensen medium (conventional method) as described by Rattan.43 The standard deviation
value is shown in terms of SD (≤ 0.75). All the newly synthesized compounds are
screened
for
their
antitubercular
activity
in
three
sets
(n꞊3)
against M. tuberculosis used in this study. The standard drugs rifampicin and isoniazid
were used for comparison. The bioassay results obtained for the efficacy of all the
synthesized compounds 4a–j, 5a–j, 6a-j and 7a–j against M. tuberculosis H37Rv are
summarized in Table 2. The antitubercular screening data revealed that all the tested
compounds showed moderate to very good inhibitory activity.
8

Table 2. In vitro antitubercular activity (% inhibition) of compounds 4a-7j against M.
tuberculosis H37Rv (at concentration 6 µg/mL).
Comp.
4a
4b
4c
4d
4e
4f
% Inhibition
Comp.
% Inhibition
55
60
70
90
92
98
79
65
71
73
50
57
60
73
80
95
74
58
60
66
47
6b
41
57
67
78
87
42
51
55
52
32
40
48
60
65
82
38
42
49
55
98
99
6c
6d
6e
6f
6g
4g
4h
4i
6h
6i
6j
4j
7a
5a
5b
5c
5d
5e
5f
7b
7c
7d
7e
7f
7g
5g
5h
5i
7h
7i
7j
5j
Rifampicin
Isoniazid
6a
The outcome of the results showed that compounds 4d, 4e, 4f and 5f are found to
possess excellent activity, respectively, 90%, 92%, 98% and 95% at 6 µg/mL against M.
tuberculosis H37Rv.Among the above four compounds, two compounds 4f and 5f also
showed brilliant activity (i.e.> 95%) at 6 µg/mL concentration.While compounds 5e and
6f were found to be moderately active against M. tuberculosis H37Rv. All other remaining
compounds showed poor inhibition of M. tuberculosis growth. From the above results, it
9

can beconcluded that compounds 4f and 5f may become a new class of antitubercular
agents in the future.
All the synthesized compounds (4a–j and 5a-7j) were tested for their antimalarial
activity in three sets (n=3) against the P. falciparum strain. The results of the
pharmacological screening data are expressed as the drug concentration resulting in 50%
inhibition (IC50) of parasite growth.
Table 3. In vitro antimalarial activity of compounds 4a-7j against P. falciparum.
S.No
1
S.No
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
IC50 (µg/mL)
2.1
IC50 (µg/mL)
2.2
Comp.
4a
4b
4c
4d
4e
4f
Comp.
6b
2
1.56
6c
0.52
3
1.45
6d
0.12
4
0.067
0.052
0.018
1.58
6e
0.089
0.056
1.14
5
6f
6g
6
7
4g
4h
4i
6h
1.87
8
1.7
6i
1.62
9
1.2
6j
1.12
10
11
12
13
14
15
16
17
18
19
20
21
4j
0.91
7a
3.12
5a
5b
5c
5d
5e
5f
2.7
7b
2.33
1.97
7c
0.81
0.62
7d
0.14
0.098
0.081
0.045
1.78
7e
0.092
0.064
2.64
7f
7g
5g
5h
5i
7h
7i
2.14
1.89
1.93
1.57
7j
1.31
5j
1.05
Chloroquine
Quinine
0.02
6a
3.5
0.271
10

Chloroquine and quinine were used as the standard drugs and their IC50 values are
represented in Table 3. It is clear observed that all the tested compounds showed moderate
to good antimalarial activity against P. falciparum.
As shown in Table 3, nine compounds (4d, 4e, 4f, 5d, 5e, 5f, 6d, 6e and 6f) were
found to have IC50 in the range of 0.02 to 0.098 µg/mL against P. falciparum strain. All
these compounds displayed excellent activity against the P. falciparum strain as compared
to quinine with IC50 0.271µg/mL. Among all the above compounds, only compound 4f
displayed marvelous activity, i.e. IC50 0.018 µg/mL, as compared to chloroquine with IC50
0.020 µg/mL. Moreover compounds 4d, 4b and 5f were found to possess moderate
activity, i.e. IC50 0.036 µg/mL in agreement with chloroquine i.e. IC50 0.020 µg/mL. All
other remaining compounds were found to be not as much active as chloroquine and
quinine against the P. falciparum strain.
The substitution pattern of the aryl ring at the second position in the thiazinan-4-
one ring was observed to affect biological activity. It emerged that the electron
withdrawing and releasing groups were found to be responsible for variation in
activity.The electronic nature of the substituents led to significant variation in all kinds of
pharmacological activities. Electron-donating substituent (–OH, –OCH3) containing
compounds in the basic skeleton led to an increasing the antibacterial activity against B.
subtilis (5g and 5h). While only the –OH group was found to increase antimalarial and
antituberculosis activities. The phenyl group (weak electron donating)was found to be
accountable for increasing antimalarial activity. The phenyl ring without any electron
donating or withdrawing group also showed poor antimalarial activity. In contrast,
compounds bearing electron withdrawing groups (Br) possessed stronger antituberculosis
and antimalarial activity (4f and 5f), whereas fluorine was observed to be responsible for
intensified antibacterial activities.
11

On the basis of biological activity, it has been observed that compounds having
electron withdrawing fluoro groups show increased antimalarial activity. While the
bromine group is responsible for enhancing the antimalarial activity. In depth analysis of
antimalarial activity of (7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one
hybrids series three important point were observed. 1) Lengthening and shortening of
carbon spacer linker does not play an important role in influencing the activity. 2) The
activity increased manifold when the electron withdrawing groups replaced by electron
donating groups. 3) The comparison of antimalarial activity of two groups of 3-hydroxy-8-
(trifluoromethyl)quinoline-1,3-thiazinan-4-one
(4a-4j)
and
(7-chloroquinolin-4-
ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one (5a-7j). Clearly indicated that 4a-4j were
displayed superior activity against P.falciparum. This shows that the point of attachment
of the spacer to the thiazinone nucleus may not have a great impact on antimalarial activity
profile.
In conclusion a series of thiazinan-4-one derivatives carrying a 4-hydroxy-8-
trifluoromethyl and 7-chloro quinoline moiety have been synthesized in good yield and
screened for their biological activity with the aim of discovering innovative structure leads
serving as potential antimicrobial, antitubercular and antimalarial agents. Maximum
compounds showed brilliant antimalarial activity against P. falciparum strain as compared
to quinine. Most of the compounds were found to be active against C.tetani and B.subtillis.
Two leading compounds 4f and 5f displayed excellent antitubercular activity against
mycobacterium tuberculosis. The results indicated that compounds bearing the electron
withdrawing bromo group in the aryl moiety showed the highest antitubercular and
antimalarial actives.
12

Acknowledgements
The authors are thankful to SIF, Indian Institute of Science, Bangalore and to SAIF
IIT- Madras for recording NMR spectra. We thank to Mr. Robert C. Goldman,
Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF), Southern
Research institute, USA.
13

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40. 3-Hydroxy-N-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-8-
(trifluoromethyl)quinoline-2-carboxamide (4a):White solid; mp- 197–198°C;
Yield (88%); C21H16F3N3O3S; Anal. Calcd. For: C, 56.35; H, 3.55; N, 9.34.
1
Found: C, 56.37; H, 3.60; N, 9.39. H NMR (400 MHz, CDCl3): δ 2.55 (m,
1H, H-8b), 2.79 (m, 2H, H-5b, H-6b), 2.75 (m, 2H, H-7b, H-8a), 2.85 (m, 2H,
H-5a, H-6a), 4.26 (dt, 1H, J = 12.8, 4.9, H-7a), 6.55 (s, 1H, H-2), 7.05 –7.2
(m, 4H, ArH of phenyl), 7.47–7.57 (m, 5H, ArH of benzyl), 7.98–8.95 (m, 4H,
ArH of pyridyl), 8.14 (s, 1H, NH, D2O exchangeable). 13C NMR (400 MHz,
CDCl3): 174.1 (C-4), 31.6 (C-2), 40.6 (C-3), 158.3 (C-OH), 167.1 (C=O),
148.9 (C=N), 138.8, 130.3, 128.2, 127.1, 125.2, 124.1, 120.8, 114.12, 70.1,
63.7, 38.2, 31.5.
41. 3-((7-Chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one
(5a)
Creamy white solid; mp - 171–172°C; Yield (90 %); C20H18ClN3OS; Anal.
Calcd. for: C, 62.57; H, 4.73; N, 10.95. Found: C, 62.53; H, 4.70; N, 10.91. 1H
NMR (400 MHz, JH-H Hz) δ 2.65 (m, 1H, H-8b), 2.78 (m, 2H, H-5b, H-6b),
2.92 (m, 2H, H-7b, H-8a), 2.79-2.74 (m, 2H, H-5a, H-6a), 4.16 (dt, 1H, J =
13.0, 4.2, H-7a), 6.85 (s, 1H, H-2), 7.19 (d, 1H, J = 8.6, Ph-H), 7.44 (td, 1H, J
= 7.7, 1.2, Ph-H), 7.56 (td, 1H, J = 7.6, 1.1, Ph-H), 8.01 (dd, 1H, J = 8.0, 1.2,
Ph-H), 6.32 (d, 1H, 3-H quinoline); 7.36 (d, 1H, 7-H quinoline), 8.01 (1H, 5-H
13
quinoline), 7.85 (1H, 8-H quinoline), 8.50 (1H, 2H quinoline). C NMR (125
17

MHz) δ 21.5 (C-6), 34.1 (C-5), 44.8 (C-7), 56.9 (C-8), 58.3 (C-2), 126.9,
128.9, 132.7, 135.4 (Ph), 169.9 (C-4).
42. NCCLS (National Committee for Clinical Laboratory Standards), Performance
Standards for Antimicrobial Susceptibility Testing: Twelfth Informational
Supplement (2002), ISBN 1-56238-454-6 M100-S12 (M7).
43. Rattan,
A.;
Churchill,
B.I.
Antimicrobials
in
Laboratory
Medicine.Livingstone, New Delhi, 2000, 85-108.
18

FIGURE CAPTIONS
Figure 1. Chemical structures of quinoline derivatives as antimalarial drugs.
Figure 2. Chemical structures of quinoline derivatives as anti-TB drugs.
Scheme 1. Synthesis protocol of quinolone antibiotic 1,3-thiazinan-4-ones (4a-7j).
Table 1. In-vitro antibacterial activity of 4a-7j in µg/mL.
Table 2. In-vitro anti-tubercular activity data 4a-7j in µg/mL.
Table 3. In-vitro antimalarial activity of compounds 4a-7j µg/mL.
19

Synthesis, Identification and in vitro biological evaluation of some novel
quinoline incorporated 1,3-thiazinan-4-one derivatives
S. Umamatheswaria and C. Sankarb*
aDepartment of Chemistry, Govt. Arts College, Tiruchirappalli, Tamil Nadu, India – 620022.
bDepartment of Chemistry, TRP Engg. College, Irungalur, Tiruchirappalli, Tamil Nadu, India - 621 105.
HO
CF3
O
N
N
O
S
a
N
H
HN
NH2
n=2-4
R
O
O
4a-j
EDC, THF
HS
OH
Cl
N
O
2
or
Cl
+
H
OH
NH2
N
N
H
N
O
R
NH
Com. No. R
b
CF3
n=2-4
N
a
b
c
d
e
f
H
1
3
p-CH3
p-OCH3
p-Cl
p-F
p-Br
S
R
5a-5j; n = 2
6a-6j; n = 3
7a-7j; n = 4
g
h
i
p-OH
m-OCH3
m-Cl
m-F
j
*Corresponding author, Tel.; +91-9944585257
E. mail address: sankschem@gmail.com (C.Sankar)
20