Isocoumarin thioanalogues as potential antibacterial agents

Article abstract of DOI:10.1080/10426500802529507

A series of 3-substituted-1H-isochromene-1-thiones (3) were prepared by the reaction of 3-substituted isocoumarins (2) with Lawesson's reagent in the presence of toluene under a nitrogen atmosphere. The antimicrobial activities of the newly synthesized pr

Full text of DOI:10.1080/10426500802529507

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Phosphorus, Sulfur, and Silicon
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Isocoumarin Thioanalogues as
Potential Antibacterial Agents
P. Manivel a b , S. Mohana Roopan a , D. Prem Kumar
a & F. Nawaz Khan a
a Organic and Inorganic Chemistry Division, School
of Science and Humanities , VIT University , Vellore,
Tamil Nadu, India
b Syngene International Limited , Bangalore,
Karnataka, India
Published online: 21 Sep 2009.
To cite this article: P. Manivel , S. Mohana Roopan , D. Prem Kumar & F. Nawaz
Khan (2009) Isocoumarin Thioanalogues as Potential Antibacterial Agents,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:10, 2576-2582, DOI:
10.1080/10426500802529507
To link to this article: http://dx.doi.org/10.1080/10426500802529507
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Phosphorus, Sulfur, and Silicon, 184:2576–2582, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802529507
Isocoumarin Thioanalogues as Potential Antibacterial
Agents
P. Manivel,1,2 S. Mohana Roopan,1 D. Prem Kumar,1 and F.
Nawaz Khan1
1Organic and Inorganic Chemistry Division, School of Science and
Humanities, VIT University, Vellore, Tamil Nadu, India
2Syngene International Limited, Bangalore, Karnataka, India
A series of 3-substituted-1H-isochromene-1-thiones (3) were prepared by the re-
action of 3-substituted isocoumarins (2) with Lawesson’s reagent in the pres-
ence of toluene under a nitrogen atmosphere. The antimicrobial activities of the
newly synthesized products were measured using Gram-negative (Escherichia coli,
Salmonella typhi, and Proteus mirabilis) and Gram-positive bacteria (Staphy-
lococcus aureus and Bacillus cereus). Synthesized thioanalogue of isocoumarins
showed good antibacterial activity against Proteus mirabilis.
Keywords Isochromene-1-thione; isocoumarins; Lawesson’s reagent
INTRODUCTION
Most methods developed for the chemical preparation of thionolactones
involve an oxygen–sulfur exchange from the corresponding carbonyl
compounds, and usually proceed from thermal processes. Resulting
from the pioneering work of Lawesson and co-workers,1,2 2,4-bis(4-
methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide, known as
Lawesson’s reagent (LR), was designed to perform, under defined con-
ditions, a single sulfurization of lactones selectively resulting in the cor-
responding thionolactones.3 Isocoumarins possess important biological
properties.4–8 With the intension of improving the biological properties
of isocoumarins, the thionation reaction was attempted. In previous
studies, Lawesson’s reagent proved to be an efficient sulfur transfer
Received 8 July 2008; accepted 25 September 2008.
The authors wish to express their gratitude to the Indian Institute of Science, SAIF,
Bangalore; Spic Science Foundation, Tuticorin; and Syngene International Limited for
their support of NMR, LCMS facilities.
Address correspondence to Dr. F. Nawaz Khan, Organic and Inorganic Chemistry Di-
vision, School of Science and Humanities, VIT University, Vellore-632 014, Tamil Nadu,
India. E-mail: nawaz f@yahoo.co.in
2576

Isocoumarin Thioanalogues
2577
SCHEME 1 Synthesis of 3-substituted-1H-isochromene-1-thione from iso-
coumarins.
reagent in the case of chromones, thiochromones, flavones, isoflavones,
benzoxapines, etc.9–14 Therefore this reagent has been utilized in our
thioisocoumarin synthesis as a part of our research interest on iso-
coumarins.15–17
RESULTS AND DISCUSSION
Our investigation began with an attempted synthesis of the precursor
of 3-substituted isochromen-1-ones derived from homophthalic acid,
followed by thionation of 3-substituted isochromen-1-ones with Lawes-
son’s reagent (Scheme 1). The 3-substituted isocoumarins were pre-
pared by a previously reported procedure.7,15 The reaction was success-
fully completed in just a few hours with excellent yields. The purified
isocoumarins were then allowed to react with Lawesson’s reagent in
the presence of toluene under nitrogen atmosphere to afford the cor-
responding 3-substituted-1H-isochromene-1-thiones. The reaction pro-
ducing 3-substituted-1H-isochromene-1-thione derivatives by a simple
and an efficient route gave modest to good yields, thereby providing
a convenient route for the synthesis of variety of thioisocoumarins.
The products of the reaction were isolated, purified, and characterized
1
by various spectral techniques such as FTIR, LC-MS, H-NMR, and
13C-NMR. All synthesized compounds exhibited excellent antibacterial
activity against Proteus mirabilis, whereas, except compound 3e, all
other compounds showed good activity against Bacillus cereus.
CONCLUSIONS
In the present study, thionation of isocoumarins was successfully car-
ried out by Lawesson’s reagent, and from antibacterial activity, we

2578
P. Manivel et al.
conclude that all thioanalogues of 3-substituted-1H-isochromene-1-one
have good activity against Proteus mirabilis.
EXPERIMENTAL
Melting points were taken in open capillary tubes and corrected with
reference to benzoic acid. IR spectra, as KBr pellets, were recorded on a
1
Nucon Infrared spectrophotometer. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker 400 MHz spectrometer in
CDCl3 or DMSO (with TMS for 1H and DMSO for 13C NMR as internal
references).
General Procedure of the Synthesis of 3-Substituted-
1H-isochromene-1-thione (3a–f)
The title compounds were synthesized from a mixture of isocoumarins,
2 (10 mmol), and Lawesson’s reagent (12 mmol). The mixture was
placed in a glass tube fitted with a tightened rubber septum and was
refluxed at 110◦C using toluene as a solvent under a nitrogen atmo-
sphere. The progress of the reaction was monitored by TLC using a hex-
ane:ethyl acetate (9:1 v/v) mixture. After the completion of the reaction,
the mixture was dissolved in dichloromethane and adsorbed on silica
gel. The compounds were purified by column chromatography using a
mixture of hexane:ethyl acetate (9:1 v/v). The products obtained were
1
characterized by FTIR, LC-MS, H-NMR, and 13C-NMR techniques.
The reactions of Lawesson’s reagent with various isocoumarins 2a–f
are tabulated (Table I). The spectral data of the compounds 3a–f are
given below.
TABLE I Synthesis of 3-Substituted Isochromene-1-
thionesa
Isocoumarins 2\Isochromene-1-thione 3 R
Yield%b
n—C4H9, 2a, 3a
Ph, 2b, 3b
p-CH3-C6H4, 2c, 3c
p-OCH3-C6H4, 2d, 3d
2—furyl, 2e, 3e
96
92
94
89
90
87
Cyclo C6H11, 2f, 3f
aIsocoumarins, 2a–f (10 mmol) in toluene (50mL), Lawesson’s
reagent, (12 mmol).
bIsolated yield for isochromene-1-thione, 3.

Isocoumarin Thioanalogues
2579
3-Butylthioisocoumarin (3a)
Yellow solid, mp 71.2–73◦C, IR (ν cm−1) 2955, 2923, 2852, 1650,
1551, 1474, 1457, 1428, 1381, 1327, 1287, 1208, 1170, 1085, 1022, 999,
1
836, 758, 576, 464. H NMR (CDCl3): δ 8.69 (m, 1H), 7.68–7.72 (m,
1H), 7.44–7.49 (m, 1H), 7.35 (m, 1H), 6.49 (s, 1H), 2.64 (t, J = 7.52
Hz, 2H), 1.71–1.79.66 (m, 2H), 1.49–1.39 (m, 2H), 0.95 (t, J = 7.52
Hz, 3H). 13C NMR (CDCl3): δ 201.53, 161.65, 135.05, 132.78, 132.25,
129.79, 128.58, 125.52, 105.44, 33.176, 29.23, 22.1, 13.7, LCMS—218.7.
C13H14OS requires Mol. Wt.: 218.3.
3-Phenylthioisocoumarin (3b)
Yellow solid, mp 115–117◦C, IR (ν cm−1) 3061, 2923, 2853, 1634,
1551, 1473, 1457, 1428, 1341, 1296, 1204, 1111, 1085, 1026, 999, 838,
1
761, 686, 517, 474. H NMR (CDCl3): 8.72 (d, 1H), 7.94–7.96 (m, 2H),
7.71–7.75 (m, 1H), 7.46–7.51 (m, 5H), δ 7.14 (s, 1H), 13C NMR (CDCl3):
δ 200.41, 156.7, 135.14, 132.87, 132.16, 131.27, 130.37, 130.19, 129.17,
128. 97, 126.47, 125.42 104.66, LCMS—238.7. C15H10OS requires Mol.
Wt.: 238.3.
3-p-Tolylthioisocoumarin (3c)
Yellow solid, mp 133.1–134◦C, IR (ν cm−1) 2922, 2852, 1630, 1548,
1474, 1447, 1340, 1283, 1219, 1198, 1172, 1113, 1033, 989, 814, 746,
1
519, 474. H NMR (CDCl3): 8.72 (d, 1H), 7.71–7.86 (m, 3H), 7.47 (m,
2H), 7.29 (d, 2H), δ 7.10 (s, 1H), 2.48 (s, 3H). 13C NMR (CDCl3): δ 200.50,
156.99, 140.77, 135.09, 132.87, 132.41, 130.08, 129.68, 128.93, 128.52,
126.33, 125.35, 103.95, 21.45, LCMS—252.9. C16H12OS requires Mol.
Wt.: 252.3.
3-p-Anisylthioisocoumarin (3d)
Yellow solid, mp 151.3–152◦C, IR (ν cm−1) 3055, 2921, 2852, 1620,
1553, 1432, 1381, 1375, 1344, 1261, 1195, 1153, 1088, 1019, 972, 823,
1
769, 629, 520, 466. H NMR (CDCl3): δ 8.71 (m, 1H), 7.83–7.92 (m,
2H), 7.73–7.69 (m, 1H),7.45–7.49 (m, 2H), 7.03–6.98 (m, 3H), 6.85 (s,
1H), 3.84 (s, 3H). 13C NMR (CDCl3): δ 200.50, 161.41, 156.89, 135.09,
132.62 129.85, 128.69, 127.05, 126.20, 123.86, 114.38, 103.14, 55.45,
LCMS—269.2. C16H12O2S requires Mol. Wt.: 268.3.
3-(Furan-2-yl)-1H-isochromene-1-thione (3e)
Yellow solid, mp 112–114◦C, IR (ν cm−1) 3067, 2923, 2853, 1650,
1542, 1472, 1458, 1384, 1340, 1285, 1204, 1169, 1092, 1030, 989, 839,
1
744, 591, 470. H NMR (CDCl3): δ 8.72–8.70 (d, 1H), 7.74–7.70 (m,
1H), 7.55–7.46 (m, 3H), 7.11–7.06 (m, 1H), 6.98–6.89 (m, 1H), 6.57 (s,

2580

Isocoumarin Thioanalogues
2581
1H), 13C NMR (CDCl3) δ 199.58, 149.07, 144.32, 135.18, 133.10, 131.79,
128.98, 126.41, 125.97, 112.29, 112.15, 110.90, 102.79. LCMS-228.0.
C13H8O2S requires Mol. Wt.: 228.2.
3-Cyclohexyl-1H-isochromene-1-thione (3f)
Yellow solid, mp 68–70◦C, IR (ν cm−1) 3015, 2921, 2849, 1657, 1548,
1464, 1426, 1379, 1333, 1277, 1216, 1168, 1072, 1036, 989, 829, 758,
474. 1H NMR (CDCl3): δ 8.71–8.69 (d, 1H), 7.72–7.67 (m, 1H), 7.49–7.44
(m, 1H), 7.38–7.36 (m, 1H), 6.49 (s, 1H), 2.62–2.57 (t, 1H), 2.12–2.09
(m, 2H), 1.90–1.86 (m, 2H), 1.79–1.74 (m, 1H), 1.52–1.26 (m, 5H). 13C
NMR (CDCl3): δ 201.50, 165.70, 134.98, 132.72, 132.36, 129.9, 128.54,
125.76, 104.00, 41.68, 30.81, 25.91, 25.80, LCMS-243.08. C15H16OS
requires Mol. Wt.: 244.3.
IN VITRO ANTIMICROBIAL ACTIVITIES EVALUATION
The in vitro antibacterial screening of synthesized compounds were
evaluated against selected Gram-positive organisms viz. Bacillus
cereus and Staphylococcus aureus and three Gram-negative organisms
viz. Escherichia coli, Salmonella typhi, and Proteus mirabilis by the
Agar well diffusion method.18 Cultures of bacteria were grown on nu-
trient broth (HiMedia) at 37◦C for 12–14 h and were maintained on
respective agar slants at 4◦C. Nutrient agar was poured onto a plate
and allowed to solidify. The test compounds (DMSO solutions) were
added dropwise to a 10 mm diameter well placed in the agar plate. The
compounds of 4mg/mL concentration were used as stock solution from
this 100 µL was loaded to each well. The plates were then kept at 5◦C
for 1 h then transferred to an incubator maintained at 36◦C. The width
of the growth inhibition zone was measured after 24 h incubation. The
activity studies have been carried out with two different concentra-
tion and triplicate measurements (Table II). The results indicate that
all the thioanalogue of 3-substituted-1H-isochromene-1-ones have good
antibacterial activity against Proteus mirabilis.
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