Synthesis and evaluation of thiochroman-4-one derivatives as potential leishmanicidal agents

Article abstract of DOI:10.3390/molecules22122041

The S-containing heterocyclic compounds benzothiopyrans or thiochromones stand out as having promising biological activities due to their structural relationship with chromones (benzopyrans), which are widely known as privileged scaffolds in medicinal chemistry. In this work, we report the synthesis of 35 thiochromone derivatives and the in vitro antileishmanial and cytotoxic activities. Compounds were tested against intracellular amastigotes of Leishmania panamensis and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Compounds bearing a vinyl sulfone moiety, 4h, 4i, 4j, 4k, 4l and 4m, displayed the highest antileishmanial activity, with EC50 values lower than 10 μM and an index of selectivity over 100 for compounds 4j and 4l. When the double bond or the sulfone moiety was removed, the activity decreased. Our results show that thiochromones bearing a vinyl sulfone moiety are endowed with high antileishmanial activity and low cytotoxicity.

Full text of DOI:10.3390/molecules22122041

molecules
Article
Synthesis and Evaluation of Thiochroman-4-One
Derivatives as Potential Leishmanicidal Agents
Esteban Vargas 1 ID , Fernando Echeverri 1, Iván D. Vélez 2, Sara M. Robledo 2,
*
ID
and Wiston Quiñones 1,
*
1
Química Orgánica de Productos Naturales, Instituto de Química, Facultad de Ciencias Exactas y Naturales,
Universidad de Antioquia, calle 70 No. 52-21, Medellin A.A 1226, Colombia;
esteban.vargasc@udea.edu.co (E.V.); fernando.echeverri@udea.edu.co (F.E.)
PECET-Facultad de Medicina, Universidad de Antioquia, calle 70 No. 52-21, Medellin A.A 1226, Colombia;
ivan.velez@udea.edu.co
2
*
Correspondence: sara.robledo@udea.edu.co (S.M.R.); wiston.quinones@udea.edu.co (W.Q.);
Tel.: +57-4-219-6503 (S.M.R.); +57-4-219-6596 (W.Q.)
Received: 24 October 2017; Accepted: 20 November 2017; Published: 29 November 2017
Abstract: The S-containing heterocyclic compounds benzothiopyrans or thiochromones stand
out as having promising biological activities due to their structural relationship with chromones
(benzopyrans), which are widely known as privileged scaffolds in medicinal chemistry. In this
work, we report the synthesis of 35 thiochromone derivatives and the in vitro antileishmanial and
cytotoxic activities. Compounds were tested against intracellular amastigotes of Leishmania panamensis
and cytotoxic activity against human monocytes (U-937 ATCC CRL-1593.2). Compounds bearing
a vinyl sulfone moiety, 4h
,
4i
,
4j
,
4k
, 4l and 4m, displayed the highest antileishmanial activity,
with EC50 values lower than 10
µM and an index of selectivity over 100 for compounds 4j and 4l
.
When the double bond or the sulfone moiety was removed, the activity decreased. Our results show
that thiochromones bearing a vinyl sulfone moiety are endowed with high antileishmanial activity
and low cytotoxicity.
Keywords: Leishmania; thiochroman-4-ones; thiochromones; thioflavones; vinyl sulfone
1. Introduction
Cutaneous leishmaniasis (CL) is an anthropozoonotic disease caused by parasites of the genus
Leishmania, and is transmitted through the bite of female insects of the genus Phlebotomus and
Lutzomyia [1]. According to the World Health Organization, the disease is widely distributed around the
world, with 310 million people at risk and about one million new cases occurring annually. The highest
numbers of cases of CL are concentrated in 10 countries (Afghanistan, Algeria, Brazil, Colombia, Iran,
Pakistan, Peru, Saudi Arabia, Syria and Tunisia) [2]. Although most cases do not become deadly,
the disease produces severe skin lesions that significantly decrease the quality of life of those who suffer
from it. Due to a lack of vaccines, disease control measures are based on chemotherapy. The current
therapeutic treatments are associated with several drawbacks affecting the adequate management of
the disease, such as severe side effects [
1
], likelihood of not ending treatment mainly in rural areas
]. Therefore, there is
due to the complexity of treatment [ ], high cost and emerging resistance [3,4
3–5
an urgent need to find new alternatives to treat CL through different mechanisms of action to facilitate
the handling of cases, given the poor therapeutic response to current available medications.
Chromones (1,4-benzopyrone) are known as privileged scaffolds [
due to their wide range of biological activities, displayed, among others, as antiprotozoal [9,10]
antioxidants [11] or anticancer agents [12 14]. The S-containing heterocyclic compounds, benzothiopyrans
or thiochromones, have been significantly less exploited, most certainly because they are not naturally
6–8] in medicinal chemistry
,
–
Molecules 2017, 22, 2041; doi:10.3390/molecules22122041
www.mdpi.com/journal/molecules

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occurring compounds; from a bioisoterically point of view, thiochromones could serve as a rational
modification for the optimization of chromone bioactivity.
In this work, the benzothiopyran scaffold (thiochroman) was analyzed as a potential source of
leishmanicidal agents. These compounds were prepared starting from thiophenol or its derivatives,
which act as nucleophiles to α,β-unsaturated carboxylic acids. Then, cyclization to give benzothiopyrans
was achieved using a process catalyzed with sulfuric acid, methanesulfonic acid or oxalyl chloride,
followed by tin chloride. After construction of benzothiopyran scaffold, oxidation of sulfur atoms
to sulfones and dehydrogenation to produce an α,β-unsaturation to the carbonyl group were made.
Thus, 34 compounds with structural changes in different parts of the benzothiopyran moiety were
synthesized. The leishmanicidal activity and cytotoxicity were tested for all compounds, and structural
activity relationships were proposed.
2. Results
2.1. Synthesis
Thiochroman-4-ones have been generally synthesized using a substitution reaction of thiophenol with
β
-halopropionic acids or
Friedel-Crafts acylation, thiochroman-4-ones were produced in moderate yields [15
involves only one step, using direct reaction between -unsaturated acids (acrylic acid derivatives)
β
-butirolactones to give 3-(phenylthio)-propanoic acids; then, upon intramolecular
–18]. Another reaction
α,β
and thiophenol in the presence of methanesulfonic acid, but the yields were low [19]. In this work,
the synthesis of 3-(phenylthio)-propanoic acids was achieved through a catalyzed reaction, either with
iodine or tetrabutylammonium fluoride (TBAF) in a solventless way (Scheme 1), in high yields [20];
after that, compounds were cyclized by reaction with sulfuric or methanesulfonic acid in moderate yields.
Scheme 1. Synthesis of thiochroman-4-one derivatives.
The cyclization of 3-aryl-3-(phenylthio)-propanoic acid failed to give 2-phenylthiochroman-4-one
(thioflavanone) under different reaction conditions. Thus, strong dehydrating agents, such as
sulfuric, methanesulfonic or p-toluenesulfonic, only gave trace amounts of the expected product;
additionally, formation of the respective acid chloride, followed by intramolecular Friedel-Crafts
acylation with aluminum trichloride, also failed. Finally, the synthetic procedure was performed

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according to Bates and Li [21], and thioflavanone was prepared from the acid chloride of 3-phenyl-
3-(phenylthio)-propanoic acid using tin(IV) chloride as a Lewis acid catalyst, with moderate yields.
The same method worked well for the preparation of other thioflavanones.
Oxidation of the thioether (sulfide) group of the thiochromanones or thioflavanones to sulfones
were carried out using an excess of Oxone® in a mixture of water/ethanol (3:1). The dehydrogenation
reactions were explored using different methods, following similar reports of treatment with DDQ [22],
PCl5 [23] or a mixture of Iodine/DMSO [22] with moderates yields.
2.2. Antileishmanial and Cytotoxic Activities
Thirty-four synthesized compounds, i.e., thiochroman-4-ones and analogues, were evaluated for their
in vitro antileishmanial and cytotoxic activities, following the methods of Pulido et al. [24]. Amphotericin B
was used as a control (Table 1) with EC50 and LC50 values of 0.32 µM and 39.6 µM respectively.
Table 1. In vitro antileishmanial and cytotoxic activities.
Compound
EC50 (µM) 1
LC50 (µM) 1
SI 2
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
2f
2i
2j
2k
2l
2m
3a
3b
3c
3h
3i
3j
3k
3l
3m
4h
4i
4j
4k
444.60 ± 7.29
422 ± 9.17
>109.88
604.21 ± 86.40
578.88 ± 59.11
705.2
279.22 ± 36.35
142.63 ± 16.80
>200
1.36
1.37
<6.42
<3.49
<1.48
<10.00
<1.100
<0.94
>10.56
1.60
<0.90
0.78
~10.00
>26.26
3.24
>80.00
>96.14
>95.59
>111.58
118.08 ± 10.51
44.06 ± 0.90
61.43 ± 1.62
80.29 ± 12.09
>72.79
>41.61
> 648.7
128.65 ± 3.45
64.36 ± 3.98
72.86 ± 9.87
>700.97
93.57 ± 10.99
>70.1
36.76 ± 1.74
160.97 ± 20.53
52.26 ± 8.92
>73.3
>965.20
522.33 ± 314.03
51.39 ± 11.55
>733.27
0.98
~10.00
<6.45
~10.00
~8.67
~9.99
~9.99
0.41
>78.04
>70.6
>95.22
>87.71
503.32 ± 381.94
>706
>825.2
>876.3
>933.6
>93.45
217.02 ± 34.89
84.81 ± 3.23
79.11± 8.98
137.09 ± 1.29
>68.9
528.90 ± 52.88
62.88 ± 10.28
>558.18
0.74
>7.06
>4.76
<10.0
~10.0
>97.94
>80.97
>173.24
>87.70
>103.26
>87.70
132.02
>651.98
688.92
>630.28
>739.92
>591.19
>561.34
>656.28
>693.75
>63.03
7.56 ± 0.33
7.30 ± 1.60
3.24 ± 0.23
7.47 ± 0.75
6.72 ± 0.16
7.23 ± 0.44
0.32 ± 1.04
4l
4m
>634.32
39.6 ± 8.7
Amphotericin B
1
2
Results reported as the mean value
selectivity (IS) = LC50/EC50. Bold data represent compounds with high activity against amastigotes of L. (V) panamensis.
±
standard deviation of the half-maximum concentration in µM; Index of
3. Discussion
Initially, modifications were made in thiochroman-4-one compounds (1a
activity relationships (Figure 1). The substitution with electron-withdrawing groups in the phenyl ring,
–m) to identify structure-

Molecules 2017, 22, 2041
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dehydrogenation to yield a double bond between C2-C3 (2f, 2i–m) and sulfones (3a–c, 3h–m) did
not improve antileishmanial activity. However, when sulfones were dehydrogenated to produce the
corresponding vinyl sulfones (4h ), compounds showed high antileishmanial activity, evidenced by
EC50 values < 10 M, low cytoxicity to human macrophages U-937 (LC50 values > 561 M) and a high
index of selectivity (IS ≥ 87).
–m
µ
µ
Figure 1. Structure activity relationships of thiochroman-4-one derivatives.
Fluorine substitution at C-6 position caused an increase in the leishmanicidal activity in comparison
to hydrogenated compound. In fact, compound 4j was the most active (EC50 = 3.23 M) and selective
µ
compound, with an IS value of 174, even higher than the reference drug, amphotericin B. It is interesting
to note that all compounds bearing the vinyl sulfone moiety displayed high antileishmanial activity
and low cytotoxicity. These types of compounds have been reported in a wide range of biological
activities, including neuroprotective [25], antiparasite [26
The generally-accepted mechanism of action of vinyl sulfones involves their ability to inhibit cystein
proteases by a nucleophilic attack on the position to the sulfone [29]. However, further studies are
,27] and inhibitor of HIV-1 integrase enzyme [28].
β
required to identify the mechanism of action of thiochromenes bearing vinyl sulfones to optimize
antileishmanial activity.
4. Materials and Methods
4.1. Chemistry
4.1.1. General
All commercially available reagents and solvents were obtained from commercial suppliers and used
without further purification. The reaction progress was monitored with thin layer chromatography on silica
gel TLC aluminum sheets (60F254, Merck, Darmstadt, Germany). The melting points were determined
using a Mel-Temp apparatus (Electrothermal, Staffordshire, UK) and are uncorrected. FTIR spectra were
1
obtained on a Bruker Alpha FTIR spectrometer (Bruker Optic GmbH, Ettlingen, Germany. H and 13
C
nuclear magnetic resonance (NMR) spectra were recorded using Bruker DRX 300 spectrometer (Bruker
Bio-Spin GmbH, Rheinstetten, Germany) operating at 300 MHz for 1H and 75 MHz for 13C. Chemical
shifts were reported relative to internal tetramethylsilane (δ δ 77.0 ppm) for
0.00 ppm) for 1H, and CDCl3 (
13C. HRMS was obtained using Q-TOF quadrupole/ orthogonal spectrometry (Waters, Milford, MA, USA)
in either negative (reported as [M − H]−) or positive mode (reported as [M + H]+).
4.1.2. Synthesis of Thiochroman-4-ones
2-Methylthiochroman-4-one (1a). To a mixture of crotonic acid (860 mg, 10 mmol) and thiophenol (1.650 g,
15 mmol) was added I2 (20 mol %, 255 mg, 1 mmol) and the mixture was stirred at room temperature for
12 h. After completion of the reaction (monitored by TLC), a cold saturated sodium thiosulfate solution
(20 mL) was added and extracted with dichloromethane (2
were mixed with a saturated solution of sodium bicarbonate and extracted to remove the unreacted
starting material. The water layer was acidified with hydrochloric acid (10% aq) and extracted with
×
50 mL); then, combined organic layers

Molecules 2017, 22, 2041
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dichloromethane (3
×
40 mL). The combined organic layers were dried over Na2SO4, evaporation of the
solvent under reduced pressure afforded 1.962 g (86%) of the desired addition product. After, 200 mg
(1.0 mmol) of this product were cooled down to 0 C in an ice bath and 3.0 mL of concentrated
◦
sulfuric acid was added; the reaction mixture was stirred for 30 min, and, after that, the ice bath was
removed allowing the reaction mixture to warm to room temperature for another 2 h under continuous
stirring. The reaction was quenched with ice and the mixture was extracted with dichloromethane
(3
×
25 mL). The combined organic layers were washed once with water, followed by addition of
a saturated NaHCO3 solution. The combined organic layers were dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column chromatography over silica gel using
hexane:EtOAc (9:1) as eluent, to give 137 mg (75%) of pure 1a as a yellowish oil. H-NMR (300 MHz,
1
CDCl3) δ 8.08 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H)
3.74–3.53 (m, 1H), 2.98 (dd, J = 17.6, 8.8 Hz, 1H), 2.84–2.66 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H)
13C-NMR
(75 MHz, CDCl3) 194.9, 141.9, 133.7, 130.1, 129.1, 127.65, 125.1, 48.0, 36.5, 20.6. IR : 2964, 1679, 1587.
HRMS (ESI) calculated for C10H11OS [M + H]+ 179.0525, found 179.0536.
,
.
δ
ν
6-Fluoro-2-methylthiochroman-4-one (1b). To a mixture of crotonic acid (172 mg, 2 mmol) and
4-fluorothiophenol (385 mg, 3.0 mmol) was added I2 (20% mol, 52 mg, 0.2 mmol) and the mixture was
stirred at room temperature for 12 h. After completion of reaction (monitored by TLC), a cold saturated
sodium thiosulfate solution (20 mL) was added and extracted with dichloromethane (2
the combined organic layers were mixed with a saturated solution of sodium bicarbonate and extracted
to remove the unreacted starting material. The water layer was acidified with hydrochloric acid
×
25 mL);
(10% aq) and extracted with dichloromethane (3
over Na2SO4, evaporation of the solvent under reduced pressure afforded 200 mg (94%) of the addition
product. Thus, compounds were cooled down to 0 C in an ice bath and 2.0 mL of concentrated
×
25 mL). The combined organic layers were dried
◦
sulfuric acid was added and the reaction mixture was allowed to warm to room temperature for 2 h
with continuous stirring. The reaction was quenched with ice and the mixture was extracted with
dichloromethane (3
×
25 mL). The combined organic layers were washed once with water, followed by
saturated NaHCO3 solution. The combined organic layers were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by column chromatography
over silica gel using hexane:EtOAc (9:1) as eluent to give 128 mg (64%) of pure 1b as a yellowish oil.
1H-NMR (300 MHz, CDCl3)
2.80–2.68 (m, 1H), 1.43 (d, J = 6.9 Hz, 3H). 13C-NMR (75 MHz, CDCl3)
δ
7.84–7.72 (m, 1H), 7.39–6.97 (m, 2H), 3.78–3.47 (m, 1H)
,
3.07–2.95 (m, 1H)
,
δ
194.2, 160.7 (d, JC–F = 246 Hz)
,
137.6, 132.3, 129.7 (d, JC–F = 7.0 Hz), 121.8 (d, JC–F = 23.1 Hz), 115.4 (d, JC–F = 22.8 Hz), 47.9, 37.0, 20.7.
IR ν: 2967, 1684, 1602. HRMS (ESI) calculated for C10H10FOS [M + H]+ 197.0431, found 197.0443.
6-Fluorothiochroman-4-one (1c). To a mixture of acrylic acid (700
µL, 720 mg, 10 mmol) and
4-fluorothiophenol (1985 mg, 15 mmol) was added I2 (20% mol, 760 mg, 3 mmol) and the mixture
◦
was stirred at 50 C for 24 h. After completion of reaction (monitored by TLC), a cold saturated
sodium thiosulfate solution (30 mL) was added and extracted with dichloromethane (2
the combined organic layers were mixed with a saturated solution of sodium bicarbonate and extracted
to remove the unreacted starting material. The water layer was acidified with hydrochloric acid
×
25 mL);
(10% aq) and extracted with dichloromethane (3
over Na2SO4, evaporation of the solvent under reduced pressure afforded 1150 mg (64%) of the desired
addition product. The product was cooled down to 0 C in an ice bath and 3 mL of concentrated
×
50 mL). The combined organic layers were dried
◦
sulfuric acid was added and the reaction mixture was allowed to warm to room temperature for
2 h with magnetic stirring. The reaction was quenched with ice and the mixture was extracted with
dichloromethane (3 × 50 mL). The combined organic layers were washed once with water, followed by
saturated NaHCO3 solution. The combined organic layers were washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by column chromatography
over silica ge◦l using hexane:EtOAc (9:1) as eluent to give 570 mg (90%) of pure 1c as a yellow solid.
1
m.p.: 86–88 C. H-NMR (300 MHz, CDCl3)
δ 8.07 (dd, J = 8.0, 1.4 Hz, 1H), 7.16–7.11 (m, 2H),

Molecules 2017, 22, 2041
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3.25–3.23 (m, 2H), 2.99–2.96 (m, 2H). 13C-NMR (75 MHz, CDCl3)
δ
193.5, 160.9 (d, JC–F = 245 Hz), 137.8,
132.7, 129.8 (d, JC–F = 7 Hz), 121.70 (d, JC–F = 23.0 Hz), 115.6 (d, JC–F = 22.6 Hz), 39.7, 27.1. IR
ν: 1659,
1595, 1565. HRMS (ESI) calculated for C9H6FOS [M − H]− 181.0123, found 181.0165.
2,3,8,9-Tetrahydro-4H,10H-thiopyran[2,3-f]thiochromene-4,10-dione (1d). To a mixture of acrylic acid
(288 mg, 280
µ
L, 4 mmol) and 1,3-benzenedithiol (350
µ
L, 3 mmol) was added I2 (240 mg, 1.0 mmol)
◦
and the mixture was stirred at 50 C for 24 h. After completion of reaction (monitored by TLC),
a cold saturated sodium thiosulfate solution (30 mL) was added and extracted with dichloromethane
(2 × 30 mL); the combined organic layers were mixed with a saturated solution of sodium bicarbonate
to form the diacid salt and extracted to remove the unreacted starting material. The water layer
was acidified with hydrochloric acid (10% aq) and extracted with dichloromethane (3
×
50 mL).
The combined organic layers were dried over Na2SO4, evaporation of the solvent under reduced
pressure afforded 490 mg (57%); the desired addition product, 100 mg (0.35 mmol) of the later
product was cooled down to 0 ◦C in an ice bath and 3 mL of concentrated sulfuric acid was added,
the reaction mixtur◦e was allowed to warm to room temperature for 2 h with magnetic stirring and
then heated to 60 C. The reaction was quenched with ice and the mixture was extracted with
dichloromethane (3 × 50 mL). The combined organic layers were washed once with water, followed by
saturated NaHCO3 solution. The combined organic layers were dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column chromatography over silica gel using
hexane:EtOAc (4:1) as eluent to give 22 mg of 1d, 25% of pure
1H-NMR (300 MHz, CDCl3)
8.15 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 3.29–3.25 (m, 2H),
3.10–3.05 (m, 4H), 2.99–2.94 (m, 2H). 13C-NMR (75 MHz, CDCl3)
194.3, 193.6, 151.4, 150.1, 132.7, 129.4,
: 1648, 1559, 1351, 834. HRMS (ESI) calculated for C12H11O2S2
2
as a white solid. m.p.: 145–147 ◦C.
δ
δ
127.6, 123.5, 40.3, 38.7, 27.3, 26.1. IR
[M + H]+ 251.0200 found 251.0209.
ν
4-Oxothiochroman-2-carboxylic acid (1e). Thiophenol (110
(maleic anhydride) (98 mg, 1.0 mmol) were mixed with triethylamine (10 µL). After stirring at 50 C
µ
L, 1.0 mmol) and furan-2,5-dio◦ne
for 24 h, the mixture was cooled with an ice-cooling bath. AlCl3 (approx. 400 mg, 3.0 mmol) was added
and the mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was
quenched with 50 mL of 2.0 M HCl and then extracted with chloroform (4
layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by
×
50 mL). The combined organic
column chromatography over silica gel using hexane:EtOAc (1:4) as eluent to give 45 mg (22%) of 1e as
a white solid. m.p.: 151–152 ◦C. 1H-NMR (300 MHz, CDCl3)
δ
8.09 (d, J = 7.8 Hz, 1H), 7.4–7.38 (m, 1H)
,
7.25–7.21 (m, 2H) 4.13–4.11 (m, 1H), 3.19–3.17 (m, 2H). 13C-NMR (75 MHz, CDCl3) δ 192.4, 175.2, 138.4,
134.3, 130.6, 129.4, 127.7, 126.3, 42.2, 41.2. IR ν: 3300-2500, 2918, 1680, 1581, 7673. HRMS (ESI) calculated for
C10H7O3S [M − H]− 207.0106 found 207.0107.
6-Nitrothiochroman-4-one (1f). Acrylic acid (510 µL, 504 mg, 7.0 mmol) and 4-nitrothiophenol (1240 mg,
8 mmol) were mixe◦d with 75% aqueous solution of TBAF (512
µL, 1.4 mmol) and the mixture was
stirred for 4h at 60 C. A saturated solution of sodium bicarbonate was added and extracted with
dichloromethane (3
with hydrochloric acid (10% aq) and extracted with dichloromethane (3
organic layers were dried over Na2SO4, evaporation of the solvent under reduced pressure gave
the crude addition product which was dissolved in anhydrous dichloromethane in an oven dried
×
25 mL) to remove the unreacted starting material. The water layer was acidified
30 mL). The combined
×
round bottomed flask under N2 in an ice cooling bath, oxalyl chloride (850 µL, 7.0 mmol) was added
dropwise followed by two drops of DMF and the reaction mixture was allowed to warm to room
◦
temperature. After stirring 2.5 h, the solution was cooled to –10 C, and a solution of 1M SnCl4 (8.4 mL,
8.4 mmol) in CH2Cl2 was added dropwise. The resulting mixture was stirred at 0 ◦C for 10 min and
then allowed to warm to room temperature. After stirring at room temperature for 12 h, water (25 mL)
was added and extracted with dichloromethane (3
anhydrous Na2SO4, and concentrated under reduce pressure. The residue was purified by column
×
25 mL). The combined organic layers dried over
chromatography over silica gel using hexane:EtOAc (2:1) as eluent to give 1.0 g (68%) of 1f as a white

Molecules 2017, 22, 2041
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solid. m.p.: 153–154 ◦C. 1H-NMR (300 MHz, CDCl3)
δ
8.91 (d, J = 2.6 Hz, 1H), 8.18 (dd, J = 8.8, 2.6 Hz,
1H), 7.43 (d, J = 8.8 Hz, 1H), 3.34 (t, J = 6.6 Hz, 2H), 3.04 (t, J = 6.6 Hz, 2H). 13C-NMR (75 MHz, CDCl3)
δ
191.7, 150.6, 145.2, 130.8, 128.6, 126.8, 124.4, 38.4, 26.3. IR ν: 1921, 1676, 1594, 1505. HRMS (ESI)
calculated for C9H6NO3S [M − H]− 208.0068 found 208.0081.
6-Aminothiochroman-4-one (1g). To a solution of the 6-nitrothiochroman-4-one 1f, (170 mg, 0.8 mmol)
in 3:1 EtOH/H2O (3 mL) was added and iron wire (400 g, 7.3 mmol) and NH4Cl (100 mg, 1.8 mmol).
The reaction mixture was stirred at 70 ◦C for 1 h. The mixture was filtered through a small pad of
silica gel and then washed with EtOAc. The filtrate was concentrated and the resulting material
was dissolved in (10% aq) hydrochloric acid and extracted with dichloromethane (3
remove unreacted staring material. The aqueous layer was basified with 2 M NaOH solution and
extracted with dichloromethane (3 30 mL). The combined organic layers were dried over Na2SO4,
×
25 mL) to
×
evaporation of the solvent under reduced pressure. The resulting residue was purified by silica gel
column chromatography using hexane:EtOAc (3:1) to provide 130 mg (75%) of 1g as a yellow solid.
◦
1
m.p.: 118–120 C. H-NMR (300 MHz, CDCl3)
δ 7.41 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H),
6.83 (dd, J = 8.4, 2.3 Hz, 1H), 3.77 (s, 2H), 3.20–3.06 (m, 2H), 2.95–2.81 (m, 2H). 13C-NMR (75 MHz,
CDCl3)
δ 195.3, 143.2, 131.5, 131.4, 128.7, 122.2, 114.9, 39.9, 26.8. IR ν: 3346, 3214, 1887, 1650, 1595.
HRMS (ESI) calculated for C9H10NOS [M + H]+ 180.0483 found 180.0485.
4.1.3. Synthesis of Thioflavanones
General Procedure I. Horner-Wadsworth-Emmons Reaction. Synthesis of Cinnamic Acids [30]
Cinnamic acids were prepared by the hydrolysis of the corresponding ethyl esters which
were prepared by Horner-Wadsworth-Emmons reaction between aromatic aldehydes and
triethylphosphonoacetate (Scheme 2).
Scheme 2. Preparation of cinnamic acid derivatives.
In a round bottomed flask equipped with a reflux condenser and an stirrer were mixed
12.0 mmol of the benzaldehyde, potassium carbonate, K2CO3 (32 mmol, 2.6 equiv.), 6.0 mL of
triethylphosphonoacetate (30 mmol, 2.5 equiv.) and 2.0 mL of water and the reaction mixture was
◦
refluxed at 110 C for 30 min. After completion of the reaction, it was quenched with water and,
extracted with dichloromethane (3
concentrated under vacuum. The pure
and then mixed with a 10% NaOH solution; then, reaction mixture was heated at 80 C until the
completion of the reaction and then 2.0 M HCl solution was added until acid pH, and extracted with
×
50 mL). The combined organic layers were dried over Na2SO4 and
α
,
β-unsaturated ester was purified by column chromatography
◦
chloroform (3
×
50 mL). Combined organic layer were dried over Na2SO4, and concentrated at reduced
pressure, the α,β-unsaturated acid (cinnamic acid) obtained was used without further purification.
General Procedure II. Preparation of Thioflavanones
A cinnamic acid derivative (2 mmol) and thiophenol (3 mmol) were mixed with 75% aqueous
◦
solution of TBAF (140
µ
L sln, 0.4 mmol) and the mixture was stirred for 4 h at 60 C. A saturated
solution of sodium bicarbonate was added and extracted with dichloromethane (3
remove the unreacted starting material. The water layer was acidified with hydrochloric acid (10% aq)
×
25 mL) to

Molecules 2017, 22, 2041
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and extracted with dichloromethane (3
Na2SO4; evaporation of the solvent under reduced pressure gave the crude addition product which
was dissolved in anhydrous dichloromethane and placed in an oven-dried round bottomed flask
×
30 mL). The combined organic layers were dried over
under N2 in an ice cooling bath. Consequently, oxalyl chloride (365 µL, 3.0 mmol) was added
dropwise followed by two drops of DMF and the reaction mixture is left to warm to room temperature.
◦
After stirring for 2.5 h, the solution was cooled to
−
10 C, and a solution of 1M SnCl4 (3.0 mL,
3.0 mmol) in CH2Cl2 was added dropwise. The resulting mixture was stirred at 0 ◦C for 10 min and
then allowed to warm to room temperature. After stirring at room temperature for 12 h, water (25 mL)
was added and extracted with dichloromethane (3
anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column
chromatography over silica gel using hexane:EtOAc (2:1) as eluent to give the desired thioflavanone.
×
25 mL). The combined organic layers dried over
2-Phenylthiochroman-4-one (thioflavanone) (1h). The title compound was prepared from thiophenol (5.0 mmol)
and cinnamic acid (310 mg, 3.0 mmol) according to the general procedure II. Yield 215 mg (45%) white
solid. m.p.: 155–157 ◦C. 1H-NMR (300 MHz, CDCl3)
δ 8.20 (dd, J = 7.9, 1.2 Hz, 1H), 7.52–7.36 (m, 6H),
7.35–7.30 (m, 1H), 7.30–7.21 (m, 1H), 4.77 (dd, J = 12.7, 3.3 Hz, 1H), 3.56–3.07 (m, 2H). IR ν: 1665, 1586, 1556,
1452, 1433. HRMS (ESI) calculated for C15H13OS [M + H]+ 241.0687, found 241.0694.
2-(4-(Trifluoromethyl)-phenyl)-thiochroman-4-one (1i). Trifluoromethylcinnamic acid (1070 mg, 5.0 mmol)
and thiophenol (660 mg, 6.0 mmol) were mixed with 75% aqueous solution of TBAF (140 L, 0.4 mmol)
and the mixture was stirred for 24 h at 50 ◦C. A saturated solution of sodium bicarbonate was added
and extracted with dichloromethane (3 25 mL) to remove the unreacted starting material. The water
µ
×
layer was acidified with hydrochloric acid (10% aq) and extracted with dichloromethane (3 × 50 mL)
.
The combined organic layers were dried over Na2SO4, evaporation of the solvent under reduced
pressure gave the crude addition product which was dissolved in methanesulfonic acid and heated at
60 C for 2 h. Ice water was added to the mixture and the white precipitate was filtered off and washed
◦
with water. The residue was purified by column chromatography over silica◦gel using hexane:EtOAc
1
(4:1) as eluent to give 650 mg (42%) of 1i as a white solid. m.p.: 108–110 C. H-NMR (300 MHz,
CDCl3)
7.3, 1.5 Hz, 1H), 7.36–7.22 (m, 3H), 4.79 (dd, J = 12.4, 3.3 Hz, 1H), 3.30 (ddd, J = 19.7, 16.4, 7.8 Hz, 2H).
13C-NMR (75 MHz, CDCl3)
193.7, 142.4, 141.3, 133.9, 130.8 (q, J = 32.4 Hz), 130.5, 129.3, 127.9, 127.3,
δ 8.18 (dd, J = 7.9, 1.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (ddd, J = 8.0,
δ
126.2 (q, J = 3.7 Hz), 125.6, 124.0 (q, J = 270.5 Hz), 46.3, 44.9. IR ν: 1677, 1323, 1106, 841, 757. HRMS
(ESI) calculated for C16H12F3OS [M + H]+ 309.0561, found 309.0572.
6-Fluoro-2-(4-(trifluoromethyl)-phenyl)thiochroman-4-one (1j). The title compound was prepared from
4-fluorothiophenol (400
to the general procedure II. Yield 346 mg (53%) of 1j as a white solid. m.p.: 55–57 ◦C. 1H-NMR
(300 MHz, CDCl3) 7.82 (dd, J = 9.2, 2.8 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H)
7.26 (dd, J = 8.9, 5.1 Hz, 1H), 7.17 (ddd, J = 8.7, 7.6, 2.9 Hz, 1H), 4.73 (dd, J = 11.6, 4.0 Hz, 1H) 3.37–3.15 (m, 2H)
13CNMR (75 MHz, CDCl3)
192.9 (d, J = 1.7 Hz), 161.0 (d, J = 247.2 Hz), 142.3, 136.6 (d, J = 3.0 Hz)
132.0 (d, J = 5.9 Hz) 131.0 (q, J = 32.7 Hz), 129.3 (d, J = 7.0 Hz), 128.1, 126.3 (q, J = 3.7 Hz) 124.0 (q, J = 272.7 Hz)
122.0 (d, J = 23.1 Hz), 115.6 (d, J = 22.8 Hz), 46.2, 45.3. IR : 1679, 1465, 1404, 1321, 1168, 1109. HRMS (ESI)
calculated for C16H11F4OS [M + H]+ 327.0467, found 327.0478.
µL, 3.0 mmol) and trifluoromethylcinnamic acid (420 mg, 2.0 mmol) according
δ
,
,
.
δ
,
,
,
,
ν
2-(4-Chlorophenyl)-thiochroman-4-one (1k). The title compound was prepared from thiophenol (440
µL,
4.0 mmol) and 4-chlorocinnamic acid (546 mg, 3.0 mmol) according to the general procedure II. Yield
◦
1
537 mg (53%) of 1k as a yellowish solid. m.p.: 123–125 C. H-NMR (300 MHz, CDCl3)
δ
8.12
(dd, J = 7.9, 1.3 Hz, 1H), 7.41 (ddd, J = 8.1, 7.1, 1.6 Hz, 1H), 7.36–7.30 (m, 4H), 7.29–7.23 (m, 1H),
7.20 (ddd, J = 8.2, 7.1, 1.2 Hz, 1H), 4.67 (dd, J = 12.2, 3.6 Hz, 1H), 3.21 (m, 2H).13C-NMR (75 MHz, CDCl3)
δ
194.0, 141.6, 137.0, 134.3, 133.8, 130.4, 129.3, 129.2, 128.8, 127.3, 125.5, 46.6, 44.8. IR ν: 1674, 1278, 1082,
851, 767. HRMS (ESI) calculated for C15H10ClOS [M − H]− 273.0141 found 273.0129.

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2-(4-Fluorophenyl)-thiochroman-4-one (1l) The title compound was prepared from thiophenol (440
4.0 mmol) and 4-fluorocinnamic acid (500 mg, 3.0 mmol) according to the general procedure II.
Yield 485 mg (63%) of 1l as a yellowish solid. m.p.: 100–102 ◦C. 1H-NMR (300 MHz, CDCl3)
8.19
(dd, J = 8.0, 1.4 Hz, 1H), 7.53–7.39 (m, 3H), 7.29 (ddd, J = 15.1, 8.9, 4.6 Hz, 2H), 7.18–7.06 (m, 2H),
4.75 (dd, J = 12.4, 3.5 Hz, 1H), 3.28 (qd, J = 16.4, 8.0 Hz, 2H). 13C-NMR (75 MHz, CDCl3)
194.2,
162.6 (d, J = 247.8 Hz), 141.8, 134.3 (d, J = 3.2 Hz), 133.8, 130.4, 129.3, 129.2 (d, J = 8.3 Hz), 127.2, 125.4,
µL,
δ
δ
116.0 (d, J = 21.7 Hz), 46.8, 44.74. IR ν: 2940, 1664, 1582, 1506, 1223, 842, 764. HRMS (ESI) calculated for
C15H12FOS [M + H]+ 259.0593, found 259.0598.
2-(4-Nitrophenyl)-thiochroman-4-one (1m). The title compound was prepared from thiophenol (165 µL,
1.5 mmol) and 4-nitrocinnamic acid (192 mg, 1.0 mmol) according to the general procedure II. Yield 199 mg
(70%) of 1m as a yellowish solid. m.p.: 158–160 ◦C. 1H-NMR (300 MHz, CDCl3) δ 8.29 (d, J = 8.7 Hz, 2H),
8.20 (dd, J = 7.9, 1.2 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.58–7.43 (m, 1H)
J = 9.1, 1.9 Hz, 1H), 4.86 (dd, J = 11.3, 3.9 Hz, 1H), 3.46–3.24 (m, 2H)
13C-NMR (75 MHz, CDCl3)
: 2920, 1666, 1587, 1514, 1515,
,
7.34 (d, J = 8.7 Hz, 1H), 7.29 (dd,
.
δ
193.2,
147.8, 145.6, 140.7, 134.1, 130.3, 129.4, 128.6, 127.3, 125.8, 124.3, 46.1, 44.7. IR
ν
1338, 761. HRMS (ESI) calculated for C15H12NO3S [M + H]+ 286.0538, found 286.0543.
4.1.4. General Procedure III. Dehydrogenation with DDQ [22]
A mixture of substrate (0.5 mmol of thiochromanones or thioflavanones), and DDQ (140 mg,
0.6 mmol) and a small amount of anhydrous p-toluenesulfonic acid in 2.0 mL of anhydrous benzene,
was refluxed in a condenser adapted with a drying tube filled with calcium chloride; after stirring for
24 h (or until the TLC showed the disappearance of the starting materials) the mixture was cooled and
the residue was purified by column chromatography using mixtures of ethyl acetate and hexane to
give the desired dehydrogenation products in moderate yields.
4.1.5. General Procedure IV. Dehydrogenation with Iodine/DMSO [22]
A mixture of 0.5 mmol of substrate (thiochromanones or thioflavanones) in 2.0 mL of DMSO was
added 125
µL of 0.1 M solution of iodine in (25% mol) was refluxed during 24 h, then cooled and
poured into water. The mixture was extracted with dichloromethane (3
×
25 mL), and the combined
organic layers were dried over sodium sulfate, and then concentrated at reduced pressure. The residue
was purified in column chromatography using mixtures of ethyl acetate and hexane to give the desired
dehydrogenation products in moderate yields.
6-Nitro-4H-thiochromen-4-one (2f). The title compound was prepared from 1f according to the general
◦
procedure III. Yield 50 mg (48%) of 2f as a yellowish solid. mp 184–185 C. 1H-NMR (300 MHz, CDCl3)
δ
9.32 (d, J = 2.5 Hz, 1H), 8.39 (dd, J = 8.9, 2.5 Hz, 1H), 7.85 (d, J = 10.5 Hz, 1H), 7.77 (d, J = 8.9 Hz, 1H)
7.06 (d, J = 10.5 Hz, 1H). 13C-NMR (75 MHz, CDCl3)
178.5, 147.4, 144.0, 137.9, 132.9, 128.5, 126.6, 125.4,
124.6. IR
: 3096, 3031, 1602, 1505, 1339. HRMS (ESI) calculated for C9H6NO3S [M + H]+ 208.0068
found 208.0077.
,
δ
ν
2-(4-(Trifluoromethyl)-phenyl)-4H-thiochromen-4-one (2i). The title compound was prepared from 1i
according to the general procedure III. Yield 69 mg (45%) of 21 as a yellowish solid. m.p.: 168–170 ◦C.
1H-NMR (300 MHz, CDCl3)
13C-NMR (75 MHz, CDCl3)
δ
8.54 (d, J = 7.6 Hz, 1H), 7.85–7.71 (m, 4H), 7.69–7.51 (m, 3H), 7.24 (s, 1H).
180.6, 151.2, 140.0, 137.3, 132.6 (d, J = 32.9 Hz) *, 131.9, 130.8, 128.7, 128.1,
δ
127.5, 126.5, 126.3 (q, J = 3.7 Hz), 124.4, 123.6 (d, J = 272.7 Hz). IR ν: 3033, 2930, 1615, 1438, 1113, 667.
HRMS (ESI) calculated for C16H10F3OS [M + H]+ 307.0404 found 307.0446.
6-Fluoro-2-(4-(trifluoromethyl)-phenyl)-4H-thiochromen-4-one (2j). The title compound was prepared
from 1j according to the general procedure III. Yield 90 mg (55%) of 2j as a yellowish solid.
◦
1
m.p.: 128–130 C. H-NMR (300 MHz, CDCl3)
7.67 (dd, J = 8.8, 4.7 Hz, 1H), 7.41 (ddd, J = 8.8, 7.6, 2.9 Hz, 1H), 7.22 (s, 1H). 13C-NMR (75 MHz, CDCl3)
180.0 (d, J = 2.2 Hz), 162.6 (d, J = 250.4 Hz), 151.8, 140.0, 133.1 (d, J = 7.5 Hz), 133.0 (q, J = 33.2 Hz),
δ 8.20 (dd, J = 9.3, 2.8 Hz, 1H), 7.82–7.72 (m, 4H),
δ

Molecules 2017, 22, 2041
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132.8 (d, J = 3.7 Hz), 128.9 (d, J = 7.7 Hz), 127.7, 126.6 (q, J = 3.7 Hz), 123.8 (q, J = 272.4 Hz), 123.7,
121.0 (d, J = 24.2 Hz), 114.6 (d, J = 23.0 Hz). IR : 2923, 1713, 1623, 1605, 1118. HRMS (ESI) calculated
for C16H9F4OS [M + H]+ 325.0310 found 325.0331.
ν
2-(4-Chlorophenyl)-4H-thiochromen-4-one (2k). The title compound was prepared from 1k◦according to
1
the general procedure III. Yield 82 mg (60%) of 2k as a yellowish solid. m.p.: 161–162 C. H-NMR
(300 MHz, CDCl3) δ 8.60–8.49 (m, 1H), 7.74–7.53 (m, 5H), 7.52–7.42 (m, 2H), 7.37 (s, 1H). 13C-NMR
(75 MHz, CDCl3)
δ 181.0, 151.9, 137.6, 137.4, 135.2, 132.0, 131.0, 129.8, 128.9, 128.4, 128.2, 126.7, 123.8. IR ν:
3014, 1627, 1588, 1087, 777. HRMS (ESI) calculated for C15H10ClOS [M + H]+ 273.0141 found 273.0172.
2-(4-Fluorophenyl)-4H-thiochromen-4-one (2l). The title compound was prepared from 1l according to
the general procedure III. Yield 74 mg (58%) of 2l as a yellowish solid. m.p.: 160–161 ◦C. 1H-NMR
(300 MHz, CDCl3)
7.26 (t, J = 8.5 Hz, 2H)
δ
8.62 (d, J = 7.7 Hz, 1H), 7.82–7.69 (m, 4H), 7.68–7.60 (m, 1H), 7.47 (s, 1H),
.
13C-NMR (75 MHz, CDCl3)
δ
180.8, 164.4 (d, J = 252.0 Hz), 151.9, 137.5, 132.8
(d, J = 3.3 Hz), 131.8, 130.8, 129.0 (d, J = 8.6 Hz), 128.7, 127.9, 126.5, 123.5, 116.5 (d, J = 22.1 Hz).
IR ν: 2921, 1608, 1582, 1500, 1225, 845. HRMS (ESI) calculated for C15H10FOS [M + H]+ 257.0436
found 257.0463.
2-(4-Nitrophenyl)-4H-thiochromen-4-one (2m). The title compound was prepared from 1m according to
the general procedure IV. Yield 128 mg (91%) of 2m as a yellowish solid. mp 183–185 ◦C. 1H-NMR
(300 MHz, CDCl3)
δ
8.54 (d, J = 7.8 Hz, 1H), 8.35 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.72–7.62
180.7, 150.3, 149.3,
: 3015, 1738, 1628, 1513, 1354, 850.
(m, J = 3.0 Hz, 2H), 7.62–7.53 (m, 1H), 7.25 (s, 1H). 13C-NMR (75 MHz, CDCl3)
δ
142.7, 137.2, 132.3, 131.0, 129.0, 128.5, 128.3, 126.8, 125.2, 124.7. IR
HRMS (ESI) calculated for C15H10NO3S [M + H]+ 284.0381 found 284.0407.
ν
4.1.6. General Procedure V. Oxidation of Sulfides to Sulfones.
To a 25-mL glass tube, sulfide (1.0 mmol), oxone (0.9221 g, 1.5 mmol), and a water ethanol mixture
◦
(1:1) (3.0 mL) were added and the mixture was stirred at 60 C for 12 h. The mixture was then cooled to
room temperature and extracted with dichloromethane (3
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by
column chromatography over silica gel using mixtures of hexane and EtOAc as eluent.
×
25 mL). The combined organic layers were
2-Methylthiochroman-4-one 1,1-dioxide (3a). The title compound was prepared from 1a according to the
general procedure V. Yield 178 mg (82%) of 3a as a white solid. m.p.: 129–131 ◦C. 1H-NMR (300 MHz,
CDCl3)
δ 8.10 (dd, J = 7.7, 1.0 Hz, 1H), 8.04 (dd, J = 7.7, 0.8 Hz, 1H), 7.81 (td, J = 7.6, 1.3 Hz, 1H),
7.72 (td, J = 7.6, 1.2 Hz, 1H), 3.76 (dd, J = 14.2, 6.9 Hz, 1H), 3.33–3.19 (m, 2H), 1.54 (d, J = 6.9 Hz, 3H).
13C-NMR (75 MHz, CDCl3)
δ 190.4, 140.7, 135.0, 133.3, 130.5, 128.5, 124.2, 54.6, 44.2, 11.7. IR ν: 3082,
2945, 1694, 1312, 1151, 728. HRMS (ESI) calculated for C10H9O3S [M − H]− 209.0272 found 209.0282.
6-Fluoro-2-methylthiochroman-4-one 1,1-dioxide (3b). The title compound was prepared from 1b according
1
to the general procedure V. Yield 161 mg (71%) of 3b as a white solid. m.p.: 119–120 ◦C. H-NMR
(300 MHz, CDCl3)
3.84–3.62 (m, 1H), 3.37–3.15 (m, 2H), 1.53 (2, J = 10.5 Hz, 3H). 13C-NMR (75 MHz, CDCl3)
(d, J = 257.5 Hz), 136.9 (d, J = 3.6 Hz), 133.4 (d, J = 7.2 Hz), 127.5 (d, J = 8.6 Hz), 122.4 (d, J = 23.0 Hz),
δ
8.06 (dd, J = 8.7, 4.9 Hz, 1H), 7.75 (dd, J = 8.7, 2.6 Hz, 1H), 7.55–7.42 (m, 1H)
,
δ
189.4, 165.2
115.4 (d, J = 23.8 Hz), 54.7, 44.3, 11.7. IR ν: 3100, 2939, 1697, 1580, 1310, 1273, 1147, 694. HRMS (ESI)
calculated for C10H8FO3S [M − H]− 227.0178 found 227.0179.
6-Fluorothiochroman-4-one 1,1-dioxide (3c). The title compound was prepared from 1c according to the
general procedure V. Yield 174 mg (81%) of 3c as a white solid. m.p.: 175–177 ◦C. 1H-NMR (300 MHz,
CDCl3)
1H), 3.74–3.62 (m, 2H), 3.48–3.37 (m, 2H). 13C-NMR (75 MHz, CDCl3)
137.6 (d, J = 3.6 Hz), 133.1 (d, J = 7.3 Hz), 126.9 (d, J = 8.7 Hz), 122.3 (d, J = 23.0 Hz), 115.7 (d, J = 23.8 Hz)
δ 8.03 (dd, J = 8.7, 4.9 Hz, 1H), 7.76 (dd, J = 8.7, 2.6 Hz, 1H), 7.48 (ddd, J = 8.7, 7.7, 2.7 Hz,
δ
189.1, 165.2 (d, J = 257.6 Hz)
,
,

Molecules 2017, 22, 2041
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49.3, 36.9. IR
213.0022 found 213.0025.
ν
: 3087, 2980, 1690, 1577, 1271, 1130, 749. HRMS (ESI) calculated for C9H6FO3S [M − H]−
2-Phenylthiochroman-4-one 1,1-dioxide (3h). The title compound was prepared from 1h according to the
general procedure V. Yield 217 mg (80%) of 3h as a white solid. m.p.: 154–155 ◦C. 1H-NMR (300 MHz
,
CDCl3)
δ 8.22–8.12 (m, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.90–7.72 (m, 2H), 7.61–7.35 (m, 5H), 4.86 (dd, J = 12.8,
3.2 Hz, 1H), 3.96 (dd, J = 17.7, 12.8 Hz, 1H), 3.41 (dd, J = 17.7, 3.2 Hz, 1H). 13C-NMR (75 MHz, CDCl3)
δ
190.9, 141.5, 135.1, 133.4, 130.5, 130.1, 129.9, 129.2, 128.8, 128.0, 124.5, 64.1, 43.1. IR ν: 2957, 1693, 1586, 1281,
1149, 1120, 764. HRMS (ESI) calculated for C15H11O3S [M − H]− 271.0429 found 271.0428.
2-(4-(Trifluoromethyl)-phenyl)-thiochroman-4-one 1,1-dioxide (3i). The title compound was prepared from 1i
according to the general procedure V. Yield 146 mg (43%) of 3i as a white solid. m.p.: 155–157 ◦C. 1H-NMR
(300 MHz, CDCl3)
7.78 (td, J = 7.6, 1.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 4.93 (dd, J = 12.8, 3.2 Hz, 1H),
3.96 (dd, J = 17.7, 12.8 Hz, 1H), 3.41 (dd, J = 17.7, 3.3 Hz, 1H). 13C-NMR (75 MHz, CDCl3)
190.4, 141.3, 135.5,
133.87, 132.4 (q, J = 33Hz), 132.1, 130.6, 130.5, 129.1, 126.3 (dd, J = 7.5, 3.7 Hz), 124.7, 123.9 (q, J = 272.5 Hz),
63.8, 43.0. IR
: 2927, 1691, 1294, 1153, 712. HRMS (ESI) calculated for C16H12F3O3S [M + H]+ 341.0459
found 341.0465.
δ 8.18 (dd, J = 7.7, 1.2 Hz, 1H), 8.07 (dd, J = 7.7, 1.0 Hz, 1H), 7.85 (td, J = 7.6, 1.5 Hz, 1H),
δ
ν
6-Fluoro-2-(4-(trifluoromethyl)-phenyl)-thiochroman-4-one 1,1-dioxide (3j) The title compound was prepared
from 1j according to the general procedure V. Yield 254 mg (62%) of 3j as a white solid. m.p.:
. δ 8.09 (dd, J = 8.7, 4.8 Hz, 1H), 7.83 (dd, J = 8.6, 2.6 Hz,
132–134 ◦C 1H-NMR (300 MHz, CDCl3)
1H), 7.72 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.56–7.47 (m, 1H), 4.92 (dd, J = 12.7, 3.1 Hz,
1H), 3.97 (dd, J = 17.8, 12.8 Hz, 1H), 3.44 (dd, J = 17.8, 3.2 Hz, 1H). 13C-NMR (75 MHz, CDCl3)
δ
189.1, 165.3 (d, J = 258.3 Hz), 137.1 (d, J = 3.6 Hz), 133.2 (d, J = 7.4 Hz), 132.3 (d, J = 33.0 Hz),
131.6, 130.3, 127.7 (d, J = 8.7 Hz), 126.1 (q, J = 3.5 Hz), 123.6 (q, J = 272.4 Hz), 122.5 (d, J = 23.0 Hz),
115.7 (d, J = 23.9 Hz), 63.6, 42.9. IR ν: 2918, 1697, 1579, 1298, 1158, 1114. HRMS (ESI) calculated for
C16H9F4O3S [M − H]− 357.0209 found 357.0201.
2-(4-Chlorophenyl)-thiochroman-4-one 1,1-dioxide (3k). The title compound was prepared from 1k
according to the general procedure V. Yield 199 mg (65%) of 3k as a white solid. m.p.: 160–161 ◦C
.
1H-NMR (300 MHz, CDCl3)
1.4 Hz, 1H), 7.76 (td, J = 7.6, 1.2 Hz, 1H), 7.47–7.36 (m, 4H), 4.83 (dd, J = 12.8, 3.2 Hz, 1H), 3.90 (dd,
J = 17.7, 12.8 Hz, 1H), 3.37 (dd, J = 17.7, 3.2 Hz, 1H).13C-NMR (75 MHz, CDCl3)
190.7, 141.4, 136.5,
: 2932, 1687, 1584, 1490 1314, 1280,
δ 8.16 (dd, J = 7.6, 1.1 Hz, 1H), 8.05 (dd, J = 7.7, 0.8 Hz, 1H), 7.83 (td, J = 7.6,
δ
135.4, 133.7, 131.3, 130.6, 129.6, 129.0, 126.6, 124.7, 63.6, 43.1. IR
ν
1147. HRMS (ESI) calculated for C15H10ClO3S [M − H]− 305.0039 found 305.0038.
2-(4-Fluorophenyl)thiochroman-4-one 1,1-dioxide (3l). The title compound was prepared from 1l according to the
general procedure V. Yield 180 mg (62%) of 3l as a white solid. m.p.: 121–123 ◦C. 1H-NMR (300 MHz, CDCl3)
δ
8.17 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.6, 1.2 Hz, 1H)
7.46 (dd, J = 8.6, 5.2 Hz, 2H), 7.14 (t, J = 8.6 Hz, 2H) 4.85 (dd, J = 12.9, 3.1 Hz, 1H), 3.91 (dd, J = 17.7, 12.9 Hz,
1H), 3.38 (dd, J = 17.7, 3.2 Hz, 1H). 13C-NMR (75 MHz, CDCl3)
190.8, 163.9 (d, J = 250.2 Hz), 141.5, 135.4,
133.7, 131.9 (d, J = 8.7 Hz), 130.6, 129.0, 124.7, 123.9 (d, J = 3.0 Hz), 116.5 (d, J = 21.8 Hz), 63.4, 43.3. IR
, 7.77 (t, J = 10.8, 4.3 Hz, 1H),
,
δ
ν
:
2927, 1697, 1589, 1506, 1490, 1314, 1284, 1152. HRMS (ESI) calculated for C15H10FO3S [M
found 289.0336.
−
H]− 289.0335
2-(4-Nitrophenyl)-thiochroman-4-one 1,1-dioxide (3m). The title compound was prepared from 1m according
◦
1
to the general procedure V. Yield 237 mg (75%) of 3m as a white solid. m.p.: 180–182 C. H-NMR
(300 MHz, CDCl3) 8.31 (d, J = 8.8 Hz, 2H), 8.19 (dd, J = 7.6, 1.2 Hz, 1H), 8.06 (dd, J = 7.6, 0.9 Hz, 1H), 7.86
(td, J = 7.6, 1.5 Hz, 1H), 7.80 (td, J = 7.5, 1.3 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 4.98 (dd, J = 12.8, 3.2 Hz, 1H),
3.97 (dd, J = 17.6, 12.8 Hz, 1H), 3.43 (dd, J = 17.6, 3.2 Hz, 1H). 13CNMR (75 MHz, CDCl3)
189.9, 149.1,
: 3078, 2921, 1695, 1586, 1517, 1342,
δ
δ
141.1, 135.5, 135.1, 134.0, 131.2, 130.5, 129.2, 124.7, 124.4, 63.6, 42.9. IR
ν
1155. HRMS (ESI) calculated for C15H10NO5S [M − H]− 316.0280 found 316.0267.

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2-Phenyl-4H-thiochromen-4-one 1,1-dioxide (4h). The title compound was prepared from 3h according
1
to the general procedure IV. Yield 120 mg (89%) of 4h as a white solid. m.p.: 134–135 ◦C. H-NMR
(300 MHz, CDCl3)
δ
8.21 (dd, J = 7.8, 0.7 Hz, 1H), 8.14–8.05 (m, 1H), 7.87 (ddd, J = 8.3, 5.5, 1.2 Hz, 3H),
178.3, 153.1, 141.7,
: 2920, 2849, 1964, 1650, 1588, 1287,
7.76 (t, J = 7.3 Hz, 1H), 7.60–7.43 (m, 3H), 6.82 (s, 1H). 13C-NMR (75 MHz, CDCl3)
δ
134.8, 133.0, 131.9, 129.3, 128.8, 128.7 (2CHs), 128.5, 128.1, 123.6. IR
1242, 1149. HRMS (ESI) calculated for C15H11O3S [M + H]+ 271.0429 found 271.0434.
ν
2-(4-(Trifluoromethyl)-phenyl)-4H-thiochromen-4-one 1,1-dioxide (4i). The title compound was prepared from 3i
according to the general procedure IV. Yield 167 mg (99%) of 4i as a white solid. m.p.: 188–189 ◦C. 1H-NMR
(300 MHz, CDCl3)
7.90 (td, J = 7.6, 1.5 Hz, 1H), 7.79 (td, J = 7.5, 1.2 Hz, 1H), 7.77 (dd, J = 7.7, 1.2 Hz, 2H), 6.82 (s, J = 5.8 Hz, 1H)
13C-NMR (75 MHz, CDCl3)
178.2, 152.1, 141.6, 135.3, 133.6 (q, J = 33.1), 133.4, 132.4, 130.3, 129.6, 128.6,
128.5, 126.4 (q, J = 3.6 Hz), 123.9, 123.7 (q, J = 272.8). IR : 2917, 1651, 1587, 1295, 1119, 837. HRMS (ESI)
calculated for C16H10F3O3S [M + H]+ 339.0303 found 339.0306.
δ 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 8.10 (dd, J = 7.9, 1.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H),
.
δ
ν
6-Fluoro-2-(4-(trifluoromethyl)-phenyl)-4H-thiochromen-4-one 1,1-dioxide (4j). The title compound was prepared
from 3j according to the general procedure IV. Yield 144 mg (81%) of 4j as a white solid. m.p.:
1
172–173◦C. H-NMR (300 MHz, CDCl3)
δ 8.12 (dd, J = 8.7, 4.7 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H),
7.86 (dd, J = 8.5, 2.6 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.71–7.46 (m, 1H), 6.83 (s, 1H). 13C-NMR (75 MHz,
CDCl3) 177.2, 165.1 (d, J = 258.3 Hz), 152.5, 137.7 (d, J = 3.8 Hz), 133.9 (q, J = 33.3 Hz), 132.1,
131.4 (d, J = 7.6 Hz), 129.9, 129.7, 127.1 (d, J = 8.8 Hz), 126.5 (q, J = 3.6 Hz), 123.7 (q, J = 272.6 Hz),
δ
122.9 (d, J = 23.3 Hz), 115.3 (d, J = 24.0 Hz). IR ν: 3040, 2918, 1658, 1580, 1292, 1119. HRMS (ESI) calculated
for C16H9F4O3S [M + H]+ 357.0209 found 357.0210.
2-(4-Chlorophenyl)-4H-thiochromen-4-one 1,1-dioxide (4k). The title compound was prepared from 3k
according to the general procedure IV. Yield 144 mg (95%) of 4k as a white solid. m.p.: 173–174 ◦C.
1H-NMR (300 MHz, CDCl3)
δ
8.21 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H),
7.80 (d, J = 8.2 Hz, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 6.80 (s, 1H).13C-NMR (75 MHz,
CDCl3) 178.3, 152.3, 141.7, 138.7, 135.2, 133.3, 130.4, 129.9, 129.2, 128.7, 128.4, 127.3, 123.9. IR : 2916,
1644, 1297, 1090. HRMS (ESI) calculated for C15H10ClO3S [M + H]+ 305.0039 found 305.0036.
δ
ν
2-(4-Fluorophenyl)-4H-thiochromen-4-one 1,1-dioxide (4l). The title compound was prepared from◦3l
according to the general procedure IV. Yield 36 mg (25%) of 4l as a white solid. m.p.: 173–174 C.
1H-NMR (300 MHz, CDCl3)
δ
8.21 (dd, J = 7.9, 1.0 Hz, 1H), 8.09 (dd, J = 7.9, 0.7 Hz, 1H), 7.94–7.82
(m, 3H), 7.77 (td, J = 7.7, 1.1 Hz, 1H), 7.21 (t, J = 8.7 Hz, 2H), 6.78 (s, 1H). 13C-NMR (75 MHz, CDCl3)
178.4, 165.2 (d, J = 254.3 Hz), 152.3, 141.8, 135.1, 133.3, 131.4 (d, J = 8.9 Hz), 129.0, 128.7, 128.4,
δ
125.0 (d, J = 3.3 Hz), 123.9, 116.9 (d, J = 22.1 Hz). IR ν: 2849, 1650, 1585, 1505, 1286, 1147. HRMS (ESI)
calculated for C15H10FO3S [M + H]+ 289.0335 found 289.0335.
2-(4-Nitrophenyl)-4H-thiochromen-4-one 1,1-dioxide (4m). The title compound was prepared from 3m
according to the general procedure IV. Yield 99 mg (63%) of 4m as a white solid. m.p.: 187–189 ◦C.
1H-NMR (300 MHz, CDCl3)
δ
8.43 (d, J = 8.4 Hz, 2H), 8.30 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H),
8.09 (d, J = 8.4 Hz, 2H), 7.99 (t, J = 7.7 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 6.92 (s, 1H). 13C-NMR (75 MHz,
CDCl3)
δ 177.8, 151.2, 149.7, 141.2, 135.3, 134.8, 133.4, 130.6, 130.2, 128.42, 128.38, 124.3, 123.7. IR ν:
2917, 2849, 1651, 1586, 1512, 1286, 1147. HRMS (ESI) calculated for C15H10NO5S [M + H]+ 316.0280
found 316.0281.
4.2. Biological Activity
4.2.1. Cytotoxic Activity
Cytotoxicity of the compounds was evaluated over human monocytes (U-937 ATCC CRL-1593.2)
in exponential growing phase and, adjusted at 1
bovine serum (FBS). One hundred microliters of cell suspension were dispensed in each well of
×
105 cells/mL in RPMI-1640 enriched with 10% fetal

Molecules 2017, 22, 2041
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a 96-wells microplate and then, 100
µL of each compound or standard drug (amphotericin B) at four
serial dilution concentrations (200, 50, 12.5 and 3.125 µg/mL) were added dissolved in pbs with 0.5%
DMSO. Cell exposed to compounds or standard drugs were incubated 72 h at 37 ◦C and 5% of CO2.
Cytotoxic activity of each compound was determined according to the effect on the cell viability by
the MTT microenzymatic method in which 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium
bromide is reduced to a purple product named formazan by mitochondrial enzyme succinate
dehydrogenase. Thus, 10
and unexposed cells, and plates were incubated at 37 C, 5% CO2 during 3 h. The reaction was
µ
L/well of MTT solution (5 m◦g/mL) were added to each well of exposed
stopped by adding 100 µL/well of isopropanol with 50% and 10% of SDS (sodium dodecyl sulfate).
The concentration of formazan was determined spectrophotometrically at 570 nm (Varioskan Flash
Multimode Reader, Thermo Scientific, Waltham, MA, USA) and intensity of color (absorbance) was
registered as O.D. Cells exposed to control drug (amphotericin B) were used as control for toxicity
(positive control) while cell incubated in absence of any compound or drug were used as control for
viability (negative control). Non-specific absorbance was corrected by subtracting absorbance (O.D) of
the blank. Determinations were done by triplicate in at least two independent experiments [31].
4.2.2. Antileishmanial Activity
Antileishmanial activity of compounds was determined according to the ability of the compound
to reduce the infection by L. panamensis parasites. For this, the antileishmanial activity was tested
on intracellular amastigotes of L. panamensis transfected with the green fluorescent protein gene
(MHOM/CO/87/UA140-EGFP strain) [24]. Briefly, U-937 human cells at a density of 3 × 105 cells/mL
in RPMI 1640 and 0.1 µg/mL of PMA (phorbol-12-myristate-13-acetate) were dispensed on 24-wells
microplate and then infected with stationary phase growing L. panamensis promastigotes in 15:1 parasites
per cell ratio. Plates were incubated at 34 ◦C and 5% CO2 for 3 h and then cells were washed twice with
phosphate buffer solution (PBS) to eliminate not internalized parasites. Fresh RPMI-1640 was added into
each well (1 mL) and plates were incubated again. After 24 h of infection, the RPMI-1640 medium was
replaced by fresh culture medium containing each compound at four serial dilutions (50, 12.5, 3.125 and
0.78
from the bottom plate with 100
µ
g/mL) and plates were then incubated at 37 ◦C and 5% CO2 during 72 h, then, cells were removed
µL of EDTA/Trypsin (250 mg) solution. The cells were centrifuged at
1100 rpm during 10 min at 4 ◦C, the supernatant was discarded and cells were washed with 1 mL of
cold PBS and centrifuged at 1100 rpm for 10 min at 4 ◦C. Cells were washed two times employing PBS,
as previously, and after the last wash, the supernatant was discarded and cells were suspended in 500
of PBS.
µL
Cells were analyzed by flow cytometry employing a flow cytometer (cytomics FC 500MPL,
Beckman Coulter. Pasadena, CA, USA) reading at 488 nm (exciting) and 525 nm (emitting) over
an argon laser and counting 10,000 events. Infected cells were determined according the events for
green fluorescence (parasites). All determinations for each compound and standard drug were carried
out by triplicate, in two experiments. Infected cells exposed to control drug (amphotericin B) were used
as control for antileishmanial activity (positive control) while infected cells incubated in absence of
any compound or drug were used as control for infection (negative control). Nonspecific fluorescence
was corrected by subtracting fluorescence of unstained cells. Determinations were done by triplicate in
at least two independent experiments [24,32].
4.2.3. Statistical Analysis
Cytotoxicity was determined according to viability and mortality percentages obtained for each
experimental condition (synthetized compounds, amphotericin B and culture medium). Results were
expressed as the mean lethal concentrations (LC50), concentration necessary to kill 50% of cells,
calculated by the parametric method of linear regression that permits doses-response analysis
(Probit analysis) [32].

Molecules 2017, 22, 2041
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Initially, viability percentages were calculated by Equation (1), where the O.D of control well,
corresponds to 100% of viability.
% viability = (O.D exposed cells/O.D unexposed cells) × 100
Then, the percentage of cell growth inhibition was calculated using Equation (2):
% inhibition = 100 − (% Viability)
(1)
(2)
The toxicity was defined according to LC50 values, using the follow scale: Toxic; LC50 < 100 µM;
moderately toxic; LC50 > 100 µM and <200 µM and potentially nontoxic; LC50 > 200 µM.
Antileishmanial activity was determined according reduction of percentage of fluorescent
parasites determined according to the median fluorescence intensity (MFI), obtained for each
experimental condition by cytometry. The parasite values for each concentration of compound
were calculated by Equation (3), where the % of parasites in the control well, corresponds to 100%
of parasites.
% parasites = (MFI exposed parasites/MFI unexposed parasites) × 100
Then, inhibition percentage was calculated with Equation (4):
% inhibition of parasites = 100 − (% parasites)
(3)
(4)
Results of antileishmanial activities were expressed as the median effective concentrations (EC50)
measured by Probit method. The activity of each compound was established according to EC50 values as:
high activity: EC50 < 25 µM; moderate activity: EC50 >25 µM and <100 µM and low activity: EC50 > 100 µM.
5. Conclusions
In summary, 34 thiochromone derivatives were synthesized and their leishmanicidal and cytotoxic
activities were evaluated; many compounds were found to possess weak to moderate activities against
intracellular amastigotes of L. panamensis. However, sulfone derivatives bearing an
α,β-unsaturated
carbonyl moiety (4h, 4i, 4j, 4k, 4l, 4m) displayed the higher antileishmanial activity and the highest
IS; accordingly, the most potent antileishmanial agent was the compound 4j (EC50 = 3.14
IS > 173.24), even higher than the reference drug amphotericin B (IS = 132.02).
±
0.23 µM,
Electron-withdrawing groups in the para position of the phenyl ring do not affect the activity;
however, the fluorine atom at C6 increases the antileishmanial activity and selectivity. The sulfone,
in addition to the
α,β-unsaturated carbonyl groups in the thiochromone moiety, were the most
responsible for the antileishmanial activity. This scaffold could be considered a starting point for
further optimization.
Acknowledgments: Authors thank la Universidad de Antioquia (CODI) for financial support through the project
7749—“Obtención de compuestos tipo tiocromano, en la búsqueda de nuevos fármacos potenciales agentes antiparasitarios”.
Esteban Vargas thanks COLCIENCIAS for a fellowship in the Program Doctorados Nacionales 2012.
Author Contributions: Esteban Vargas, Wiston Quiñones and Fernando Echeverri were responsible for the
synthesis and characterization of the compounds and the data analysis; Sara M. Robledo and Iván D. Vélez were
responsible for the biological studies and analysis of results.
Conflicts of Interest: The authors declare no conflicts of interest.

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