Synthesis of Unsymmetrical Sulfides and Their Oxidation to Sulfones to Discover Potent Antileishmanial Agents

Article abstract of DOI:10.1021/acscombsci.5b00044

Unsymmetrical sulfides were first synthesized using combinations of a 1,3-dicarbonyl, an aromatic aldehyde and a thiol in the presence of 10 mol % ethanolic piperidine. These sulfides derivatives were subsequently converted into corresponding sulfones via

Full text of DOI:10.1021/acscombsci.5b00044

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Article
Synthesis of Unsymmetrical Sulfides and Their Oxidation
to Sulfones to Discover Potent Antileishmanial Agents
Ajaz A. Dar, Nagasuresh Enjamuri, Md. Shadab, Nahid Ali, and Abu Taleb Khan
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.5b00044 • Publication Date (Web): 06 Oct 2015
Downloaded from http://pubs.acs.org on October 12, 2015
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Synthesis of Unsymmetrical Sulfides and Their
Oxidation to Sulfones to Discover Potent
Antileishmanial Agents
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Ajaz A. Dar,a Nagasuresh Enjamuri, a Md. Shadab, Nahid Ali, c,* and Abu T. Khan a ,b,
*
aDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039,
India
bAliah University, IIA/27, New Town, Kolkataꢀ700 156, West Bengal, India.
cInfectious Diseases and Immunology Division, Indian Institute of Chemical Biology, 4, Raja
S.C. Mullick Road, Kolkata 700 032, India.
ABSTRACT
Unsymmetrical sulfides were first synthesised using combinations of a 1,3ꢀdicarbonyl, an
aromatic aldehyde and a thiol in presence of 10 mol% ethanolic piperidine. These sulfides
derivatives were subsequently converted into corresponding sulfones via oxidation in
presence of mꢀchloroperoxybenzoic acid (mꢀCPBA) at iceꢀbath to room temperature. The
former reaction was achieved at room temperature through oneꢀpot threeꢀcomponent. The
later was obtained in good yields using mild reaction conditions with flexibility in choice
from a range of substrates. The antimicrobial properties of the newly synthesized sulfone
derivatives were investigated against the protozoan parasite, Leishmania donovani, a
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causative agent of visceral leishmaniasis (VL). Nine sulfone derivatives were found to be
efficacious and exhibited significant antimicrobial activity. Further, these compounds were
nontoxic on murine peritoneal macrophages thus eliminating potential cytoxicity in the host
cells. These compounds may be indicated as potential leads in the treatment of visceral
leishmaniasis.
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KEYWORDS: KnoevenagelꢀthiaꢀMichael reaction, Unsymmetrical sulfides (βꢀMercapto
diketones), mꢀChloroperoxybenzoic acid, Sulfones, protozoan parasite, Leishmania donovani,
visceral leishmaniasis.
INTRODUCTION
Many sulfur containing compounds particularly dithioacetals,1a oxathioacetal, sulfides,
sulfoxide, sulfones and sulfonamides have immense importance because of their wide
synthetic utility in organic synthesis.1 In addition, many naturally occurring sulfur based
compounds exhibit anticancer activity.2 A large number of synthetic drugs containing a
sulfur atom are used for treatment of various diseases.3 Moreover, sulfides are usually used
for generation of αꢀmetallated sulfide, βꢀacylvinyl cation, homoenolate anion, equivalents as
stabilized carbanion, extensively used for natural and nonꢀnatural product synthesis.4
Additionally, they are the key starting material for the synthesis of other sulfur derivatives
like sulfoxides and sulfones.
The synthesis of unsymmetrical sulfides such as βꢀmercapto diketones are of great interest
amongst the synthetic organic chemists. These compounds exhibit remarkable
pharmacological activities such as diuretic and HIV protease inhibitory activities.5 Our
research group and others have demonstrated synthesis of unsymmetrical sulfides using
multiꢀcomponent reactions (MCRs) strategy by employing tandemꢀKnoevenagelꢀthiaꢀ
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Michael reaction.6 Nowadays, MCRs are well recognized synthetic strategy for the synthesis
of a wide variety of organic compounds due to high atom economy and bondꢀforming
efficiency, mild reaction conditions, ease of handling, no tedious work up and isolation
procedures, regioꢀselectivity and diversity. Recently, we have shown the usefulness of 1,3ꢀ
dicarbonyl compounds as key starting material for construction of numerous heterocycles
through MCRs.7 They also have been explored by others for the synthesis of many bioactive
compounds such as furans,8 pyrroles,9 thiophenes10 and valuable synthetic intermediates.11
We have realised that a wide variety of unsymmetrical sulfides can be obtained from 1,3ꢀ
dicarbonyl compounds, aromatic aldehydes and thiols under milder reaction conditions.
However, reported methodologies limit the lack of substrate scope, low yield, high
temperatures12 and synthesis of various benzyl sulfides prior to use.13 Therefore, there is a
need to develop a newer methodologies, which works under milder reaction conditions.
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Similarly, sulfones are key intermediates14 in organic synthesis. The sulfonyl group in the
sulfone makes it susceptible to the changes in chemical reactivity called as “chemical
chameleons”15 and exhibit interesting chemical properties.16 The desulfonylation reactions of
sulfones gives a sulfinate anion17 and stabilizes the neighbouring carbanions.18 The sulfonyl
group serves as a possible stereoenriched centre, due to lack of inherent asymmetry.19
Recently, Chi et al., developed the enantioselective synthesis of βꢀsulfonyl ketones and the
transformation of γꢀketosulfone into cyclopropane with good enantioselectivity.20 Benzylic
sulfones acts as source for the generation of αꢀsulfonyl carbanions under different reaction
conditions owing to carbonꢀcarbon bond formation.21 Moreover, sulfones play a prominent
role in the field of pharmaceuticals,22 polymers23 and agrochemicals24 with an extensive
range of biological activities and applications. For instance, sulfone derivatives are potent
inhibitors for several enzymes such as HIVꢀ1 reverse transcriptase,25 γꢀsecretase,26
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cyclooxygenaseꢀ227 and matrix metalloproteinase.28 They are also biologically active agents
for drugs used for the treatment of Alzheimer’s disease29 and cancer related diseases.30
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Leishmaniasis is a vectorꢀborne protozoan disease. Being one of the world’s most
neglected diseases, its prevalence is in 98 countries with 350 million people at risk of
infection.31 Clinical manifestations include visceral, cutaneous and mucocutaneous forms.
Visceral leishmaniasis caused by L. donovani is often fatal if left untreated.32 There is no
licenced Leishmania vaccine and current therapy relies on a limited number of drugs
including pentavalent antimonials (still used as first line therapy), amphotericin B,
pentamidine and miltefosine (the second line therapies), which are also not free from
limitations including adverse side effects, requirement of long term treatment regimen and
emergence of drug resistant parasites.33 Consequently, these issues lay emphasis on an urgent
need to develop alternative (safer, cheaper and more effective) chemotherapeutic agents with
potential antileishmnial activity.34 Few studies on the activity of sulfonamides and sulfones
against L. major and L. donovani promastigotes and on intracellular amastigotes indicate that
these molecules could be promising for the treatment of cutaneous and visceral
leishmaniasis, respectively.35 Infact, studies have shown the efficacy of dapsone in the
treatment of cutaneous leishmaniasis.36 However, to improve case management of severe
visceral leishmaniasis (VL) and achieve rapid control of outbreaks, the development of an
effective antileishmanial drug is highly desirable. Therefore, much attention has been paid to
the synthesis of benzylic sulfones which could be useful in developing potential
antileishmanial drug. Although several new methods have recently been reported to improve
the synthesis of benzylic sulfones, they require expensive reagents/catalysts and/or harsh
reaction conditions.37 Herein, we report a synthesis of highly substituted unsymmetrical
sulfides through oneꢀpot piperidine catalyzed threeꢀcomponent reaction using 1,3ꢀdicarbonyl
compounds, aromatic aldehydes and thiols followed by the oxidation of sulfides into the
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corresponding sulfones (as shown in scheme 1) and evaluated the activity of sulfones against
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promastigotes of L. donovani.
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Scheme 1. Synthesis of sulfides through MCR strategy and their oxidation into
corresponding sulfones.
RESULTS AND DISCUSSION
Synthesis of Sulfides. For the present study, pentaneꢀ2,4ꢀdione 1{1}, benzaldehyde 2{1}
and ethanethiol 3{1} were used as the model substrates to find a suitable reaction condition.
A trial reaction was carried out in 3 mL ethanol at room temperature in absence of catalyst
and a trace amount of desired product was formed (Table 1, entry 1). Then, similar reactions
were conducted in presence of 5, 10 and 20 mol% piperidine at room temperature,
respectively and the results are summarized in Table 1. It was observed that 10 mol%
piperidine in ethanol at room temperature gave the best yield (Table 1, entry 3). Other
catalysts,
such as pyridine,
pyrrolidine,
triethylamine
(Et3N) and
1,8ꢀ
diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) in ethanol were also scrutinized (Table 1, entries 9ꢀ
12). These catalysts provided lower yields and required longer reaction time. Various other
solvents were also examined with 10 mol% of piperidine under identical reaction conditions
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(Table 1, entries 5ꢀ8) and ethanol proved to be the best solvent as compared to the other
tested solvents.
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Table 1. Optimization of reaction conditionsa
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Entry
Catalyst (mol %)
No catalyst (0)
Piperidine (5)
Piperidine (10)
Piperidine (20)
Piperidine (10)
Piperidine (10)
Piperidine (10)
Piperidine (10)
Pyridine (10)
Pyrrolidine (10)
Et3N (10)
Solvent
EtOH
EtOH
EtOH
EtOH
DCE
Time (h)
Yield (%)b
1
2
24
5
trace
40
75
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64
70
46
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15
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5
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DMF
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DCM
CH3CN
EtOH
EtOH
EtOH
EtOH
5
8
5
9
12
12
12
12
10
11
12
DBU (10)
aAll the reactions were carried out using 1{1} (1 mmol), 2{1} (1 mmol) and 3{1} (1.2
mmol) in 3 mL of solvent at room temperature. bIsolated yield.
After optimization of reaction conditions, the reaction were carried out with various aromatic
aldehydes (Figure 1) to generalize the scope of this reaction. In case of aromatic aldehydes
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with both electron donating or withdrawing groups, the desired products were obtained with
moderate to good yields, such as Me, OMe, 3,4,5ꢀOMe, OH, Br, Cl, CN, F and NO2 groups.
The reaction between pentaneꢀ2,4ꢀdione (1{1}), benzaldehyde (2{1}) with aliphatic or
aromatic thiols (3) were inspected under optimized reaction conditions. The desired products
4{1,1,1ꢀ5} were obtained in 75ꢀ83% yields (Table 2, entries 1–5). The reaction between
pentaneꢀ2,4ꢀdione (1{1}), 4ꢀmethoxybenzaldehyde (2{2}) with benzylthiol (3{3}) or 4ꢀ
methylthiophenol (3{5}) were examined in a similar manner in the presence of the same
amount of catalyst. The desired products 4{1,2,3} and 4{1,2,5} were obtained in 81% and
85% yields, respectively (Table 2, entries 6 and 7). The reactions between pentaneꢀ2,4ꢀdione
(1{1}), aromatic aldehydes with different electron donating or withdrawing substituents in
the aromatic ring, and thiophenol (3{4}) were performed under identical conditions, the
products 4{1,3ꢀ6,4} were obtained in 57ꢀ89% yield (Table 2, entries 8ꢀ11). Also, reactions
between pentaneꢀ2,4ꢀdione (1{1}), aromatic aldehydes with various electron donating or
withdrawing substituents in the aromatic ring, and 4ꢀmethylthiophenol (3{5}) were examined
under similar conditions, the products 4{1,7,5}ꢀ 4{1,10,5} were obtained in 57ꢀ68% yields
(Table 2, entries 12ꢀ14). Furthermore, we scrutinised the reactions of pentaneꢀ2,4ꢀdione
(1{1}), 2ꢀnapthaldehyde (2{12}) with 4ꢀmethylthiophenol (3{5}) and 2ꢀnapthalenethiol
(3{8}), the reactions proceeded smoothly to give 4{1,12,5} and 4{1,12,8}, respectively, in
good yields (Table 2, entries 15 and 16). Due to the steric hindrance at orthoꢀposition, 2ꢀNO2
(2{13}), 2ꢀCl (2{14}) or 2ꢀOH (2{15}) benzaldehyde with pentaneꢀ2,4ꢀdione (1{1}) and 4ꢀ
methylthiophenol (3{5}) did not give the desired product. However, 2ꢀMe (2{16}), 2ꢀOMe
(2{17}), 2ꢀF (2{18}) or 2ꢀBr (2{19}) benzaldehyde with pentaneꢀ2,4ꢀdione (1{1}) and 4ꢀ
methylthiophenol (3{5}) produced the desired product in good yields (Table 2, entries 17–
20). Similarly, heterocyclic aldehydes 2ꢀpyridinecarboxaldehyde (2{20}) and 2ꢀ
thiophenecarboxaldehyde (2{21}) also worked well with pentaneꢀ2,4ꢀdione (1{1}) and
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Figure 1. Substrates used in the synthesis of compounds 4 and 5.
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4ꢀmethylthiophenol (3{5}) to produce the desired products 4{1,20,5} and 4{1,21,5}, in good
yield respectively (Table 2, entries 21ꢀ22). The reactions of 1,3ꢀdiphenylpropaneꢀ1,3ꢀdione
(1{2}), benzaldehyde (2{1}) with benzylthiol (3{3}) or different aromatic thiols (3) were
examined under the optimized reaction condition. The desired products 4{2,1,3ꢀ7} were
obtained in 61ꢀ70% yields (Table 2, entries 23–27). Similarly, the reactions of 1,3ꢀ
diphenylpropaneꢀ1,3ꢀdione (1{2}), aromatic aldehydes containing various electron donating
or withdrawing substituents at the para or metaꢀposition on the benzene ring, with varied
aromatic thiols (3) were also carried out. The desired products 4{2,2,5}ꢀ 4{2,11,7} were
isolated in good yields (Table 2, entries 28–32). By these successful results, we also
scrutinized the reactions of unsymmetrical 1,3ꢀdicarbonyl, 1ꢀphenylꢀ1,3ꢀbutanedione (1{3}),
benzaldehyde (2{1}), with benzylthiol (3{3}), thiophenol (3{4}) or 4ꢀmethylthiophenol
(3{5}) by following the same reaction procedure. The desired products 5{3,1,3ꢀ5} were
isolated in good yields (Table 3, entries 1–3). Likewise, the reactions of 1ꢀPhenylꢀ1,3ꢀ
butanedione (1{3}), aromatic aldehydes, which have various electron donating or
withdrawing substituents in the aromatic ring, and different aromatic thiols (3) were
examined, the desired products 5{3,2,3}ꢀ 5{3,6,5} were obtained in 55ꢀ80% yields (Table 3,
entries 4–9) .
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From the above results, the reactions were found to be sensitive to the steric and electronic
effects of the R1 and R2 groups. pentaneꢀ2,4ꢀdione (1{1}) reacted with benzaldehyde (2{1})
and thiophenol (3{4}) to provide the product 4{1,1,4} in 82% yield (Table 2, entry 4), while
the 1,3ꢀdiphenylpropaneꢀ1,3ꢀdione (1{2}) and 1ꢀphenylꢀ1,3ꢀbutanedione (1{3}) reacted in
similar fashion gave the products 4{2,1,4} and 5{3,1,4} (68% and 75% yield) respectively
(Table 2, entry 24 and Table 3, entry 2). The aromatic aldehydes bearing electron donating
groups provided better yield along with shorter reaction time as compared to those aromatic
aldehydes having electron withdrawing substituents. It was also observed that the electron
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donating substituents in thiophenol increased the yield of the products. Furthermore, it was
noted that while replacing the pentaneꢀ2,4ꢀdione with 1ꢀphenylꢀ1,3ꢀbutanedione or 1,3ꢀ
diphenylpropaneꢀ1,3ꢀdione provided lower yield of the expected product as well as required
longer reaction time, these changes were found to be gradual respectively. This observation
can be explained due to the formation of stable Knoevengel intermediate that gives extended
conjugation to the system. In addition, when the reaction of unsymmetrical diketone i.e. 1ꢀ
phenylꢀ1,3ꢀbutanedione (1{3}), benzaldehyde (2{1}) or 4ꢀmethoxybenzaldehyde (2{2}) and
benzylthiol (3{3}), was performed the mixture of two diastereomers were obtained in the
ratio of 1:1. The diastereomeric ratio was determined from 1H spectra.
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Table 2. Synthesis of unsymmetrical sulfides from symmetrical diketonesa
Entry
Product
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,2,3}
4{1,2,5}
4{1,3,4}
Yield (%)b
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75
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4{1,4,4}
4{1,5,4}
4{1,6,4}
4{1,7,5}
4{1,8,5}
4{1,10,5}
4{1,12,5}
4{1,12,8}
4{1,16,5}
4{1,17,5}
4{1,18,5}
4{1,19,5}
4{1,20,5}
4{1,21,5}
4{2,1,3}
4{2,1,4}
4{2,1,5}
4{2,1,6}
4{2,1,7}
4{2,2,5}
4{2,3,4}
4{2,3,5}
4{2,9,6}
89
57
62
68
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58
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4{2,11,7}
56
aAll the reactions were carried out using 1{1} or 1{2} (1 mmol), 2 (1 mmol) and 3 (1.2
5
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mmol) in 3 mL of solvent at room temperature. bIsolated yield.
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Table 3. Synthesis of unsymmetrical sulfides from unsymmetrical diketonea
Entry
Product
5{3,1,3}
5{3,1,4}
5{3,1,5}
5{3,2,3}
5{3,2,5}
5{3,3,4}
5{3,4,6}
5{3,5,7}
5{3,6,5}
Yield (%)b
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2
3
4
5
6
7
8
9
73
75
77
76
80
76
79
72
55
aAll the reactions were carried out using 1{3}(1 mmol), 2 (1 mmol) and 3 (1.2 mmol) in 3
mL of solvent at room temperature. bIsolated yield.
Mechanism. The formation of the product can be explained as follows: Initially piperidine
reacts with the aldehyde (2) to form iminium ion, the iminium ion is being attacked by the
active methylene group of the 1,3ꢀdiketone that results in the formation Knoevengel
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intermediate A. The Knoevengel intermediate A subsequently undergoes thiaꢀMichael
addition reaction with thiol (3) to give desired product as shown in Scheme 2.
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The structures of two representative products 4{1,1,3} and 5{3,1,4}, one each from both the
categories, that is symmetrical diketone and unsymmetrical diketone respectively, have been
categorically proved by the singleꢀcrystal XRD (Figure S1 in the Supporting Information).
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Scheme 2. Plausible mechanism for the formation of unsymmetrical sulfide.
Synthesis of Sulfones. After the successful synthesis of sulfides, the oxidation of
unsymmetrical sulfides into sulfone was carried out by using mꢀCPBA as oxidant, because of
its outstanding reactivity, availability and easy to handle than hydrogen peroxide, peracid and
peracetic acids. It was found that a wide variety of dibenzyl, aryl benzyl and alkyl benzyl
sulfides were oxidized to their corresponding sulfones in excellent yields in dichloromethane
at 0 oC to room temperature, the results are summarized in Table 4 and Table 5. The oxidant
mꢀchloroperoxybenzoic acid (mꢀCPBA) was used to convert sulfides to sulfones easily under
an optimized reaction condition (Table 4 and Table 5) in excellent yields without further
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purification. All of the reactions occurred with complete selectivity for sulfone formation, no
other products such as sulfoxides and BayerꢀVilliger products were obtained in the present
study. The selectivity of the present method is fairly wide, as other functionalities remain
unaffected under these reaction conditions. Prominent effects of the substituents were not
observed in sulfone formation and excellent yields were obtained in all cases (Table 4 and
Table 5).
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Table 4. Oneꢀpot oxidation of sulfides containing symmetric diketones to sulfonesa
Entry
Substrate
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,2,5}
4{1,3,4}
4{1,4,4}
4{1,5,4}
4{1,6,4}
4{1,7,5}
4{1,8,5}
Product
6{1,1,1}
6{1,1,2}
6{1,1,3}
6{1,1,4}
6{1,1,5}
6{1,2,5}
6{1,3,4}
6{1,4,4}
6{1,5,4}
6{1,6,4}
6{1,7,5}
6{1,8,5}
Yield (%)b
1
2
91
92
88
90
93
94
89
95
87
90
90
86
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6
7
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4{1,10,5}
6{1,10,5}
6{1,12,5}
6{1,12,8}
6{1,17,5}
6{1,18,5}
6{1,21,5}
6{2,1,4}
6{2,1,5}
6{2,1,6}
6{2,1,7}
6{2,2,5}
6{2,3,4}
6{2,3,5}
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4{1,12,5}
4{1,12,8}
4{1,17,5}
4{1,18,5}
4{1,21,5}
4{2,1,4}
4{2,1,5}
4{2,1,6}
4{2,1,7}
4{2,2,5}
4{2,3,4}
4{2,3,5}
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aReaction conditions: substrate (0.5 mmol), mꢀCPBA (1.5 mmol), and dichloromethane (3
mL) at 0 °C for 3 h. bIsolated yield.
Table 5. Oneꢀpot oxidation of sulfides containing unsymmetric diketone to sulfonesa
Entry
Substrate
5{3,1,4}
5{3,1,5}
5{3,2,5}
Product
7{3,1,4}
7{3,1,5}
7{3,2,5}
Yield (%)b
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2
3
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5{3,3,4}
5{3,4,6}
5{3,5,7}
5{3,6,5}
7{3,3,4}
7{3,4,6}
7{3,5,7}
7{3,6,5}
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aReaction conditions: substrate (0.5 mmol), mꢀCPBA (1.5 mmol), and dichloromethane (3
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These products were confirmed on the basis of their analytical data (1H NMR, C NMR, IR
and ESIꢀMS) and physicoꢀchemical data like melting point. The structures of compounds
6{1,1,3} and 7{3,1,4} were further confirmed by Xꢀray analysis (Figure S2 in the Supporting
Information). The crystal structure shows that 6{1,1,3} forms a dimer through nonꢀcovalent
weak intermolecular CꢀH···π interactions (C7ꢀC12···H5A = 2.859 Å). Similarlly, the crystal
structure 7{3,1,4} also forms a dimer through nonꢀcovalent weak intermolecular oxygenꢀ
hydrogen interactions (O2···H13 = 2.460 Å, ∠O2···H13ꢀC13 = 167.79° and O3···H12 =
2.491 Å, ∠C15ꢀO3···H12 = 168.15°) (Figure S3 in the Supporting Information). In the last
few years, these noncovalent interactions involving aromatic rings such as C−H···π,
C−H···O−H and C−H···O−S interactions have attracted a great deal of interest among the
family of pharmaceutical, optical, functional materials and in biological systems.38
Antimicrobial Activity. In this study, we evaluated the antileishmanial activity of sixteen
sulfone derivatives against promastigotes of L. donovani and found that most of them
displayed significant antileshmanial activity with low cytotoxicity against mammalian cells.
Table 6. Leishmanicidal activity of compounds against L. donovani promastigotes
Activity
Cytotoxicity
L. donovani promastigotes
Macrophages
Compounds
(IC50µg/ml±SD)a (IC90µg/ml±SD)a (IC50µg/ml±SD)a
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4.085±0.7283
4.485±0.9546
7.355±1.308
8.075±1.718
8.655±2.708
10.13±2.949
6{1,1,3}
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O
S
O
O
O
6{1,1,4}
O
O
O
O
S
4.55±0.8202
8.395±1.761
16.75±2.56
CH3
6{1,1,5}
O
S
O
O
O
5.59±1.329
10.08±2.397
19.24±1.648
H3CO
CH3
6{1,2,5}
4.325±0.7283
7.785±1.308
15.02±2.574
6{1,4,4}
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O
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O
O
O
3.99±0.297
7.185±0.5303
11.73±2.157
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CH3
6{1,12,5}
O
S
O
O
4.095±0.3323
7.365±0.601
11.17±2.249
O
6{1,12,8}
O
O
Ph
O
Ph
4.985±1.69
8.975±2.033
8.73±3.168
S
O
6{2,1,4}
O
O
Ph
O
Ph
S
3.655±0.2051
6.58±0.3677
15.08±1.188
O
Cl
6{2,1,6}
O
S
O
Ph
O
Ph
3.67±0.1131
6.61±0.198
22.79±3.663
O
Br
6{2,1,7}
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O
S
O
Ph
O
Ph
3.645±0.2475
6.57±0.4525
22.15±4.943
O
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H3CO
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CH3
6{2,2,5}
O
O
Ph
O
O
3.855±0.3041
6.94±0.5515
8.47±1.499
S
7{3,1,4}
O
O
Ph
O
O
S
4.455±0.5445
8.02±0.9758
17.25±1.435
CH3
7{3,1,5}
6.435±0.859
11.59±1.046
23.04±5.317
7{3,2,5}
4.105±0.7142
7.39±1.287
14.78±1.478
7{3,4,6}
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O
S
O
Ph
O
O
4.045±0.5445
7.29±0.9758
7.335±2.652
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Cl
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Br
7{3,5,7}
an=2
Evaluation of in vitro antileishmanial activity (Table 6) are represented as IC50 and IC90
values of compounds against promastigotes of L. donovani. The cytotoxicity of all
compounds were evaluated against murine macrophages. Statistical analysis showed that all
these sixteen compounds have no significant difference amongst them in exhibiting activity
against the promastigotes of L. donovani. This means that all these sulfones possess potent to
moderate antileishmanial activity. However, the results showed that out of these, seven
compounds namely 7{3,5,7}, 7{3,1,4}, 6{1,1,3}, 6{2,1,4}, 6{1,1,4}, 6{1,12,8} and
6{1,12,5} displayed toxicity towards the mammalian macrophage cells with IC50 values of
7.335±2.652 µg/ml, 8.47±1.499 µg/ml, 8.655±2.708 µg/ml, 8.73±3.168 µg/ml, 10.13±2.949
µg/ml, 11.17±2.249 µg/ml, and 11.73±2.157 µg/ml, respectively. These IC50 values against
macrophages are close to IC90 values against promastigoes. Therefore, the efficacy of these
compounds is limited due to their toxicity. The compounds 7{3,4,6}, 6{1,4,4}, 7{3,1,5},
6{1,1,5}, 6{1,2,5} and 7{3,2,5} with IC50 values of 4.105±0.7142 µg/ml, 4.325±0.7283
µg/ml, 4.455±0.5445 µg/ml, 4.55±0.8202 µg/ml, 5.59±1.329 µg/ml and 6.435±0.859 µg/ml,
respectively could be potent antileishmanial agents as their toxic effect towards macrophage
is negligible at the doses used against the parasite (as depicted by their IC50 values). Thus, the
compounds whose cytotoxicity towards normal murine macrophage cells is low or negligible
and at the same time displaying antileishmanial activity at low to moderate doses could have
therapeutic prospects. Herein, the compounds 6{2,2,5}, 6{2,1,6} and 6{2,1,7} are found to
be most effective against promastigotes with IC50 values of 3.645±0.2475 µg/ml,
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3.655±0.2051 µg/ml and 3.67±0.1131 µg/ml, respectively. These three compounds (whose
IC50 values against macrophage are quite high) represent promising lead compounds for
antileishmanial therapy. The percent cell viability of L. donovani and peritoneal macrophages
with increase in concentration from 0.00 to 10.0 mg/mL were also evaluated as shown in
Figure 2.
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Figure 2: Leishmanicidal effect of 6{2,1,7}, 6{2,2,5} and 6{2,1,6} on promastigotes of L.
donovani and toxic effect on murine peritoneal macrophages. (A) L. donovani promastigotes
were treated for 24 h with increasing concentrations of three different compounds 6{2,1,7},
6{2,2,5} and 6{2,1,6}, and then cell viability was assessed using alarm blue reagent (as
described in material and methods). (B) Similarly, peritoneal macrophages were treated for
24 h with increasing concentrations of these three compounds 6{2,1,7}, 6{2,2,5} and
6{2,1,6}, and cell viability was assessed.
Structure–activity relationship (SAR). SAR studies were carried out to identify how the
structurural differences, in terms of chemical modifications, in our sulfone derivatives affect
their antiꢀleshmanial activity. We found that in all the structures, the dicarbonyl group in its
enol form, which is the interacting moiety, is necessary for their activity. Moreover, the
hydrophobic moiety involved in πꢀcation interaction significantly contributed to maximize
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the activity. Although, all these sixteen compounds showed no significant difference amongst
them in exhibiting activity against the promastigotes of L. donovani, however, SAR studies
revealed that the introduction of phenyl rings close to the dicarbonyl group and electron
donating groups in the phenyl rings in close proximity to sulfone functionality enhanced the
activity of (6{2,2,5}, 6{2,1,6}and 6{2,1,7}) when used at low to moderate doses and which
simultaneously exhibited low or negligible cytotoxicity towards normal murine macrophage
cells. Furthermore, sulfone derivatives containing electron donating (7{3,4,6}, 6{1,4,4},
7{3,1,5}, 6{1,1,5}, 6{1,2,5}and 7{3,2,5}) substituents in the meta and/or para position in the
phenyl moiety displayed promising antiꢀleishmanial activity owing to their negligible toxic
effect towards macrophages at the doses used against the parasite. Incontrast, the introduction
of either electron withdrawing substituents (7{3,5,7}) or unsubstituted sulfone derivatives
(7{3,1,4}, 6{1,1,3}, 6{2,1,4}, 6{1,1,4}, 6{1,12,8}and 6{1,12,5}) displayed toxicity towards
the mammalian macrophage cells with IC50 values close to IC90 values against promastigoes.
Molecular Docking Study of Sulfone derivatives against Trypanothione Reductase.
Trypanothione reductase (TryR) is a key drug target enzyme involved in the redox
metabolism of the parasite and inhibition of TryR may disrupt the redox balance of the
parasite leading to parasite death. Thus, sulfone derivatives have been designed which can
bind the active site of TryR leading to its inhibition. In order to understand the binding
interactions of these sulfones against trypanothione reductase, we have performed the
molecular docking study of all the sixteen compounds on L. infantum trypanothione reductase
by using Glide 5.8 module in maestro 9.3.39 There is no crystal structure available for
trypanothione reductase of L. donovani and thus we started our molecular docking studies
with trypanothione reductase from Leishmania infantum as there is 98% sequence similarity
between the trypanothione reductase of L. donovani and L. infantum. The molecular docking
study was carried out using Xꢀray crystal structures of trypanothione reductase from
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Leishmania infantum (PDB code: 2jk6, 2.95 Å).40 The crystal structure is coꢀcrystallized with
cofactor FAD. The enzyme (TryR) is a dimer consisting of two active sites. Active sites are
buried at the interface of chains A and B. The molecular docking study suggests that sulfone
derivatives bind in the trypanothione reductase binding pocket with hydrogen bonds and
hydrophobic contacts with the Aꢀchain and Bꢀchain. The molecular docking of sulfone
derivatives showed that the most of the interactions are close to Glu 466, Glu 467, Ser 470,
Arg 472 indicating that the binding is preferentially happening in γ−Glutamate and new
interacting sites. These residues are found around the active site Cysꢀ52 and Cysꢀ57.
Interestingly, some of these derivatives show hydrophobic interaction with His 461 which is a
part of catalytic triad (Cysꢀ52ꢀ His 461ꢀ Cysꢀ57). In all the cases, the 1,3ꢀdicarbonyl group in
its enol form is interacting with Glu 467, Ser 470. The phenyl/napthyl moiety involved in πꢀ
cation interaction with amino acids which includes mainly Arg 472, His 461. All the sixteen
compounds were docked into the active site of TryR. A maximum of 10 docking poses per
ligand were generated in each case and analyzed further for the binding mode and
intermolecular interactions. The two representative examples revealing the mode of
interactions are shown in Figure 3.
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Figure 3: Binding modes of ligands at the interface of homodimer. Ligands are shown in
stick models (magenta colour). Hydrogen bonding interactions are shown as black dashes and
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residues involved in hydrogen bonding or hydrophobic interactions (π−π, π−cation) are
represented in stick models (A) Represent the binding mode of 7{3,1,4} and (B) Represent
the binding mode of 6{1,12,5}.
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CONCLUSION
In conclusion, we have developed an efficient and general method for synthesis of
unsymmetrical sulfides which in turn were transformed into alkylꢀbenzyl and benzylꢀaryl
sulfones with various functional groups that can also be extended to the preparation of vinyl
sulfones. In synthetic organic chemistry, importance of the sulfone functional group provides
significant interest in the development of new methodologies related to the introduction of
the sulfone functionality into an organic molecule as well as the further synthetic
transformation of the sulfone intermediate, and its eventual elimination from the target when
needed. Also from evaluation of biological activity as well as docking study, into the active
site of trypanothione reductase (TryR) enzyme, against visceral leishmaniasis, it may be
concluded from the present study, that most of these newly synthesized sulfone derivatives
have promising antileishmanial activity and further study on lead optimisation through in
vitro and in vivo model of visceral leishmaniasis could allow development of new
anitleishmanial drug.
EXPERIMENTAL SECTION
Material and Method for Biological Screening.
Cell Culture and Parasite. L. donovani strain AG83 (MHOM/IN/1983/AG83), originally
isolated from an Indian kalaꢀazar patient was maintained by serial passage in hamsters. L.
donovani amastigotes periodically recovered from the spleens of infected hamsters were
transformed into promastigotes through amastigote culture in M199 supplemented with 10%
FCS, 2 mM glutamine, penicillin G (100 U/ml), streptomycin sulfate (100 ꢁg/ml) at 22°C.
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Promastigotes were used at the log phase of growth, approximately 2 to 3 days after
subculture. Parasites were kept in culture by weekly passaging.
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In vitro antipromastigote activity. Antiparasitic activities of compounds against L.
donovani (AG83) promastigotes were determined using alamarBlue cytotoxicity assays
(Thermofisher). Resazurin (7ꢀHydroxyꢀ3Hꢀphenoxazinꢀ3ꢀone 10ꢀoxide) is the active
ingredient of AlamarBlue reagent and is a nonꢀtoxic, nonꢀfluorescent and cell permeable
compound that is blue in color. Healthy living mamalian cells maintain a reducing
environment within their cytosol. Upon entering cells, the “reducing potential” reduces
resazurin to resorufin, which is red in colour and highly fluorescent. Viable cells
continuously convert resazurin to resorufin, increasing the overall fluorescence and colour of
the culture media.
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Assays were performed in sterile 96ꢀwell plates using 100 µl of logꢀphase promastigotes
adjusted to 2x106 cells/ml. BALB/c mice (8ꢀ10 week old) were used for this experiment.
Resident peritoneal macrophages were obtained by injecting 5ꢀ10 ml RPMI medium
supplemented with 10% FCS into the peritoneal cavity of BALB/c mice. The pulled medium
containing the peritoneal exudates cells were plated (1x105 cells /well) in a 96 well culture
plate. Nonꢀadherent cells were washed off after 20 h culture. These cells were incubated in
control and in presence of 0.1562 ꢁg/ml, 0.3125 ꢁg/ml, 0.625 ꢁg/ml, 1.25 ꢁg/ml, 2.50 ꢁg/ml,
5.0 ꢁg/ml and 10.0 ꢁg/ml compounds and DMSO for 24 h. Next 10 ꢁl of the resazurin dye
(0.01%) were added, and plates were further incubated for 4 h at 37 °C. After incubation,
cells were analyzed in a microplate reader (SpectraMax spectrofluorometer, Molecular
Devices) at a wavelength of 570 nm, using 600 nm as a reference wavelength (normalized to
the 600 nm value). Absorbance in the absence of any inhibitor or solvent was set as the
control. Cell viability was evaluated based on a comparison between the untreated control
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cells, solvent and at inhibitory concentrations of inhibitors necessary to reduce the growth of
promastigotes by 50% (IC50 values) and 90% (IC90 values).
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Statistical analysis. Data are expressed as the arithmetic mean±standard deviation values.
IC50 and IC90 values of all sixteen compounds for both promastigotes and macrophages were
calculated using dose–response curves in Origin 5.0 software (Microcal Software, Inc.,
Northampton, MA, USA). These values were compared by 1way ANOVA employing
Turkeys multiple comparision test. The p values for all comparisons were determined and p <
0.05 was taken as significant difference.
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Molecular Docking Study. For the purpose of molecular docking studies, Xꢀray crystal
structure of L. Infantum trypanothione redictase was selected (PDB ID: 2jk6, resolution: 2.95
Å).39 The crystal structure is in dimeric form and it is coꢀcrystalized with cofactor FAD. Both
the chains were considered for molecular docking studies because the binding site of
trypanothione reductase is at the interface of the chain A and chain B. Protein preparation
was done using Maestro. Hydrogen atoms were added during protein preparation wizard.
Receptor Grid Generation Panel within Glide suite was used to set up receptor grid for the
prepared structures. The grid was defined by 16 Å by considering the amino acids of all the
subpockets. Then, this step is followed by restrained minimization using the OPLS 2005
force field to RMSD of 0.3 Å. Threeꢀdimensional structures of these compounds were then
prepared using LigPrep module of maestro implementing OPLS_2005 force field and ionic
states for the ligands at pH values of 7.0 ± 2.0 were generated. Docking was performed using
Glide 5.8 (Gridꢀbased Ligand Docking with Energetics), with the standard precision (SP)
mode to estimate protein–ligand binding affinities and static intermolecular interactions.
General Experimental Details.
Melting point was determined on a Büchi melting point apparatus and are uncorrected. IR
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spectra were recorded on PerkinꢀElmer 281 IR spectrophotometer. H and C NMR spectra
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were recorded on Varian 400 MHz and Bruker 600 MHz spectrometer TMS as internal
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reference; chemical shifts (δ scale) are reported in parts per million (ppm). H NMR Spectra
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are reported in the order: multiplicity, coupling constant (J value) in hertz (Hz) and no of
protons; signals were characterized as s (singlet), d (doublet), dd (doublet of doublets), t
(triplet), m (multiplet). Mass spectra were recorded using WATERS MS system, Qꢀtof
premier and data analyzed using Mass Lynx 4.1. Elemental analyses were carried out using
PerkinꢀElmer 2400 Series II CHNS/O analyzer at the Department of Chemistry, Indian
Institute of Technology Guwahati. Column chromatographic separations were performed
using Merck silica gel (60ꢀ120 mesh). Complete crystallographic data of 4{1,1,3}, 5{3,1,4},
6{1,1,3} and 7{3,1,4} for the structural analysis have been deposited with the Cambridge
Crystallographic Data Centre, CCDC No. 1019727, 958054, 930603 and 958055
respectively. Copies of this information may be obtained free of charge from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44ꢀ1223ꢀ336033, eꢀmail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
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General procedure for synthesis of compounds (4 and 5). To a stirred solution of 1,3ꢀ
diketone (1 mmol) in 3 mL of ethanol were added piperidine (0.1 mmol) and aldehyde (1
mmol) successively and the reaction mixture was kept for stirring for 5ꢀ10 min at room
temperature. Then, thiol (1.2 mmol) was added either directly if it is a solid or dropꢀwise
through a syringe into the reaction mixture. The solid products namely 4{1,1,4ꢀ5}, 4{1,2,5}
to 4{1,12,8}, 4{1,18,5}, 4{1,21,5}, 4{2,1,4} to 4{2,11,7} and 5{3,1,4} to 5{3,1,5}, 5{3,2,5}
to 5{3,6,5} were precipitated out during the reaction after appropriate reaction time. Finally,
the products were filtered off through a Büchner funnel and dried. The pure product was
obtained after recrystallization from methanol. The following work up procedure was
followed for the products such as 4{1,1,1ꢀ3}, 4{1,2,3}, 4{1,16ꢀ17,5}, 4{1,19,5}, 4{1,20,5},
4{2,1,3}, 5{3,1,3} and 5{3,2,3} because the solid precipitate did not come out during the
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reaction time. After completion of reaction as checked by TLC, ethanol was removed in a
rotary evaporator and the crude residue was extracted with dichloromethane (2 × 15 mL). The
organic layer was washed with water, brine solution (2 x 5 mL) and dried over anhydrous
Na2SO4. Then, it was concentrated in a rotary evaporator and the crude residue was passed
through a silica gel (60ꢀ120 mesh) column to get the desired pure product.
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3-((ethylthio)(phenyl)methyl)pentane-2,4-dione 4{1,1,1}: Yield: (187.8 mg, 75%); White
solid, mp 73ꢀ75 °C; IR (KBr): 3396, 3054, 2975, 2956, 1692, 1496, 1454, 1421, 1357, 1270,
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1185, 1150, 1099, 717, 700 cmꢀ1. H NMR (400 MHz, CDCl3): δ 1.14 (t, J = 7.6 Hz, 3H),
1.88 (s, 3H), 2.27ꢀ2.35 (m, 2H), 2.37 (s, 3H), 4.26 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 12.0 Hz,
1H), 7.24ꢀ7.31 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 14.3, 25.3, 29.5, 30.1, 48.3, 74.8,
128.0, 128.3 (2C), 128.9 (2C), 139.5, 201.6 (2C) ppm; ESIꢀMS m/z: calcd for C14H18O2SNa:
273.09; Found 273.15 [M + Na]+. Anal Calcd for C14H18O2S (250.36): C, 67.16; H, 7.25%.
Found C, 67.03; H, 7.16%.
General procedure for synthesis of compounds (6 and 7). mꢀChloroperoxybenzoic acid
(mꢀCPBA, 1.5 mmol) was added in portion for a period of 15 min to a stirred solution of
corresponding unsymmetrical sulfide (0.5 mmol) in 3 mL of dichloromethane at iceꢀbath
temperature and stirring was continued for 45 min at the same temperature. Then, the reaction
mixture was brought to room temperature slowly and it was stirred for another 2 h. After
completion of reaction, it was extracted with by adding 18 mL of dichloromethane, which
was washed with 5% aqueous NaHCO3 solution (10 mL) and brine solution (10 mL). Finally,
the organic layer was dried over anhydrous Na2SO4 and it was concentrated in a rotary
evaporator. The desired sulfone was obtained after recrystallization from methanol.
3-((ethylsulfonyl)(phenyl)methyl)pentane-2,4-dione 6{1,1,1}: Yield: (257 mg, 91%);
White solid, mp 140ꢀ142 °C. IR (KBr): 3395, 3048, 2974, 2944, 2659, 2549, 1965, 1908,
1733, 1701, 1596, 1574, 1452, 1424, 1364, 1335, 1308, 1294, 1260, 1246, 1217, 1169, 1134,
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1069, 1051, 1036, 877, 851, 795, 707 cmꢀ1. H NMR (400 MHz, CDCl3): δ 1.25 (t, J = 7.6
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Hz, 3H), 1.85 (s, 3H), 2.42 (s, 3H), 2.64ꢀ2.81 (m, 2H), 4.88 (d, J = 11.6 Hz, 1H), 5.16 (d, J =
11.6 Hz, 1H), 7.37 (s, 5H). 13C NMR (150 MHz, CDCl3): δ 6.2, 29.0, 30.7, 45.9, 66.8, 66.9,
129.6 (2C), 129.9, 130.2 (2C), 131.1, 199.1, 200.0 ppm; ESIꢀMS m/z: calcd for
C14H18O4SNa: 305.08; Found 305.16 [M + Na]+. Anal Calcd for C14H18O4S (282.35): C,
59.55; H, 6.43%. Found C, 59.43; H, 6.35%.
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ACKNOWLEDGMENTS
ATK are grateful to Council of Scientific and Industrial Research (CSIR) 02(0181)/14/EMRꢀ
II for their financial support. AAD is thankful to IIT Guwahati for providing senior research
fellowship. The authors are also grateful to Director, IIT Guwahati for providing the general
research facility to carry out this work. We are also thankful to CIF, IIT Guwahati for
providing the instrument facilities. We are also grateful to Professor Prasad V. Bharatam and
his Ph.D student Deepika Kathuria, National Institute of Pharmaceutical Education and
Research, S. A. S Nagar, Mohali for molecular docking study.
Supporting Information
Experimental details and spectroscopic characterization for compounds of chemset 4, 5, 6 and
7. Complete crystallographic description of 4{1,1,3}, 5{3,1,4}, 6{1,1,3} and 7{3,1,4}. This
information is available free of charge via the Internet at http://pubs.acs.org/.
Corresponding Author
*Eꢀmail: atk@iitg.ernet.in (A.T. Khan); nali@iicb.res.in (Nahid Ali).
Tel.: +91 361 2582305; fax: +91 361 2582349.
Notes
The authors declare no competing financial interest.
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