Microwave assisted solvent-free synthesis of novel chenodeoxycholic acid thiosemicarbazone derivatives and studies on antibacterial activities

Article abstract of DOI:10.2174/157017812802850212

A rapid and efficient method for the synthesis of novel chenodeoxycholicacid acid thiosemicarbzones under solvent-free conditions using microwave has been developed. Their structures were elucidated by ESI-MS, IR, ¹H NMR and elemental analysis.

Full text of DOI:10.2174/157017812802850212

604
Letters in Organic Chemistry, 2012, 9, 604-608
Microwave Assisted Solvent-Free Synthesis of Novel Chenodeoxycholic
Acid Thiosemicarbazone Derivatives and Studies on Antibacterial
Activities
Zhi-Gang Zhao*, Ping Yan, Xing-Li Liu and Zhi-Chuan Shi
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu
610041, P.R. China
Received December 28, 2011: Revised June 04, 2012: Accepted June 24, 2012
Abstract: A rapid and efficient method for the synthesis of novel chenodeoxycholicacid acid thiosemicarbzones under
1
solvent-free conditions using microwave has been developed. Their structures were elucidated by ESI-MS, IR, H NMR
and elemental analysis. Nine novel compounds have been synthesized in good yields. Compared to the conventional
method, microwave irradiation method, main advantages are short reaction times, good conversions and the environmen-
tally friendly nature of the process. Preliminary results showed that some of these compounds possess inhibitory effects
against S. typhimurium and E. coli.
Keywords: Antibacterial activity, chenodeoxycholic acid, microwave irradiation, solvent-free, thiosemicarbazone.
1. INTRODUCTION
2. RESULTS AND DISCUSSION
Thiosemicarbazones and their metal complexes have re-
ceived considerable attention in view of their various bio-
logical activities, variables bonding modes, and structural
diversity [1-3]. The biological activity of thiosemicarbazones
was exploited in the 1960s using 1-methylisatin-3-thiosemi-
carbazone, which was effective as prophylactic against
smallpox [4] and vaccinia [5]. 3-aminopyridine-2-carbox-
aldehyde thiosemicarbazones are now being evaluated in
clinical trials against several malignancies [6]. Compounds
with thiosemicarbazones structures have numerous applica-
tions like anti-tubercular, anti-tumor, anti-viral, anti-fungal,
anti HIV, anticancer and other biological activities [7-15].
The structures of all the compounds 4a-i were confirmed
by Mass, IR, 1H NMR, elemental analysis. Their mass spec-
tra showed the expected molecular ions at high intensity. The
IR spectra of these compounds exhibited a characteristic
strong absorption at 3287-3003 cm-1 due to NH stretching
vibration; the strong bands in the region 1731-1736 cm-1
indicated the adsorption of C=O. Strong absorption bands
falling within the range of 1519-1543cm-1 and the range of
1034-1065 cm-1 were assigned to the C=N and C=S respec-
tively. In the 1H NMR spectra, between ꢀ 9.08-9.45 ppm and
ꢀ 8.59-8.94 ppm were assigned to the protons of the NH. In
addition, the singlet peaks at 1.16-1.19 ppm, 0.68-0.74 ppm
and the doublet at 0.95-0.97 ppm were the characteristics of
steroidal structure. The singlet at 3.66-3.68 ppm was as-
signed to the protons of COOCH3.
Recent development in “green chemistry” can minimize
the environment harmfulness of classical reactions. One of
the most popular approaches is the application of microwave
techniques for organic synthesis. This technology can en-
hance the selectivity and improve product yields [16, 17].
For this reason, the application of microwave irradiation
under solvent-free conditions has gained popularity over the
usual homogeneous and heterogeneous reactions.
In searching for the best conditions, we also carried out a
series of experiments, varying the microwave irradiation
(MWI) power, time and different supporters. We used the
synthesis of 4a for example and we found that the highest
yield was obtained when the time was 5.0 min at 450 W by
using neutral aluminum oxide as the solid support.
As is evident from the literature, our research group has
been working on the microwave solvent-free synthesis of
thiosemicarbazone derivatives [18-20]. As a continuation of
this work, we report good yields in the synthesis of novel
chenodexoycholic acid thiosemicarbazone under solvent-free
conditions using neutral aluminum oxide as a mineral sup-
port. Some compounds were tested in vitro against bacteria
such as Salmonella typhimurium, Staphylococcus pyogenes
and Escherichia coli. The synthesis route is depicted in
Scheme 1.
As shown in Table 1, we carried out the synthetic com-
parison of 4a-i between MWI in the solvent-free conditions
and conventional heating. It was easy to see that MWI
greatly decreased the reaction time form 360-500 min to 4.5-
6.5 min. However, the yields also increased from 45-52% to
84-93%. Consequently, the use of microwave technology in
conjunction with the use of solvent-free conditions allows
expeditious and efficient procedures in this organic synthe-
sis.
The compounds 4a-e were tested for their antibacterial
activities by disc-diffusion method using nutrient broth me-
dium. The Gram-positive and Gram-negative bacteria util-
ized in this study consisted of S. typhimurium, S. pyogenes,
*Address correspondence to this author at the College of Chemistry and
Environmental Protection Engineering, Southwest University for Nationali-
ties, Chengdu 610041, P. R. China; Tel: +86-28-85522315; Fax: +86-28-
85524382; E-mail: zzg63129@yahoo.com.cn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Microwave Assisted Solvent-Free Synthesis of Novel Chenodeoxycholic
Letters in Organic Chemistry, 2012, Vol. 9, No. 8
605
CH3OH
COOCH3
COOH
p-CH3-Ph-SO3H
OH
OH
OH
1
OH
S
H
N
H
R
C
N
NH2
3a-i
COOCH3
PCC, CH2Cl2
MWI
solvent-free
O
r.t.
O
2
R=
COOCH3
OCH3
N
Br
F
4c
OCH3
N
NH
4a
4d
4e
4b
NH
C
C
S
S
CH3
NH
R
NH
R
Br
F
CH3
4h
4a-i
4f
Scheme 1. Synthesis of the chenodeoxycholic acid thiosemicarbazone derivatives 4a-i.
4g
4i
Table 1. Synthetic Comparison of the Chenodeoxycholic Acid Thiosemicarbazone Derivatives 4a-i Between MWI and Conventional
Heating.
Conventional method
T/min
Microwave method
T/min
Compd.
Tca/Tmwb
Solvent(ml)
Yield/%
Solvent(ml)
Yield/%
4a
4b
4c
4d
4e
4f
20
20
20
20
20
20
20
20
20
360
450
360
400
420
450
400
500
420
52
46
50
52
47
49
48
45
49
/
/
/
/
/
/
/
/
/
5.0
5.5
4.5
4.5
5.0
5.0
6.0
6.5
6.0
91
84
91
93
87
89
86
84
87
72
82
80
89
84
90
67
77
70
4g
4h
4i
aTime of conventional heating
bTime of MWI
E.coli. In the disc-diffusion method, sterile paper discs (5
mm) were impregnated with compound dissolved in DMSO
at the concentration of 0.01% (mass fraction). The plates
were incubated at 35°C for 24 h. The result is presented in
Table 2. The compounds investigated have good biological
activity against S. typhimurium and E. coli. Further antibac-
terial activities are under study.
3. CONCLUSIONS
In summary, we have developed a highly efficient and
eco-friendly method for the preparation of chenodeoxycholic
acid thiosemicarbazones. The reaction was conducted in the
presence of neutral aluminum oxide, without using solvent,
and assisted by microwave irradiation. The present method
has many advantages compared to the conventional method,

606 Letters in Organic Chemistry, 2012, Vol. 9, No. 8
Zhao et al.
Table 2. Antibacterial Activities of Compounds 4a-e.
Compounds
S. typhimurium
S. pyogenes
E. coli
4a
++
+
-
-
++
++
++
++
++
-
4b
4c
++
++
+
+
+
-
4d
4e
DMSO
-
-
++: strong; +: moderate; -: weak or no.
including shorter reaction times, good product yields and it
fulfills green chemistry protocols. The importance of such
work lies in the possibility that these new compounds might
be more helpful in designing more potent antibacterial agents
for biological and therapeutic use.
were placed in a porcelain mortar, then two drops of concen-
trated acetic acid were added. After grinding, the mixture
was put in round-bottom flask (25 ml) in a microwave oven.
It was irradiated for 4.5~6.5 min at 400~600 W. The reaction
mixture was cooled to room temperature, dissolved in
DMSO and filtered. The filtrate was added to water and the
product precipitated. It was recrystallized from ethanol and
obtained in 84~93% yields. The physical and spectra data of
the compounds 4a-i are as follows.
4. EXPERIMENTAL
4.1. General
Melting points were determined on a micro-melting point
apparatus and are uncorrected. IR spectra were obtained on
1700 PerkinElmer FTIR using KBr disks. H NMR spectra
4.3.1. Methyl (5ꢀ)-3,7-bis[2-
[[(phenylamino)thioxomethyl]hydrazinylidene]-12-
oxocholan-24-oate (4a)
1
recorded on a Varian INOVA 400 MHz spectrometer spectra
were determined on FinniganLCQDECA instrument. Elemen-
tal analysis was performed on a Carlo-Erba-1106 auto ana-
lyzer. Optical rotation was measured on a Wzz-2B polarime-
ter. All reactions were performed in a commercial micro-
wave apparatus (XH-100A, 100-1000W, Beijing Xianghu
Science and Technology Development Co. Ltd, Beijing,
China). All the solvents were purified before use. Methyl
(3ꢀ, 5ꢁ, 7ꢀ)-3,7-dihydroxycholan-24-oate [21] and Methyl
(5ꢁ)-3,7-dioxocholan-24-oate [22] were prepared by known
procedures. Thiosemicarbazides 3a-i were also prepared by
known procedures [22].
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 91%; Mp: 188-189 °C.
= -73.50 (c 0.10,
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢂ 0.73 (s, 3H, 18-
CH3), 0.96 (d, 3H, J = 6.4 Hz, 21-CH3), 1.19 (s, 3H, 19-
CH3), 3.67 (s, 3H, COOCH3), 7.22 (dd, 2H, J = 9.6, 7.6 Hz,
ArH), 7.34-7.43 (m, 4H, ArH), 7.64-7.71 (m, 4H, ArH), 8.63
(s, 1H, NH), 8.66 (s, 1H, NH), 9.25-9.36 (m, 2H, NH); IR
(KBr, cm-1): 3303, 2942, 1734, 1595, 1536, 1441, 1327,
1266, 1182, 1064, 751; ESI—MS m/z (%): 701 [(M+1)+,
100]; Elemental analysis: Found (%): C, 66.85; H, 7.47; N,
12.01 Calcd. For C39H52N6O2S2: C, 66.82; H, 7.48; N, 11.99.
4.3.2. Methyl (5ꢀ)-3,7-bis[2-[[(4-
methoxyphenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxochola n-24-oate (4b)
4.2. Methyl (5ꢀ)-3,7-dioxocholan-24-oate (2)
Pyridinium chlorochromate [23] (PCC) (3.03 mmol) was
added to a solution of methyl (3ꢀ, 5ꢁ, 7ꢀ)-3,7-dihydroxy-
cholan-24-oate (0.25 g, 0.615 mmol) in dried CH2Cl2 (20 ml)
at room temperature. The reaction was completed in 24 h.
The solvent was removed under reduced pressure, and the
crude product was purified by column chromatography on
silica gel using ethyl acetate to give 2 as white solid; yield
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 84%; Mp: 197-198 °C.
= -108.40 (c 0.10,
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢂ 0.74 (s, 3H, 18-
CH3), 0.96 (d, 3H, J = 6.4 Hz, 21-CH3), 1.16 (s, 3H, 19-
CH3), 3.66 (s, 3H, COOCH3), 3.81 (s, 3H, Ar-OCH3), 3.83
(s, 3H, Ar-OCH3), 6.89-6.96 (m, 4H, ArH), 7.45-7.53 (m,
4H, ArH), 8.59 (s, 1H, NH), 8.61 (s, 1H, NH), 9.08-9.15 (m,
2H, NH); IR (KBr, cm-1): 3301, 2943, 1733, 1595, 1520,
1469, 1244, 1177, 1034, 829; ESI—MS m/z (%): 761
[(M+1)+, 100]; Elemental analysis: Found (%): C, 64.76; H,
7.40; N, 11.03 Calcd. For C41H56N6O4S2: C, 64.71; H, 7.42;
N, 11.04.
86%; Mp: 155-156 °C (lit. Mp: 154-156 °C [24]).
20 = -
[ꢀ]D
21.5 (c 0.12, CH2Cl2). 1H NMR (400 MHz, CDCl3) ꢂ 0.69 (s,
3H, 18-CH3), 0.93 (d, 3H, J = 6.4 Hz, 21-CH3), 1.31 (s, 3H,
19-CH3), 3.67 (s, 3H, COOCH3); IR (KBr, cm-1): 2953,
2873, 1709, 1403, 1375, 1214, 1174, 1010, 966; ESI—MS
m/z (%): 827 [(2M+23)+, 100]; Elemental analysis: Found
(%):C, 74.53; H, 9.52 Calcd. For C25H38O4: C, 74.59; H,
9.51.
4.3.3. Methyl (5ꢀ)-3,7-bis[2-[[(4-
fluorophenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxocholan- 24-oate (4c)
4.3. Microwave Procedure for the Preparation of Steroi-
dal Thiosemicarbazones 4a-i
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 91%; Mp: 156-157 °C.
= -80.37 (c 0.10,
The steroidal diketone 2 (1 mmol), the thiosemicar-
bazides 3a-i (2 mmol) and neutral aluminium oxide (1.0 g)
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢂ 0.74 (s, 3H, 18-

Microwave Assisted Solvent-Free Synthesis of Novel Chenodeoxycholic
Letters in Organic Chemistry, 2012, Vol. 9, No. 8
607
1
CH3), 0.96 (d, 3H, J = 6.0 Hz, 21-CH3), 1.19 (s, 3H, 19-
CH3), 3.67 (s, 3H, COOCH3), 7.02-7.12 (m, 4H, ArH), 7.53-
7.62 (m, 4H, ArH), 8.71 (s, 1H, NH), 8.79 (s, 1H, NH), 9.15-
9.31 (m, 2H, NH); IR (KBr, cm-1): 3297, 2944, 1733, 1608,
1519, 1373, 1263, 1219, 1181, 1062, 830; ESI—MS m/z
(%): 737 [(M+1)+, 100]; Elemental analysis: Found (%): C,
63.50; H, 6.86; N, 11.43 Calcd. For C39H50F2N6O2S2: C,
63.56; H, 6.84; N, 11.40.
CH2Cl2). H NMR (400 MHz, CDCl3) ꢀ 0.74 (s, 3H, 18-
CH3), 0.96 (d, 3H, J = 6.4 Hz, 21-CH3), 1.17 (s, 3H, 19-
CH3), 3.67 (s, 3H, COOCH3), 7.18-7.24 (m, 2H, ArH), 7.27-
7.36 (m, 2H, ArH), 7.46-7.51 (m, 1H, ArH), 7.57-7.67 (m,
1H, ArH), 7.90-7.99 (m, 2H, ArH), 8.79 (brs, 2H, NH), 9.24-
9.34 (m, 2H, NH); IR (KBr, cm-1): 3288, 2944, 1731, 1584,
1530, 1474, 1424, 1258, 1181, 1063, 773, 671; ESI—MS
m/z (%): 859 [(M+1)+, 100]; Elemental analysis: Found (%):
C, 54.57; H, 5.86; N, 9.81 Calcd. For C39H50Br2N6O2S2: C,
54.54; H, 5.87; N, 9.79.
4.3.4. Methyl (5ꢀ)-3,7-bis[2-[[(4-
bromophenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxocholan- 24-oate (4d)
4.3.8. Methyl (5ꢀ)-3,7-[2-[[(4-
methylphenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxocholan-24 -oate (4h)
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 93%; Mp: 164-165 °C.
= -109.50 (c 0.10,
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢀ 0.68 (s, 3H, 18-
CH3), 0.96 (d, 3H, J = 6.0 Hz, 21-CH3), 1.19 (s, 3H, 19-
CH3), 3.68 (s, 3H, COOCH3), 7.44-7.50 (m, 4H, ArH), 7.52-
7.62 (m, 4H, ArH), 8.70 (s, 1H, NH), 8.77 (s, 1H, NH), 9.21-
9.32 (m, 2H, NH); IR (KBr, cm-1): 3291, 2944, 1732, 1585,
1530, 1260, 1179, 1065,1010, 823; ESI—MS m/z (%): 859
[(M+1)+, 100]; Elemental analysis: Found (%): C, 54.59; H,
5.85; N, 9.81 Calcd. For C39H50Br2N6O2S2: C, 54.54; H,
5.87; N, 9.79.
Obtained according to the MWI method as a white solid;
yield 84%; Mp: 190-191 °C.
20 = -90.50 (c 0.10, CH2Cl2).
[ꢀ]D
1H NMR (400 MHz, CDCl3) ꢀ 0.72 (s, 3H, 18-CH3), 0.95 (d,
3H, J = 6.0 Hz, 21-CH3), 1.17 (s, 3H, 19-CH3), 2.33 (s, 3H,
Ar-CH3), 2.34 (s, 3H, Ar-CH3), 3.67 (s, 3H, COOCH3), 7.14-
7.22 (m, 4H, ArH), 7.46-7.54 (m, 4H, ArH), 8.75 (d, 1H, J =
4.0 Hz, NH), 8.81 (d, 1H, J = 6.8 Hz, NH), 9.16-9.28 (m,
2H, NH); IR (KBr, cm-1): 3295, 2941, 2868, 1734, 1590,
1532, 1371, 1263, 1177, 1062, 812, 731; ESI—MS m/z (%):
729 [(M+1)+, 100]; Elemental analysis: Found (%): C, 67.57;
H, 7.72; N, 11.57 Calcd. For C41H56N6O2S2: C, 67.55; H,
7.74; N, 11.53.
4.3.5. Methyl (5ꢀ)-3,7-bis[2-[[(3-
methoxyphenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxochola n-24-oate (4e)
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 87%; Mp: 191-192 °C.
= -139.50 (c 0.10,
4.3.9. Methyl (5ꢀ)-3,7-bis[2-[[(2-
methylphenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxocholan -24-oate (4i)
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢀ 0.74 (s, 3H, 18-
CH3), 0.96 (d, 3H, J = 6.0 Hz, 21-CH3), 1.19 (s, 3H, 19-
CH3), 3.67 (s, 3H, COOCH3), 3.81-3.87 (m, 6H, Ar-OCH3),
6.77 (dd, 2H, J = 6.0, 6.8 Hz, ArH), 7.06 (d, 1H, J = 8.0 Hz,
ArH), 7.11-7.20 (m, 1H, ArH), 7.23-7.32 (m, 2H, ArH),
7.47-7.55 (m, 2H, ArH), 8.61 (brs, 2H, NH), 9.26-9.37 (m,
2H, NH); IR (KBr, cm-1): 3287, 2943, 1734, 1601, 1540,
1488, 1460, 1286, 1216, 1160, 1047, 851, 693; ESI—MS
m/z (%): 761 [(M+1)+, 100]; Elemental analysis: Found (%):
C, 64.74; H, 7.41; N, 11.06 Calcd. For C41H56N6O4S2: C,
64.71; H, 7.42; N, 11.04.
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 87%; Mp: 196-197 °C.
= -60.78 (c 0.10,
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢀ 0.74 (s, 3H, 18-
CH3), 0.96 (d, 3H, J = 6.4 Hz, 21-CH3), 1.18 (s, 3H, 19-
CH3), 2.38 (s, 3H, Ar-CH3), 2.39 (s, 3H, Ar-CH3), 3.67 (s,
3H, COOCH3), 7.02-7.07 (m, 2H, ArH), 7.23-7.32 (m, 2H,
ArH), 7.40-7.44 (m, 1H, ArH), 7.48 (d, 2H, J = 6.0 Hz,
ArH), 7.56 (d, 1H, J = 8.0 Hz, ArH), 8.61 (s, 1H, NH), 8.94
(s, 1H, NH), 9.20-9.28 (m, 2H, NH); IR (KBr, cm-1): 3294,
2942, 1736, 1602, 1543, 1487, 1326, 1271, 1197, 1164,
1063, 780, 698; ESI—MS m/z (%): 729 [(M+1)+, 100]; Ele-
mental analysis: Found (%): C, 67.51; H, 7.77; N, 11.48
Calcd. For C41H56N6O2S2: C, 67.55; H, 7.74; N, 11.53.
4.3.6. Methyl (5ꢀ)-3,7-bis[2-[[(3-
fluorophenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxocholan- 24-oate (4f)
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 89%; Mp: 188-187 °C.
= -100.89 (c 0.10,
1
CH2Cl2). H NMR (400 MHz, CDCl3) ꢀ 0.73 (s, 3H, 18-
CH3), 0.97 (d, 3H, J = 6.0 Hz, 21-CH3), 1.17 (s, 3H, 19-
CH3), 3.68 (s, 3H, COOCH3), 6.85-6.94 (m, 2H, ArH), 7.19-
7.39 (m, 4H, ArH), 7.65-7.79 (m, 2H, ArH), 8.69 (s, 1H,
NH), 8.74 (s, 1H, NH), 9.29-9.45 (m, 2H, NH); IR (KBr, cm-
1): 3300, 2944, 1735, 1604, 1539, 1486, 1436, 1272, 1200,
1064, 858, 775; ESI—MS m/z (%): 737 [(M+1)+, 100]; Ele-
mental analysis: Found (%): C, 63.54; H, 6.86; N, 11.37
Calcd. For C39H50F2N6O2S2: C, 63.56; H, 6.84; N, 11.40.
4.4. Conventional Procedure for the Preparation of Ster-
oidal Thiosemicarbazones 3a-i
The steroidal diketone 2 (1 mmol) and the thiosemicar-
bazides 3a-i (2 mmol) were dissolved in ethanol (20 ml).
After completely dissolving, two drops of acetic acid were
added. The mixture was stirred for 360-500 min at 80 °C.
After cooling, the products were filtered, recrystallized from
ethanol and obtained 45-52% yields.
4.3.7. Methyl (5ꢀ)-3,7-bis[2-[[(3-
bromophenyl)amino]thioxomethyl]hydrazinylidene]-12-
oxocholan- 24 -oate (4g)
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
Obtained according to the MWI method as a white solid;
[ꢀ]2D0
yield 86%; Mp: 142-143 °C.
= -131.80 (c 0.10,

608 Letters in Organic Chemistry, 2012, Vol. 9, No. 8
Zhao et al.
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ACKNOWLEDGEMENTS
We greatly thank the Science and Technology Depart-
ment of Si Chuan Province (No. 2011JY0035) and the Fun-
damental Research Funds of Central Universities, Southwest
University for Nationalities (No. 11NZYTH05) for the fi-
nancial support.
[11]
[12]
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
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