Synthesis, spectral characterization, and biological activity of some new substituted 10H-phenothiazines, its ribofuranosides, and sulfones

Article abstract of DOI:10.1080/15257771003708538

This article describes the synthesis of new substituted 10 H-phenothiazines by Smiles rearrangement. These compounds are then used as a base to form ribofuranosides by treating them with a sugar (1-O-acetyl-2,3,5-tri-O-benzoyl- β-ribofuranose). On oxidati

Full text of DOI:10.1080/15257771003708538

Nucleosides, Nucleotides and Nucleic Acids, 29:178–189, 2010
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257771003708538
SYNTHESIS, SPECTRAL CHARACTERIZATION, AND BIOLOGICAL
ACTIVITY OF SOME NEW SUBSTITUTED 10H-PHENOTHIAZINES,
ITS RIBOFURANOSIDES, AND SULFONES
Naveen Gautam,1 Neha Ajmera,2 Shikha Gupta,2 and D. C. Gautam2
1Department of Chemistry, L.B.S. Govt. P.G. College, Kotputli, Jaipur, India
2Department of Chemistry, University of Rajasthan, Jaipur, India
This article describes the synthesis of new substituted 10 H-phenothiazines by Smiles rearrange-
2
ment. These compounds are then used as a base to form ribofuranosides by treating them with
a sugar (1-O-acetyl-2,3,5-tri-O-benzoyl-β-ribofuranose). On oxidation with hydrogen peroxide in
glacial acetic acid, these phenothiazines yield their sulfones. These compounds are screened for an-
tioxidant and antimicrobial activity and their structure has been established by elemental analysis
and spectroscopic data.
Keywords Smiles rearrangement; ribofuranosides; antioxidant and antimicrobial
activity
INTRODUCTION
10H-Phenothiazines as well as the ribofuranosides obtained from them
have been found to possess promising pharmacological and biological ac-
tivity and are employed for many purposes, such as tranquilizers, sedatives,
antibacterial, antifungal, anticancer, and central nervous system (CNS) de-
pressants, and so on. A slight change in the substitution pattern results
in large difference in their biological activities.[1–15] The synthesized com-
pounds were screened for antioxidant and antimicrobial activity.
RESULTS AND DISCUSSION
Synthesis of 10H-phenothiazines (5a–b) have been carried out by Smiles
rearrangement of substituted 2-formamido-2ꢁ-nitrodiphenylsulfides (4a–b).
Received 6 October 2009; accepted 10 February 2010.
The authors are grateful to the Department of Chemistry, University of Rajasthan, Jaipur for pro-
viding necessary facilities. UGC Research Award Scheme and UGC (New Delhi) are duly acknowledged
for financial support.
Address correspondence to Neha Ajmera, 62, Vivek Vihar, Jagatpura, Jaipur- 302025, Rajasthan,
India. E-mail: ajmneha@yahoo.com
178

Some New Substituted 10 H-Phenothiazines, Their Ribofuranosides, and Sulfones 179
The formyl derivatives were prepared by the formylation of 2-amino-2ꢁ-
nitrodiphenylsulfides (3a–b), which in turn were prepared by conden-
sation of 2-amino-4,6-dimethylbenzenethiol (Ia) with o-halonitrobenzene
[1,4-dibromo-2-nitrobenzene (2a) and 2,4-dichloro-5-nitrobenzotrifluoride
(2b)] in ethanolic sodium acetate solution. 1-Nitrophenothiazines (5c–d)
were prepared by refluxing 2-amino-4,6-dimethylbenzenethiol (Ia) and 2-
amino-3,4,5-trifluorobenzenethiol (Ib) with reactive halonitrobenzenes [2,4-
dichloro-3,5-dinitrobenzotrifluoride (2c), and 1,2-dichloro-3-nitrobenzene
(2d)], respectively, (which have either two nitro or one halo and one nitro
group ortho to the reactive halogen atom) in alcohol in the presence of
sodium hydroxide, whereby Smiles rearrangement occured in situ. Com-
pounds (5a–d) on refluxing with 30% H2O2 in glacial acetic acid were
converted into their corresponding sulfones (7a–d). Compounds (5a–d)
when treated with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose in toluene
in vacuum at 155–160◦C for 10 hours give the corresponding ribofuranosides
(6a–d) (Scheme 1).
R1
R5
R5
R1
R2
R3
NH2
SH
X
R6
R7
C2H5OH
NaOH
R2
R3
NH2
X
R6
R7
CH3COONa
C2H5OH
+
Cl
X
X
R
= Cl(2d),
S
=
NO2 (2c)
X
= NO2(2a,2b)
R4
R8
2a-d
R4
R8
3a-b
8 = NO2
R8 = H
Ia-b
Formylation
90% HCOOH
Smiles rearrangement
Smiles rearrangement
H
R1
9
R8
1
CHO
R5
R1
2
R2
R3
8
7
N 10
R7
Acetone
R2
R3
NH
X
R6
3
KOH/EtOH
R6
S
6
4
5
S
R7
R4
R5
R4
R8
5a-d
4a-b
R4
R5
5
4
6
R3
R2
S
3
R6
7
BzO
OCOCH
3
O
H
R1
9
R8
1
2
R2
R3
N 10
R7
R6
8
BzO
8
R7
N 10
30% H2O2
gl. Acetic Acid
2
9
R1
1
Where Bz = benzoyl group
Tol
R8
uene
unde
r vac
uum
7
3
S
5
BzO
6
O
4
R5
155-160°C
O
O
4´
R4
1´
2´
7a-d
3´
BzO OBz
Compound
5a, 6a, 7a
5b, 6b, 7b
5c, 6c, 7c
5d, 6d, 7d
R1
R2
CH3
CH3
CH3
F
R3
H
H
H
F
R4
CH3
CH3
CH3
H
R5
H
R6
R7
R8
H
6a-d
H
H
H
F
Br
CF3
CF3
H
H
Cl
H
H
H
Cl
H
NO2
NO2
H
SCHEME 1 Diagramatic representation of the preparatory methods of 10H-phenothiazines, their ribo-
furanosides, and sulfones.
The structures proposed for the synthesized compounds are well sup-
ported by elemental analysis and spectral data. The synthesized compounds
were also screened for antioxidant and antimicrobial activity. The present

180
N. Gautum et al.
TABLE 1 Characterization data of synthesized compounds 5a–d, 6a–d, 7a–d
Elemental analysis (%) Found (calcd.)
Compd. no.
Mol. Formula
M.P. ◦
C
Yield%
C
H
N
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
C14H12NBrS
60
99
84
220
75
72
85
81
50
77
61
88
87
56
80
67
76
52
69
58
60
58
42
51
55.11(54.90)
54.88(54.62)
48.25(48.06)
48.53(48.32)
64.30(64.00)
63.82(63.60)
60.35(60.10)
61.62(61.45)
49.86(49.70)
49.99(49.79)
44.45(44.28)
43.84(43.63)
3.93(3.92)
3.29(3.33)
2.65(2.67)
1.65(1.67)
4.24(4.26)
4.02(4.00)
3.64(3.66)
3.38(3.36)
3.58(3.55)
3.02(3.04)
2.49(2.46)
1.50(1.51)
4.52(4.57)
4.23(4.24)
7.42(7.47)
9.42(9.39)
1.85(1.86)
1.78(1.80)
3.40(3.42)
3.75(3.77)
4.12(4.14)
3.85(3.87)
6.91(6.88)
8.44(8.48)
C
C
C
C
C
C
C
C
C
C
C
15H11NClF3S
15H10 N2O2ClF3S
12H5 N2O2F3S
40H32NO7BrS
41H31 NO7ClF3S
41H30 N2O9ClF3S
38H25 N2O9F3S
14H12 NO2BrS
15H11NO2ClF3S
15H10 N2O4ClF3S
12H5 N2O4F3S
study demonstrated that the synthesised compounds showed mixed radi-
cal scavenging activity in both DPPH and ABTS r+ assay. These compounds
showed good chemopreventive and antigenotoxic effect.
(a) Compounds 5a, 5c, 6a, 6b, and 7a showed strong radical scavenging
activity in DPPH assay that have DPPH% inhibition ≥50.
(b) Compounds 5b, 6c, and 7b showed moderate radical scavenging ac-
tivity in DPPH assay that have DPPH% inhibition ≥30.
(c) Compounds 5d, 6d, 7c, and 7d showed mild radical scavenging activity
in DPPH assay that have DPPH% inhibition <30.
(d) Compounds 5a, 5d, 6c, 7a, 7b, and 7d showed good activity in ABTS r+
assays.
All these compounds were found to be moderately active against various
bacteria and fungi. The results of antibacterial screening indicated that good
activity was shown by compounds 5a, 5b, 5c, 6b, 6c, 7a, 7c, 7d against Coagulase
negative staphylococci strain while moderate activity was shown by compounds
5d and 6a. Regarding antifungal activity, 5c, 5d, 6b, 6d showed good results
against Candida albicans strain. Other compounds showed moderate activity.
The structural assignments of the synthesised compounds were based on
elemental analysis (Table 1) and spectral data (Table 2).
Infrared Spectra
The infrared (IR) spectral data of compounds 3a–b showed two peaks
in region 3460–3400 cm−1 and 3350–3320 cm−1 due to asymmetric and sym-
metric vibrations of NH2 group. Two peaks in the regions 1570–1560 cm−1
and 1370–1360 cm−1 are also observed due to asymmetric and symmetric

181

182

Some New Substituted 10 H-Phenothiazines, Their Ribofuranosides, and Sulfones 183
vibrations of NO2 group. In compounds 4a–b, a single sharp peak due to
>N H stretching in the 3350–3320 cm−1 region was observed and a peak
in the 1705–1680 cm−1 region due to >C O stretching. Stretching vibra-
tions due to NO2 are also observed in the 1580–1570 and 1380–1350 cm−1
region. Compounds 5a–d showed a single sharp peak in 3420–3120 cm−1
regions due to >N H stretching vibrations.−C1 ompounds 7a–d showed a
peak due to N H stretching in 3430–3130 cm region and also two intense
peaks in the 1365–1345 cm−1 and 1180–1140 cm−1 region due to asymmet-
ric and symmetric stretching vibration of sulfonyl group. Also in compounds
7a–d, a band due to C S stretching occurs in the 1070–1050 cm−1 region.
In compounds 6a–d, a peak due to >N H stretching is found to be absent
indicating its ribosylation. Also bands due to C O and C O C appeared
at 1750–1745 cm−1 and 1190–1140 cm−1 respectively.
,
Nuclear Magnetic Resonance Spectra
The 1H NMR spectra of compounds 5a–d showed two main resonances.
One singlet was observed in between δ 9.08–8.53 ppm due to N H proton
and a multiplet due to aromatic protons in between δ 8.05–6.28 ppm. In the
case of compounds 3a–b broad resonances at δ 4.24–3.68 ppm was observed
due to NH2 group. In the case of compound 4a–b, one signal (singlet) at
δ 10.14–9.85 was also observed due to the formyl proton and another due
to >NH proton at 8.68–8.92 ppm. The synthesized compounds showed res-
onances in between δ 2.37–2.05 ppm due to the CH3 group. In compounds
7a–d a singlet due to the N H proton was observed in between δ 9.10–8.64
ppm.
1
The H NMR spectra of ribofuranosides 6a–d did not show any reso-
nances due to >NH indicating the site of ribosylation but showed a multiplet
ꢁ
ꢁ
at δ 8.06–6.24 due to aromatic protons. The C4 -H and C5 CH2 protons of
ꢁ
the sugar moiety gave a multiplet between δ 4.34–4.83, while C2 H and Cꢁ3H
at δ 5.71–5.84 as multiplets and doublet at δ 6.35–6.48 (J = 8 Hz) due to
ꢁ
C1 -H proton.
EXPERIMENTAL
All the melting points were determined in open capillary tubes and are
1
uncorrected. H NMR and 13C NMR spectra were recorded on JEOL AL-
300 spectrometer (300 MHz) in DMSO-d6 using TMS (tetramethylsilane)
as an internal standard. IR spectra were recorded in KBr on SHIMADZU
8400 S FTIR spectrophotometer. Mass spectra were recorded on JEOL SX
102/DA 600 using Ar/Xe as fast atom bombardment (FAB) gas. Purity of
compounds was checked by thin layer chromatography (TLC) using silica
gel ‘G’ as adsorbent, visualizing these by ultraviolet (UV) light or in an iodine
chamber.

184
N. Gautum et al.
Synthesis of 2-Amino-2ꢁ-nitrodiphenylsulfides (3a–b)
2-Amino-4,6-dimethylbenzenethiol Ia (0.01 mole) was dissolved in
ethanol (20 ml) containing (0.01 mole) of anhydrous sodium acetate in a
50 ml round bottom flask and halonitrobenzene (2a–b) (0.01 mole) in 10 ml
ethanol was added. The reaction mixture was refluxed for 4–5 hours. The re-
sultant solution was cooled and kept overnight in an ice chamber. The solid
was filtered, washed with 30% ethanol and recrystallized with methanol.
Synthesis of 2-Formamido-2ꢁ-nitrodiphenylsulfides (4a–b)
The 2-amino-2ꢁ-nitrodiphenylsulfides 3a–b (0.01 mole) obtained above
was refluxed for 4 hours in 90% formic acid (20 ml). The contents were then
poured onto crushed ice and the solid was filtered, washed with water, and
recrystallized from benzene.
Synthesis of 10H-Phenothiazine (5a–b)
Formyl derivatives 4a–b (0.01 mol) in acetone (15 ml) were refluxed
and an alcoholic solution of potassium hydroxide (0.2 gm in 5ml ethanol)
was added. These solutions were then heated for 30 minutes. A second lot
of KOH (0.2 gm in 5 ml ethanol) was added and refluxing was done for 4
hours. The contents were then poured into a beaker containing crushed ice
and filtered. The residue was washed with cold water, then with 30% ethanol
and then crystallized from benzene.
Synthesis of 1-Nitro-10H-phenothiazines (5c–d)
To a stirred suspension of substituted 2-amino-4,6-dimethylbenzen
ethiol/2-amino-3,4,5-trifluorobenzenethiols Ia/Ib (0.01 mole), NaOH (0.01
mole) and 20 ml absolute alcohol in round bottom flask fitted with re-
flux condenser, 0.01 mole of substituted reactive o-halonitrobenzene (2c–d)
was added. The reaction mixture was refluxed for two hours, concentrated,
cooled, and filtered. The precipitate was washed well with hot water, then
20% alcohol and crystallized from acetone.
Synthesis of substituted N-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)
phenothiazines (6a–d)
To the solution of 5a–d (0.002 mole) in 20 ml toluene, 1-O-acetyl-2,3,5-
tri-O-benzoyl-β-D-ribofuranose (0.002 mole) was added and the contents
were refluxed under vacuum with stirring in an oil bath at 155–160◦C for 15
minutes. The vacuum was broken and reaction was protected from moisture
through a guard tube. Stirring was further continued for 10 hours and
a vacuum was applied for 10 minutes after every hour. The viscous mass

Some New Substituted 10 H-Phenothiazines, Their Ribofuranosides, and Sulfones 185
obtained was dissolved in methanol, boiled for 10 minutes and cooled to
room temperature. The reaction mixture was filtered and the methanol
was removed by distillation under reduced pressure. The viscous residue
thus obtained was dissolved in ether, filtered, concentrated, and kept in
refrigerator overnight to afford crystalline ribofuranosides.
Synthesis of 10H-phenothiazine-5,5-dioxide (Sulfones) (7a–d)
A mixture of substituted phenothiazines 5a–d (0.01 mole), 20 ml glacial
acetic acid and 5 ml 30% hydrogen peroxide (5 ml) in round bottom flask
were refluxed for 15 minutes at 50–60◦C, then additional hydrogen peroxide
(5 ml) was added. The reaction mixture was refluxed for 4 hours. The
contents were then poured into a beaker containing crushed ice. Residue
obtained was filtered and washed with water and crystallized from ethanol.
BIOLOGICAL ACTIVITY
Antioxidant Activity
All the synthesized compounds were screened for their antioxidant
activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging as-
say (Table 3) and 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid)
(ABTS r+) radical cation decolorization assay (Table 4 and Figure 1).
TABLE 3 Antioxidant activity of synthesized compounds (DPPH
assay)
DPPH% inhibition∗ of
Compd. no.
1 mg/ml of the compound
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
68.98 0.05
46.81 0.07
70.68 0.09
17.00 1.2
66.44 1.9
75.37 1.07
36.31 0.06
17.98 0.08
71.82 0.04
33.33 0.02
28.55 1.1
24.53 1.3
∗The assay was carried out in triplicate and the percentage of in-
hibition was calculated using the following formula:% inhibition =
(AB−AA) × 100/ AB, where, AB = absorption of blank; AA = absorp-
tion of test.

186
N. Gautum et al.
ABTS activity (at different time intervals) of 10H-phenothiazines (5a-d)
0.8
0.7
0.6
5b
0.5
0.4
5c
0.3
0.2
0.1
0
5a
5d
0
1
2
4
6
Time (minutes)
5a 5b
5c
5d
ABTS activity (at different time intervals) of 10H-phenothiazine ribofuranosides (6a-d)
0.8
0.7
0.6
6a
0.5
0.4
0.3
6c
0.2
6d
6b
0.1
0
0
1
2
4
6
Time (minutes)
6a
6b 6c
6d
ABTS activity (at different time intervals) of 10H-phenothiazine sulfones (7a-d)
0.8
0.7
0.6
0.5
0.4
7c
0.3
0.2
7b
7d
0.1
0
7a
0
1
2
4
6
Time (minutes)
7a
7b
7c
7d
FIGURE 1 The effect of time on the suppression of absorbance of ABTS by synthesized compounds.
After addition of 1 ml of diluted ABTS r+ solution (A 734 nm = 0.700 0.020) to 10 µl of the compound,
the absorbance reading was taken at 30◦C exactly 1 minute, after initial mixing (no more than 6 minutes
after initial mixing). All determinations were carried out in triplicate.

Some New Substituted 10 H-Phenothiazines, Their Ribofuranosides, and Sulfones 187
TABLE 4 Antioxidant activity of synthesized compounds (ABTS r+ assay)
ABTS r+ activity at different time intervals (minutes)
Compd. no.
0 minutes
1 minutes
2 minutes
4 minutes
6 minutes
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
0.696
0.699
0.697
0.698
0.699
0.687
0.624
0.713
0.686
0.696
0.711
0.686
0.57
0.323
0.498
0.324
0.176
0.506
0.066
0.162
0.131
0.022
0.253
0.367
0.194
0.1
0.02
0.439
0.16
0.555
0.335
0.231
0.525
0.106
0.376
0.384
0.124
0.273
0.392
0.328
0.463
0.213
0.04
0.029
0.439
0.017
0.021
0.02
0.006
0.041
0.262
0.024
0.465
0.025
0.027
0.031
0.007
0.097
0.294
0.062
DPPH Radical Scavenging Assay
Radical scavenging activity of synthesized compounds against stable 1,1-
diphenyl-2-picrylhydrazyl (DPPH) radical was determined spectrophotomet-
rically as described by Cuendet et al.[16] DPPH is stable free radical by virtue
of delocalization of electron over the whole molecule. For hydrogen atom
transfer, antioxidants quench the free radicals by donating hydrogen, while
for single electron transfer, antioxidants transfer one electron to the radical.
A stock solution containing 1 mg/ml of the compound was prepared
in methanol. An amount of 50 µl of the solution were added to 5 ml of a
0.004% methanol solution of DPPH. After 30 minutes incubation in the dark
at room temperature, the absorbance was read against a blank at 517 nm.
ABTS Radical Cation Decolorization Assay
The 2,2-azinobis(3-ethybenzothiazoline-6-sulphonic acid) radical cation
(ABTS r+) decolorization test was also used to assess the antioxidant activity
r+
of the synthesized compounds. The ABTS
assay was carried out using
r+
the improved assay of Re et al.[17] ABTS was generated by oxidation of
ABTS with potassium persulphate. For this purpose ABTS was dissolved in
deionized water at a concentration of 7mM, and potassium persulphate was
added to a concentration of 2.45 mM. The reaction mixture was left at room
r+
temperature overnight (12–16 hours) in the dark before use; the ABTS
solution then was diluted with ethanol to an absorbance of 0.700 0.020
at 734 nm. After addition of 1 ml of the diluted ABTS solution to 10 µl of
compound and mixing, absorbance readings were taken at 30◦C at intervals
of exactly 1–6 minutes later. All determinations were carried out in triplicate.

188
N. Gautum et al.
TABLE 5 Antimicrobial activity of synthesized compounds
Antibacterial activity
Antifungal activity
(zone of inhibition in mm)
(zone of inhibition in mm)
Coagulase
negative
Coagulase
positive
Candida
albicans
Candida
albicans
Compd.
no.
E. coli
Enterobacter
staphylococci
Staphylococci
(Strain 1)
(Strain 2)
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
12
10
—
11
10
—
—
—
12
—
10
—
—
—
17
10
13
10
10
—
10
—
—
—
11
—
—
—
—
17
16
22
>30
10
12
13
14
—
20
10
13
17
—
10
11
16
—
—
—
—
—
12
—
—
15
—
15
—
11
11
>30
18
—
14
—
13
14
10
—
12
13
>28
15
11
—
—
18
—
—
12
—
25
—
—
11
25
—
Flucanazole
Vancomycin
Gatifloxacin
15
—
—
Note: < 7 mm, inactive; 7–9 mm, weakly active; 10–12 mm, moderately active; >12 mm, active, < 7mm,
inactive; 7–11mm, weakly active; 12–17 mm, moderately active; > 17 mm, active.
Antimicrobial Activity
The synthesized compounds were tested for their antibacterial activity
by using the Paper Disc method[18] by measuring the zone of inhibition on
agar plates with Escherichia coli, Enterobacter, Coagulase negative Staphylococci,
Coagulase positive Staphylococci as test organisms at concentration of 100 µg per
disc using vancomycin, gatifloxacin as standard compounds and antifungal
activity against various strains of Candida albicans at concentration of 100
µg/disc using flucanazole as standard compound. Results of antimicrobial
activity has been shown in Table 5.
CONCLUSION
The structures proposed for the synthesized compounds are well sup-
ported by elemental analysis and spectroscopic data. Regarding DPPH ac-
tivity, compound 5a showed good activity and compound 6a and 7a, which
were formed from 5a, also showed good activity. In fact 7a is more active
than 5a. Compounds 5a and 6a showed almost similar activity. Nucleoside
6b showed more activity than its phenothiazine base 5b. Regarding ABTS
activity, compounds 7a and 7d which were formed from 5a and 5d, respec-
tively, are more active. In fact, compounds 5a and 7a showed good activity
in both DPPH and ABTS assays. Regarding antimicrobial activity compound

Some New Substituted 10 H-Phenothiazines, Their Ribofuranosides, and Sulfones 189
6b is slightly more active than 5b against Candida albicans (strain 1) and 6d
is also slightly more active than 5b against Candida albicans (strain 2). These
data showed that nucleosides 6b and 6d are similar in their activity as anti-
fungal agents to their phenothiazine precursors. All these compounds were
found to be moderately active against various bacteria and fungi. All the
synthesized compounds showed good chemopreventive and antigenotoxic
effect.
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