Synthesis and antimicrobial activities of novel biologically active heterocycles: 10H-phenothiazines, their ribofuranosides, and sulfone derivatives

Article abstract of DOI:10.1080/15257770903362206

This article deals with the synthesis and antimicrobial activity of a series of novel substituted 10H-phenothiazines, their ribofuranosides, and sulfone derivatives. 10H-Phenothiazines were prepared by Smiles rearrangement. These prepared phenothiazines w

Full text of DOI:10.1080/15257770903362206

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Synthesis and Antimicrobial
Activities of Novel Biologically Active
Heterocycles: 10H-Phenothiazines, Their
Ribofuranosides, and Sulfone Derivatives
Yogesh Dixit a , Rahul Dixit a , Naveen Gautam b & D. C. Gautam a
a Department of Chemistry , University of Rajasthan , Jaipur, India
b Department of Chemistry , L. B. S. Government. P. G. College ,
Kotputli, Jaipur, India
Published online: 24 Nov 2009.
To cite this article: Yogesh Dixit , Rahul Dixit , Naveen Gautam & D. C. Gautam (2009) Synthesis
and Antimicrobial Activities of Novel Biologically Active Heterocycles: 10H-Phenothiazines, Their
Ribofuranosides, and Sulfone Derivatives, Nucleosides, Nucleotides and Nucleic Acids, 28:11-12,
998-1006, DOI: 10.1080/15257770903362206
To link to this article: http://dx.doi.org/10.1080/15257770903362206
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Nucleosides, Nucleotides and Nucleic Acids, 28:998–1006, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903362206
SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF NOVEL
BIOLOGICALLY ACTIVE HETEROCYCLES: 10H-PHENOTHIAZINES,
THEIR RIBOFURANOSIDES, AND SULFONE DERIVATIVES
Yogesh Dixit,1 Rahul Dixit,1 Naveen Gautam,2 and D. C. Gautam1
1Department of Chemistry, University of Rajasthan, Jaipur, India
2Department of Chemistry, L. B. S. Government. P. G. College, Kotputli Jaipur, India
R4
H
N
R1
R3
R2
S
O
O
(VIIIa-d
)
30% H2O2
gl. acetic
acid
(i) CH3COONa/C2H5OH, reflux
(ii) Formylation, 90% HCOOH
(iii) KOH/C2H5OH, Acetone
R1
R4
R1
H
N
R2
R3
NH2 O2N
R3
+
SH
Cl
NaOH, C2H5OH
R4 = NO2
S
(Va-d
R2
R4
(II a-d
)
(I)
)
O
O C CH3
BzO
O
BzO
OBz
(VI)
R2
S
N
R3
R4
R1
OBz
O
BzO
(VIIa-c
OBz
)
This article deals with the synthesis and antimicrobial activity of a series of novel substi-
2
tuted 10H-phenothiazines, their ribofuranosides, and sulfone derivatives. 10H-Phenothiazines
Received 21 May 2009; accepted 8 September 2009.
The authors are thankful to the Department of Chemistry and the Department of Botany, University
of Rajasthan, Jaipur (India) for providing laboratory facilities. Thanks are also due to UGC, New Delhi
for financial support.
Address correspondence to Yogesh Dixit, Department of Chemistry, University of Rajasthan, Jaipur-
303004, India. E-mail: yogeshdixit15@yahoo.co.in
998

Novel Biologically Active Heterocycles
999
were prepared by Smiles rearrangement. These prepared phenothiazines were used as the base
to prepare ribofuranosides by treatment with sugar (1-O-acetyl-2,3,5-tri-O-benzoylribofuranose).
Sulfone derivatives were prepared by the oxidation of 10H-phenothiazines. The structure of the
synthesized compounds was established by elemental analysis and spectroscopic data.
Keywords Antimicrobial activity; phenothiazines; ribofuranosides; Smiles rearrange-
ment
INTRODUCTION
Constructing biologically active molecules such as phenothiazines and
their ribofuranosides by molecular modification has been of enormous
interest in recent years. A review of the literature on pharmaceutical studies
reveals their chemotherapeutic importance. The compounds have been ex-
tensively examined as potential antibacterial, antifungal, anti-inflammatory,
antitumor, anticancer, anti-herpes, and anti-AIDS agents. A slight change in
the substitution pattern in the phenothiazine nucleus causes distinguishable
differences in their biological activities.[1–6,8–12,14–24]
Phenothiazines serve as nitrogen and sulfur containing heterocyclic
bases for the formation of ribofuranosides by treatment with the appropriate
sugar. The formation of sulfone derivatives helps us to investigate the
structure of 10H-phenothiazines by the study of the change in infrared
and nuclear magnetic resonance (NMR) spectra caused by oxidation of
sulfide linkage into sulfones. The Kerby Bauer procedure[7,13] was used
for the study of the antimicrobial activity of newly synthesized compounds.
RESULTS AND DISCUSSION
The synthesis of substituted 10H-phenothiazine (Va) has been car-
ried out by the Smiles rearrangement of substituted 2-formamido-2ꢁ-
nitrodiphenyl-sulfide (IIIa). The formyl derivatives have been prepared
from 2-amino-2ꢁ-nitrodiphenylsulfide (IIa), which in turn was prepared by
the condensation of 2-aminobenzenethiol (Ia) with an o-halonitrobenzene
(IIa) in ethanolic sodium acetate solution. 1-Nitrophenothiazines (Vb-d
)
have been prepared by the condensation of 2-aminobenzenethiols (Ia-b)
with o-halonitrobenzenes (IIb-d) containing a nitro group at both ortho
positions to the reactive halo atom in ethanolic sodium hydroxide solution
in which Smiles rearrangement has occurred in situ. The substituted
10H-phenothiazines (Va-d) dissolved in toluene were then treated with 1-
O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (VI) and stirred in vacuo on
an oil bath at 150–155◦C for 10 hours to yield ribofuranosides (VIIa-c).
The sulfone derivatives (VIIIa-d) have been prepared by the oxidation of

1000

1001

1002
Y. Dixit et al.
10H-phenothiazines (Va-d) with 30% hydrogen peroxide in glacial acetic
acid (Scheme 1). The structures proposed to the synthesized compounds
are well supported by elemental analysis (Table 1) and spectroscopic data.
The characteristic IR bands and 1H NMR data of the synthesized
compounds are presented in Table 2.
S
S
S
O
O
O
O
O
O
v2
v3
v1
Asymmetric
Banding
Symmetric
Compounds Va-d exhibit a single sharp peak in the region 3410–
3310 cm−1 due to the NH- stretching band, which was found absent
in compounds VIa-c, clearly indicating it to be the site of ribosylation.
Compounds VIIIa-d showed three characteristic absorption peak due to
asymmetric stretching vibration ν3 (1380–1370 cm−1), symmetric stretching
vibration ν1 (1195–1140 cm−1), and bending vibration ν2 (575–520 cm−1)
in chloroform solution.
The 1H NMR data of synthesized compounds are presented in Table 2.
Compounds Va-d showed a singlet due to NH protons, which appeared
1
in the region δ 9.71–9.21 ppm. The H NMR spectra of ribofuranosides
(VIa-c) did not show any peak due to NH proton, indicating the formation
of ribofuranosides. Molecular ion peaks in the mass spectra of synthesized
compounds are observed in accordance with their molecular weights.
These synthesized compounds were screened for their antimicrobial
activities. In the present investigation, the compounds showed good to
moderate activity when evaluated against four organisms: Staphylococcus
aureus, Pseudomonas fluorescens, Aspergillus niger, and Aspergillus flavus (see
Table 2).
CONCLUSIONS
All these synthesized 10H-phenothiazines, their ribofuranosides, and
sulfone derivatives are novel and showed good and moderate antifungal and
antibacterial activities against the respective S. aureas, P. fuoroscens (bacteria),
and A. niger, A. flavus (fungi). Hence, these compounds can be used as
antifungal and antibacterial drugs after further study and analysis of their
biomedical aspects; further biomedical research is required.
EXPERIMENTAL
All melting points were determined in open capillary tubes and are
uncorrected. IR spectra were recorded in KBr on NICOLET-MEGNA FT-IR

1003

1004
Y. Dixit et al.
1
550 spectrometer and the H NMR spectra were recorded on JEOL AL-
300 spectrometer (300 MHz) in dimethyl sulfoxide (DMSO)-d6 using tetra
methyl silane (TMS) as an internal standard (chemical shifts are measured
in δ ppm). Mass spectra were recorded on JEOL SX 102/DA 600 using
Argon/Xenon as fast atom bombardment (FAB) gas. The purity of the all
synthesized compounds were checked by thin layer chromatography (TLC)
using silica gel “G” as adsorbent, visualizing these by ultraviolet (UV) light
or an iodine chamber.
Synthesis of 2-Amino-2ꢁ-nitro Diphenylsulfide (IIIa)
2-Aminobenzenethiol Ia (0.1 mole) was dissolved in ethanol (20 mL)
containing 0.1 mole of anhydrous sodium acetate in 50 mL round bottom
flask and halonitrobenzene IIa (0.1 mole) in 10 mL ethanol was added.
The reaction mixture was refluxed for 4–5 hours and concentrated in an ice
bath overnight. The solid that separated out was filtered, washed with 30%
ethanol, and recrystallized from methanol.
Synthesis of 2-Formamido-2ꢁ-nitrodiphenylsulfide (IVa)
The diphenylsulfide IIIa (0.1 mole) obtained was refluxed for 4 hours
in 90% formic acid (20 mL). The contents were then poured into
a beaker containing crushed ice, the solid separated out was filtered,
washed with water until the filtrate was neutralized and crystallized from
benzene.
Synthesis of Phenothiazine (Va)
Formyl derivative IVa (0.1 mole) in acetone (15 mL) was refluxed and
an alcoholic solution of potassium hydroxide (0.2 gm in 5 mL ethanol)
was added. The contents were heated for 30 minutes. A second lot of
potassium hydroxide (0.2 gm in 5 mL ethanol) was added to the reaction
mixture and further refluxed for 4 hours. The contents were poured into
beaker containing crushed ice and were filtered. The residue obtained was
repeatedly washed with cold water and finally with 30% ethanol and then
crystallized from benzene.
Synthesis of 1-Nitro-10H-phenothiazines (Vb-d
)
A mixture of reactive o-halonitrobenzene IIb-d (0.1 mole), substi-
tuted 2-aminobenzenethiol Ia-b (0.1 mole), sodium hydroxide (0.1 mole),
and absolute alcohol (25 mL) was refluxed for 2 hours. The reac-
tion mixture was concentrated on water bath, cooled, and filtered. The

Novel Biologically Active Heterocycles
1005
precipitate was washed with hot water and ethanol, then crystallized from
acetone.
Synthesis of Substituted N-(2,3,5-tri-O-benzoyl-β-D-
ribofuranosyl) Phenothiazines (VIIa-c
)
To a concentrated solution of Va-c (0.002 mole) in toluene, 1-O-acetyl-
2,3,5-tri-O-benzoyl-β-D-ribofuranose VI (0.002 mole) was added and stirred
in vacuo on an oil bath at 150–155◦C for 15 minutes. The vacuum was
broken and the reaction was protected from moisture, by using a guard
tube. Stirring was further continued for 10 hours with application of vacuum
for 15 minutes after every hour. The melt was dissolved in methanol, boiled
for 10 minutes and cooled to room temperature. The precipitate was filtered
and the filtrate was evaporated to dryness. The viscous residue thus obtained
was dissolved in ether, filtered, concentrated, and kept in a refrigerator
overnight to get crystalline ribofuranosides.
Synthesis of Sulfone Derivatives of 10H-Phenothiazines (VIIIa-d
)
To obtain sulfone derivatives of 10H-phenothiazines a solution of sub-
stituted 10H-phenothiazines Va-d (0.01 mole) in 20 mL of 30% glacial
acetic acid, 5 mL of 30% hydrogen peroxide was added and refluxed for
15 minutes. Heating was stopped and another lot of 30% hydrogen peroxide
(5 mL) was added. The reaction mixture was again refluxed for 3–4 hours.
The contents were poured in a beaker containing crushed ice. The yellowish
residue obtained was filtered and washed with water and then crystallized
from ethanol.
Antimicrobial Activity
All the synthesized compounds were screened for their antibacterial
activity against Staphylococcus aureus and Pseudomonas fluoroscens and antifun-
gal activity against Aspergillus niger and Aspergillus flavus (Table 2) by the
Kerby Bauer procedure (filter paper disc method) using streptomycin (an-
tibacterial) and flucanozole (antifungal) as a standard drug. Natural agar
medium for antibacterial activities and standard dextrose agar medium for
antifungal activities were used as a medium. From the activity data (Table 2)
it may be concluded that the compounds Va-d, VIIa-c, and VIIIa-d showed
good and moderate activity.
The variation in effectiveness of different compound against different
organism depends on impermeability of cells of the microbes. The antimi-
crobial activities of compound given in terms of activity index in Table 2.

1006
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