Synthesis and pharmaceutical importance of 2-azetidinone derivatives of phenothiazine

Article abstract of DOI:10.1007/s12039-012-0257-x

A new series of N-[3-(10H-phenothiazin-1-yl)propyl]-4-(substituted phenyl)-3-chloro-2-oxo-1- azetidinecarboxamide 4(a-m) have been synthesized from phenothiazine in four steps. Phenothiazine on reaction with Cl(CH ₂)3Br at room temperature gave 1-(3-chlorophenyl)-10H-phenothiazine, 1. The compound 1 yielded the condensation product with urea at room temperature, N-[3-(10H-phenothiazin-1-yl)propyl]urea 2. The compound 2 on further reaction with several substituted aromatic aldehydes produced N-[3-(10Hphenothiazin- 1-yl)propyl]-N'-[(substituted phenyl)methylidene]-urea 3(a-m). The compounds 3(a-m) on treatment with ClCH2COCl in the presence of Et3N furnished final products 4(a-m). The structures of all the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and FAB-Mass spectra and chemical methods. All the final synthesized compounds were evaluated for their antibacterial, antifungal and antitubercular activities which displayed acceptable activities. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-012-0257-x

c
J. Chem. Sci. Vol. 124, No. 3, May 2012, pp. 633–637. ꢀ Indian Academy of Sciences.
Synthesis and pharmaceutical importance of 2-azetidinone derivatives
of phenothiazine
RITU SHARMA, PUSHKAL SAMADHIYA∗, S D SRIVASTAVA and S K SRIVASTAVA
Synthetic Organic Chemistry Laboratory, Department of Chemistry, Dr. H S Gour University (A Central
University), Sagar 470 003, India
e-mail: pushkalsamadhiya@rediffmail.com
MS received 12 June 2011; revised 4 December 2011; accepted 20 January 2012
Abstract. A new series of N-[3-(10H-phenothiazin-1-yl)propyl]-4-(substituted phenyl)-3-chloro-2-oxo-1-
azetidinecarboxamide 4(a–m) have been synthesized from phenothiazine in four steps. Phenothiazine on reac-
tion with Cl(CH2)3Br at room temperature gave 1-(3-chlorophenyl)-10H-phenothiazine, 1. The compound 1
yielded the condensation product with urea at room temperature, N-[3-(10H-phenothiazin-1-yl)propyl]urea
2. The compound 2 on further reaction with several substituted aromatic aldehydes produced N-[3-(10H-
phenothiazin-1-yl)propyl]-Nꢁ-[(substituted phenyl)methylidene]-urea 3(a–m). The compounds 3(a–m) on
treatment with ClCH2COCl in the presence of Et3N furnished final products 4(a–m). The structures of all
1
the newly synthesized compounds were confirmed by IR, H NMR, 13C NMR and FAB-Mass spectra and
chemical methods. All the final synthesized compounds were evaluated for their antibacterial, antifungal and
antitubercular activities which displayed acceptable activities.
Keywords. Synthesis; 2-azetidinone; phenothiazine; antimicrobial.
1. Introduction
Phenothiazine on reaction with Cl(CH2)3Br at room
temperature gave 1-(3-chlorophenyl)-10H-phenothia-
zine, compound 1. The compound 1 react with urea at
room temperature to yield condensation product, N-[3-
(10H-phenothiazin-1-yl)propyl]urea, compound 2. The
compound 2 on further reaction with several substituted
aromatic aldehydes produced N-[3-(10H-phenothia-
zin-1-yl)propyl]-Nꢁ-[(substituted phenyl)methylidene]-
urea, compounds 3(a–m). The compounds 3(a–m) on
treatment with ClCH2COCl in the presence of Et3N
furnished final products, N-[3-(10H-phenothiazin-
The β-lactam ring is the main feature of the most of the
penicillins and other antibiotics. The β-lactam ring
shows various biological activities such as antifungal,1,2
antibacterial,3,4 antitubercular,5,6 anticonvulsant,7 anal-
gesic, anti-inflammatory,8 synthetic precursor for ami-
no acids,9 antiviral,10 CNS,11 cholesterol absorption,12
etc. Phenothiazine is also bioactive heterocyclic com-
pound and having pharmaceutical importance possess-
es different biological activities viz. antibacterial,13
antifungal,2 antitubercular,14 antischizophrenic,15 anti-
inflammatory,16 etc. Phenothiazine derivatives are ma-
jor content of several antipsychotic drugs. Chemically
phenothiazine has two active sites at 2 and 10 posi-
tions. In the present study our research group reporting
substitution at 10th position of phenothiazine and intro-
ducing phenothiazine and 2-azitidinone ring in a sin-
gle frame work. Phenothiazine and 2-azitidinone ring
together display important biological activities. The
titled compounds were synthesized in four different
steps according to scheme 1.
1-yl)propyl]-4-(substituted
phenyl)-3-chloro-2-oxo-
1-azetidinecarboxamide, compounds 4(a–m). The
structures of all the newly synthesized compounds were
1
confirmed by IR, H NMR, 13C NMR, FAB-Mass and
chemical methods. All the final synthesized compounds
were evaluated for their antibacterial, antifungal and
antitubercular activities which displayed acceptable
activity.
2. Experimental
Melting points were taken in open capillaries and are
uncorrected. Progress of reaction was monitored by
silica gel-G coated TLC plates using MeOH:CHCl3
system (1:9). The spot was visualized by exposing
∗For correspondence
633

634
Ritu Sharma et al.
S
S
BrCH2CH2CH2Cl
NH2CONH2
N
H
N
1
CH2CH2CH2Cl
S
S
ArCHO
Et3N+ClCH2COCl
N
N
CH2CH2CH2NHCONH2
CH2CH2CH2NHCON=CHAr
2
3(a-m)
S
N
CH CH CH NHCO
N
CHAr
Cl
2
2
2
4(a-m)
O
Ar= substituted phenyl ring
Scheme 1. Synthesis of compounds 1, 2, 3(a–m) and 4(a–m).
dry plate at iodine vapours chamber. IR spectra were raphy using CH3OH: CHCl3 (7:3 v/v) system as elu-
recorded in KBr disc on a Schimadzu 8201 PC, FTIR ant (90 ml). The purified product was dried under vacuo
spectrophotometer (νmax in cm−1) and 1H NMR and 13C and recrystallized from acetone at room temperature to
NMR spectra were measured on a Brucker DRX-300 furnish compound 3a.
spectrometer in CDCl3 at 300 and 75 MHz, respec-
Compounds 3(b–m) have also been synthesized by
tively using TMS as an internal standard. All chemical using similar method as above.
shifts were reported on δ scale. The FAB-Mass spec-
tra were recorded on a Jeol SX–102 mass spectro-
meter. Elemental analyses were performed on a Carlo
Erba–1108 analyzer. The analytical data of all the com-
pounds were highly satisfactory. For the column chro-
matographic purification of the products, Merck silica
Gel 60 (230–400 Mesh) was used. The reagent grade
chemicals were purchased from the commercial sources
and further purified before use.
2.2 Synthesis of N-[3-(10H-phenothiazinyl)-propyl]-
2.1 Synthesis of 1-(3-chloropropyl)-10H-
phenothiazinyl, compound 117,18, synthesis
of N-[3-(10H-phenothiazinyl)-propyl]- urea,
compound 2,19 and synthesis of N-[3-(10H-
phyenothiazinyl)-propyl]-N65-[(phenyl)-methylidene]
urea, compound 3a
4-(phenyl)-3-chloro-2-oxo-1-azetidine-carboxamide,
compounds 4a20,21
The compound 3a (2.70 g, 0.007 mol), chloroacetyl
chloride (0.791 g, 0.007 mol) and Et3N (0.707 g,
0.007 mol) in methanol (50 ml) were first stirred on a
magnetic stirrer for about 2.00 h at room temperature
The compound 2 (7.77 g, 0.026 mol) and benzaldehyde followed by reflux on a steam bath for about 4.00 h. The
(2.75 g, 0.026 mol) in ethanol (100 ml) in the presence completion of the reaction was monitored by silica gel-
of 2–4 drops glacial acetic acid were first stirred on a G coated TLC plates. The product was filtered, cooled
magnetic stirrer for about 2.00 h at room temperature and purified over a silica gel packed column chromatog-
followed by reflux on a steam bath for about 3.30 h. The raphy using CH3OH: CHCl3 (7:3 v/v) system as elu-
completion of the reaction was monitored by silica gel- ant (70 ml). The purified product was dried under vacuo
G coated TLC plates. The product was filtered, cooled and recrystallized from ethanol at room temperature to
and purified over a silica gel packed column chromatog- furnish compound 4a.

Synthesis and pharmaceutical importance of azetidinones
635
Table 1. Antibacterial and antifungal activities of compounds 4(a–m). Minimum Inhibition Concentration
(MIC) given in μg/mL.
Antibacterial activity
Antifungal activity
Comp. B. subtilis E. coli S. aureus K. pneumoniae A. niger A. flavus F. oxisporium C. albicans
4a
4b
4c
4d
4e
4f
4g
4h
4i
12.5
3.50
9.25
6.25
3.50
3.75
3.50
3.25
6.25
3.75
3.25
3.75
8.25
25.00
4.25
12.5
3.25
6.25
3.50
3.25
6.25
3.75
3.50
6.25
3.25
3.25
3.25
8.25
18.50
10.25
27.25
12.25
13.50
12.75
132.5
12.75
15.25
13.25
12.50
12.25
25.75
29.25
18.25
27.75
13.25
25.00
25.50
15.00
13.50
17.50
12.50
13.50
13.25
27.25
50.00
20.50
28.25
25.75
15.50
12.75
12.50
12.75
16.75
13.50
12.25
12.75
26.25
50.00
12.50
29.75
12.25
19.50
13.25
15.75
13.50
18.25
15.50
14.50
13.75
28.75
31.25
14.50
6.25
3.75
6.25
3.50
5.75
3.25
3.25
3.25
12.75
25.00
7.25
6.25
3.25
3.25
6.25
7.25
3.25
3.75
3.25
13.50
19.50
6.25
4j
4k
4l
4m
The MIC values of standard streptomycin for all bacterial strain and griseofulvin for all fungi strain were in
the range of 1.25–3.25 and 6.25–12.5 μg/ml, respectively
Compounds 4(b–m) have also been synthesized by aureus, K. pneumoniae and fungi A. niger, A. flavus, F.
using similar method as above.
oxisporium, C. albicans and M. tuberculosis (H37Rv
strain), respectively. The MIC of compounds 4(a–
m) were determined using filter paper disc diffusion
method (antibacterial and antifungal activity) and L.J.
medium (Conventional) method (antitubercular acti-
vity). Streptomycin and Griseofulvin used as standard
for antibacterial and antifungal activity, respectively
and for antitubercular activity, Isoniazid and Rifampicin
taken as standards. Concentration of the compounds
was given in μg/mL. Results of all given activities of
above compounds were given in tables 1 and 2.
Spectral and physical data of compounds 3(a–m) and
4(a–m) are submitted as supplementary data.
3. Results and discussion
N-[3-(10H-phenothiazinyl)-propyl]-2-(substituted phenyl)-
3-chloro-4-oxo-1-azetidine-carboxamide, compounds 4(a–
2.3 Biological study
2.3a Antibacterial, antifungal and antitubercular m) were synthesized in four different steps. Phenothiazine
activities: The antibacterial, antifungal and antituber- on reaction with Cl(CH2)3Br at room temperature
cular activity of compound 4(a–m) has been assayed afforded 1-(3-chlorophenyl)-10H-phenothiazine, com-
in vitro against selected bacteria, B. subtilis, E. coli, S. pound 1. IR spectrum of compound 1 displayed
Table 2. Antitubercular activity of compounds 4(a–m). MIC given in μg/mL.
Compound Concentration Compound Concentration Compound Concentration
4a
4b
4c
4d
4e
13.50
2.75
3.25
2.50
2.75
4f
4g
4h
4i
2.50
6.25
2.50
2.50
2.75
4k
4l
4m
–
12.75
13.75
6.25
–
4j
–
–
Isoniazid and Rifampicin were used as standards, MIC values in the range of 1.25–
2.50 μg/ml for M. tuberculosis (h37rv strain)

636
Ritu Sharma et al.
absorption at 1320 and 744 for (C-N) and (C-Cl), substitution. Nitro group containing compounds (4h,
respectively, this clearly indicated the disappearance of 4i and 4j) showed higher activity than chloro (4c,
NH absorption (3465) of Phenothiazine. The compound 4d), or bromo group containing compounds (4e, 4f).
1 on reaction with urea at room temperature yielded N- Chloro and bromo derivatives also have higher activity
[3-(10H-phenothiazin-1-yl)propyl]urea, compound 2. than other rested compounds. On the basis of SAR,
IR spectrum of compound 2 showed absorption for concluded that the activity of compounds depends on
NH and NH2 at 3290 and 3413 cm−1, respectively, electron withdrawing nature of the substituted groups.
while absorption for (C-Cl) has been disappeared in The sequence of the activity is following
1
IR spectrum of compound 1. The H NMR spectrum
of 2 displayed a signal at δ 5.64 and 5.86 ppm for NH
NO2 > Cl > Br > OH > OCH3 > H > CH3.
and NH2, respectively. The compound 2 on further
reaction with selected several substituted aromatic alde-
hydes produced N-[3-(10H-phenothiazin-1-yl)propyl]-
Nꢁ-[(substituted phenyl) methylidene]-urea, compounds
3(a–m). The characteristic absorption for Schiff base in
IR spectra of compounds 3(a–m) appeared in the range
of 1539–1560 cm−1 and in the 1H and 13C NMR spectra,
signal appeared at δ 7.85–8.05 and δ 152.1–157.6 ppm,
The investigation of antimicrobial (antibacterial, anti-
fungal and antitubercular) data revealed that the com-
pounds (4c), (4d), (4e), (4f), (4h), (4i) and (4j)
displayed high activity in the series, the compounds
(4b), (4g) and (4m) showed moderate activity and
rested compounds showed less activity against all the
strains compared with standard drugs.
1
respectively. In the H NMR spectrum of compound
4. Conclusions
2 a broad signal of NH2 has been disappeared. The
compounds 3(a–m) on treatment with ClCH2COCl in
the presence of Et3N furnished final products com-
pounds 4(a–m). In the IR spectra of compounds 4(a–
m) carbonyl group of β-lactam ring showed character-
istic absorption in the range of 1725–1746 cm−1 and
1H NMR spectra of compounds 4(a–m) showed two
doublet for (N-CH) and (CH-Cl) in the range δ 5.09–
5.23 and 4.40–4.61 ppm, respectively. In 13C NMR
spectra of compounds 4(a–m) three characteristic sig-
nals appeared for (N-CH), (CH-Cl) and (CO cyclic)
in the range of (δ) 60.2–65.7, 51.6–56.7 and 165.7–
In conclusion, a new series of compound 4(a–m) were
synthesized, Synthesized compounds screened for their
biological study. The investigation of antimicrobial
(antibacterial, antifungal and antitubercular) activities
data revealed that the compounds (4b), (4d), (4e), (4f),
(4h), (4i) and (4j) displayed excellent activity, the com-
pounds (4c), (4g) and (4m) showed moderate activity
and rested compounds showed less activity compared
with standard drugs.
1
170.7 ppm, respectively. The IR absorption, H and
Supplementary information
13C NMR signals of N=CH have been disappeared.
The compounds 4(a–m) shows stereoisomerism, spec-
tral data as well as literature support the synthesis of
diastereomer of azetidine in good yield.22 These all fact
collectively suggested for the synthesis of all above
compounds. Spectral and physical data of compounds
3(a–m) and 4(a–m) are given as supplementary data
(table S1).
The results of the all described activities (antibacte-
rial, antifungal and antitubercular) were summarized
in tables 1 and 2. The results of the antimicrobial
screening data revealed that all the compound 4(a–
m) showed considerable and varied activity against
the selected microorganism. A new series of N-[3-
(10H-phenothiazinyl)-propyl]-2-(substituted phenyl)-
3-chloro-4-oxo-1-azetidine-carboxamide, compound
4(a–m) were prepared and screened for their antimi-
crobial and antitubercular activities data (as shown
in tables 1 and 2) revealed that all the synthesized
compound 4(a–m) have a structure activity relation-
ship (SAR) because activity of compounds varies with
Table S1 as supplementary information can be seen in
www.ias.ac.in/chemsci.
Acknowledgements
The authors are thankful to Sophisticated Analytical
Instrument Facility (SAIF), Central Drugs Research
Institute, Lucknow (India) for providing spectral and
analytical data of the compounds. We are thankful to
Head, Department of Biotechnology, Dr. H S Gour,
University, Sagar (India) for antimicrobial (antibac-
terial and antifungal) and for providing the facilities
to carryout the work, and Microcare Laboratory and
Tuberculosis Research Center, Surat, Gujrat (India) for
antituberculosis activity.
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