An efficient synthesis of thiophene conjugated benzothiazepines: In vitro screening for their antimicrobial activity

Article abstract of DOI:10.14233/ajchem.2020.22861

A series of novel thiophene conjugated benzothiazepines were synthesized by the reaction of chalcones with 2-aminobenzenethiol in citrus juice medium. The new compounds were characterized by spectroscopic studies. Results of in vitro antimicrobial evaluation of newly synthesized compounds 5a-j shows that the compounds 5a and 5c have excellent antimicrobial inhibition in the range of 12.5-25.0 μg/ mL against bacteria S. aureus, E. coli, P. aeruginosa and fungi A. niger, A. flavus organisms comparable to ciprofloxacin and nystatin and therefore these compounds might acts as lead molecules as antimicrobial agents.

Full text of DOI:10.14233/ajchem.2020.22861

Asian Journal of Chemistry; Vol. 32, No. 10 (2020), 2601-2605
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22861
An Efficient Synthesis of Thiophene Conjugated Benzothiazepines:
in vitro Screening for their Antimicrobial Activity
1,2,
1,
1,
1,*,
K.R. RAGHAVENDRA
, P. SUDEEP , K. AJAY KUMAR and H.P. JAYADEVAPPA
1Department of Chemistry, Yuvaraja College, University of Mysore, Mysuru-570006, India
2Department of Chemistry, S.B.R.R. Mahajana College, Mysuru-570012, India
*Corresponding author: E-mail: hpjayadevappa@gmail.com
Received: 17 June 2020;
Accepted: 15 July 2020;
Published online: 25 September 2020;
AJC-20076
A series of novel thiophene conjugated benzothiazepines were synthesized by the reaction of chalcones with 2-aminobenzenethiol in
citrus juice medium. The new compounds were characterized by spectroscopic studies. Results of in vitro antimicrobial evaluation of
newly synthesized compounds 5a-j shows that the compounds 5a and 5c have excellent antimicrobial inhibition in the range of 12.5-25.0 µg/
mL against bacteria S. aureus, E. coli, P. aeruginosa and fungi A. niger, A. flavus organisms comparable to ciprofloxacin and nystatin and
therefore these compounds might acts as lead molecules as antimicrobial agents.
Keywords: 2-Aminobenzenethiol, Thiophene, Benzothiazepines, Chalcone, Antibacterial activity, Antifungal activity.
α,β-unsaturated keto esters and 2-aminobenzenethiol [14], acid
catalyzed annulation reaction of chalcone with 2-aminobenz-
enethiol [15-18], the reaction of chalcones with 2-aminothio-
phenol in the presence of potassium dodecatungstocobaltate
trihydrate (PDTC) as reusable heterogeneous catalyst [19].
Interesting report is that a base catalyzed ring enlargement reac-
tions of monochloro-β-lactam-fused 2-aryl-1,3-benzothiazines
in methyl alcohol with 2 equiv. of sodium methoxide yields
1,4-benzothiazepines via ring expansion, also led to the form
indolo-1,4-benzothiazepines via rearrangement [20].
Literature reveals that small molecules with benzothiaze-
pine core wide range of biological applications. For instance,
benzofuran conjugated 1,5-benzothiazepines display a selec-
tive inhibition for butyrylcholinesterase (BChE) [21], anti-
microbial [22], antifungal and antibacterial [23], antioxidant
[24] activities. A library of 32-hydroxy-2,3-dihydrobenzo-
thiazepines prepared through Wang resin as solid support show
potential crown gall tumor and butyrylcholinesterase inhibition
properties [25]. Coumarin fused benzothiazepines shows in
vitro antioxidant activity against free radical form of ABTS
and cytotoxic activity against U87 human glioma cells [26],
Mannich bases derived from 2,3-dihydro-1,5-benzothiazepines
show anticonvulsant [27] activity. Benzothiazepines also
known to exhibitVRV-PL-8a and H+/K+ ATPase inhibitor [28],
INTRODUCTION
An interest in design and synthesis of novel small
molecules with antimicrobial effects is propelling research in
the wider research community. Benzothiazepines constitute
valuable structural units in the field of pharmaceutical research
[1]. In particular, 1,5-benzothiazepine entity in compounds
result with attractive biological profiles [2]. Such a large number
of biological activities has provided impetus for chemists to
invent a number of synthetic strategies to access 1,5-benzothia-
zepine scaffold. Chalcones or α,β-unsaturated carbonyl comp-
ounds or alkenes are regarded as useful intermediates for the
five membered heterocycles such as pyrazoles [3], pyrrolines
[4,5], thiadiazoles [6], isoxazoles [7,8], six-membered hetero-
cycles like pyrimidines [9], seven membered heterocycles
benzothiazepines [10], etc. For example, synthesized 1,5-benzo-
thiazepines show drug likeness property using Lipinski’s rule
of five, by binding to active site amino acid and specific inhibition
with MAP kinase protein [11]. More commonly employed
methods off the several protocols being; an efficient onepot
synthesis of polysubstituted benzothiazepines by ring expansion
reaction under ultrasonic conditions [12], the reaction of cyclic
sulfenamides with methylpropiolate catalyzed by pyridine, via
a postulated allenolate intermediate [13], by the reactions of
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2602 Raghavendra et al.
Asian J. Chem.
benzodiazepine receptor affinity [29] properties. In present
study, an efficient protocol for the synthesis of novel benzo-
thiazepines by greener approach using citrus juice medium
and their in vitro antimicrobial evaluation results is reported.
136.1 (1C), 152.0 (1C), 164.8 (1C, C-4). MS (ES+) m/z: 355.02
(M+, 35Cl, 100), 357.01 (M+2, 37Cl, 32); Anal. calcd. (found)
for C19H14NS2Cl (%): C, 64.12 (64.01); H, 3.97 (3.95); N, 3.94
(3.92).
4-(5-Chlorothiophen-2-yl)-2-(4-fluorophenyl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5b):Yield 75%, m.p. 108-
110 ºC; IR (KBr disc, νmax, cm-1): 679, 1230, 1644, 2892; 1H
NMR (CDCl3, δ ppm): 2.644 (dd, 1H, J = 6.8, 17.1 Hz, C3-Ha),
2.980 (dd, 1H, J = 6.9, 13.0 Hz, C3-Hb), 4.450 (dd, 1H, J =
7.3, 13.5 Hz, C2-H), 6.966-6.995 (m, 2H, Ar-H), 7.165-7.392
(m, 8H, Ar-H); 13C NMR (CDCl3, δ ppm): 39.7 (1C, C-3), 52.7
(1C, C-2), 116.2 (2C), 117.8 (1C), 125.0 (1C), 125.3 (1C),
125.8 (1C), 127.3 (1C), 128.1 (1C), 129.0 (2C), 130.2 (1C),
132.7 (1C), 136.3 (1C), 138.3 (1C), 160.6 (1C), 150.5 (1C),
165.5 (1C, C-4). MS (ES+) m/z: 373.01 (M+, 35Cl, 100), 375.04
(M+2, 37Cl, 31); Anal. calcd. (found) for C19H13NS2ClF (%):
C, 61.04 (61.12); H, 3.50 (3.48); N, 3.75 (3.72).
2-(4-Chlorophenyl)-4-(5-chlorothiophen-2-yl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5c):Yield: 75%, m.p. 158-
160 ºC; IR (KBr disc, νmax, cm-1): 685, 755, 1635, 2848; 1H NMR
(CDCl3, δ ppm): 2.563 (dd, 1H, J = 6.3, 16.6 Hz, C3-Ha), 2.955
(dd, 1H, J = 6.6, 12.8 Hz, C3-Hb), 4.433 (dd, 1H, J = 6.7, 12.9
Hz, C2-H), 6.947-6.973 (m, 2H, Ar-H), 7.172-7.450 (m, 8H,
Ar-H); 13C NMR (CDCl3, δ ppm): 40.7 (1C, C-3), 54.9 (1C, C-2),
117.3 (1C), 125.1 (1C), 125.4 (1C), 125.7 (1C), 127.6 (1C),
128.2 (2C), 128.6 (1C), 129.5 (2C), 130.4 (1C), 130.9 (1C),
134.1 (1C), 136.5 (1C), 142.4 (1C), 151.3 (1C), 165.3 (1C, C-4).
MS (ES+) m/z: 389.04 (M+, 100), 391.05 (M+2, 63), 393.03
(M+4, 10);Anal. calcd. (found) for C19H13NS2Cl2 (%): C, 52.37
(58.32); H, 3.04 (3.34); N, 4.70 (4.57).
EXPERIMENTAL
Melting points were determined in an open capillary tube
and are uncorrected. Elemental analysis was obtained on aThermo-
Finnigan Flash EA 1112 CHN analyzer. 1H & 13C NMR spectra
were recorded onAgilent-NMR 400 MHz and 100 MHz spectro-
meter, respectively. Mass spectra were obtained on ESI/APCI-
Hybrid Quadrupole, Synapt G2 HDMSACQUITY UPLC model
spectrometer.
General procedure for the synthesis of thienyl-benzo-
thizepines (5a-j):A series of new thienyl-benzothizepines (5a-j)
was synthesized by the reaction of chalcones (3a-j) with 2-
aminothiophenol (4) in citrus juice medium. Initially, the inter-
mediate 3-aryl-1-(5-chlorothiophen-2-yl)prop-2-en-1-ones
(3a-j) were synthesized via Claisen-Schmidt reaction of 5-chloro-
2-acetylthiophene (1) with aromatic aldehydes 2a-j in methyl
alcohol [30-32]. The reaction of compounds 3a-j with 2-amino-
thiophenol (4)in freshly prepared lemon juice [32] in the presence
of tetrabutylammonium bromide (TBAB) under reflux conditions
yielded benzothizepine analogues 5a-j (Scheme-I). Alterna-
tively, compounds were synthesized by conventional acetic
acid medium of which produced 5-10% of higher yields comp-
arable to citrus juice mediated method.
4-(5-Chlorothiophen-2-yl)-2-phenyl-2,3-dihydrobenzo-
[b][1,4]thiazepine (5a): Yield: 78% yield, m.p. 136-137 ºC;
IR (KBr disc, νmax, cm-1): 675, 1630, 2890;1H NMR (CDCl3, δ
ppm): 2.592 (dd, 1H, J = 5.8, 16.1 Hz, C3-Ha), 2.926 (dd, 1H,
J = 6.5, 12.0 Hz, C3-Hb), 4.345 (dd, 1H, J = 6.3, 12.5 Hz, C2-H),
4-(5-Chlorothiophen-2-yl)-2-(p-tolyl)-2,3-dihydro-
benzo[b][1,4]thiazepine (5d): Yield 73%, m.p. 113-114 ºC;
IR (KBr disc, νmax, cm-1): 685, 1626, 2857; 1H NMR (CDCl3,
δ ppm): 2.140 (s, 3H, CH3), 2.601 (dd, 1H, J = 6.8, 16.7 Hz,
C3-Ha), 3.010 (dd, 1H, J = 6.3, 12.7 Hz, C3-Hb), 4.336 (dd, 1H,
J = 7.2, 13.6 Hz, C2-H), 6.980-7.016 (m, 2H, Ar-H), 7.222-7.607
6.904-6.946 (m, 2H, Ar-H), 7.180-7.355 (m, 9H, Ar-H); 13
C
NMR (CDCl3, δ ppm): 39.2 (1C, C-3), 51.4 (1C, C-2), 118.0
(1C), 125.0 (1C), 125.5 (1C), 125.9 (1C), 127.1 (1C), 127.5 (2C),
127.9 (2C), 128.5 (2C), 129.0 (1C), 130.4 (1C), 134.5 (1C),
CHO
R
O
R
S
MeOH/KOH
+
Cl
Cl
COCH3
Room temp.,
3-4 h
S
(
)
R1
3 a-j
R1
2 a-j
(
)
1
R1
SH
Cl
S
NH2
5 a
b
) R=H, R'=H;
) R=H, R'=F;
4
c) R=H, R'=Cl;
d) R=H, R'=CH3;
f
S
R
N
e
) R=H, R'=OCH3; ) R=H, R'=NO2;
i). Aq. citrus juice (40%),
TBAB, reflux, 2-3 h and/or
ii). CH3COOH (30%),
reflux, 2-3 h.
g) R=H, R'=N(Me)2; h) R=H, R'=Br;
i
j
) R=CH3, R'=CH3; ) R=Cl, R'=Cl.
5 a-j
( )
Scheme-I: Schematic diagram for the synthesis of thienyl-benzothiazepines, 5(a-j)

Vol. 32, No. 10 (2020)
Efficient Synthesis of Thiophene Conjugated Benzothiazepines 2603
(m, 8H, Ar-H); 13C NMR (CDCl3, δ ppm): 21.2 (1C, CH3), 42.9
(1C, C-3), 50.4 (1C, C-2), 116.8 (1C), 125.1 (1C), 125.4 (1C),
125.8 (1C), 126.6 (2C), 127.5 (1C), 128.3 (1C), 129.4 (2C), 130.9
(1C), 132.3 (1C), 136.7 (1C), 137.6 (1C), 141.0 (1C), 150.8
(1C), 161.0 (1C, C-4). MS (ES+) m/z: 369.06 (M+, 35Cl, 100),
371.07 (M+2, 37Cl, 31); Anal. calcd. (found) for C20H16NS2Cl
(%): C, 64.94 (64.80); H, 4.36 (4.34); N, 3.79 (3.76).
4-(5-Chlorothiophen-2-yl)-2-(4-methoxyphenyl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5e): Yield 60%, m.p. 107-
109 ºC; IR (KBr disc, νmax, cm-1): 690, 1623, 2877; 1H NMR
(CDCl3, δ ppm): 2.612 (dd, 1H, J = 6.7, 16.5 Hz, C3-Ha), 2.977
(dd, 1H, J = 6.8, 12.7 Hz, C3-Hb), 3.840 (s, 3H, OCH3), 4.303
(dd, 1H, J = 7.1, 12.4 Hz, C2-H), 6.904-7.058 (m, 4H, Ar-H),
7.174-7.402 (m, 6H, Ar-H); 13C NMR (CDCl3, δ ppm): 43.0
(1C, C-3), 52.5 (1C, C-2), 55.4 (1C, OCH3), 114.5 (2C), 116.4
(1C), 124.8 (1C), 125.2 (1C), 125.7 (1C), 126.6 (1C), 127.6
(1C), 128.3 (2C), 130.4 (1C), 134.0 (1C), 135.6 (1C), 137.7 (1C),
151.1 (1C), 154.8 (1C), 160.4 (1C, C-4). MS (ES+) m/z: 385.06
(M+, 35Cl, 100), 387.05 (M+2, 37Cl, 32); Anal. calcd. (found)
for C20H16NOS2Cl (%):C, 62.25 (62.13); H, 4.18 (4.16); N,
3.63 (3.60).
131.6 (2C), 134.5 (1C), 142.0 (1C), 150.1 (1C), 160.1 (1C, C-4).
MS (ES+) m/z: 433.04 (M+, 100), 435.01 (98), 437.03 (32),
439.04 (2); Anal. calcd. (found) for C19H12NS2BrCl (%): C,
52.49; H, 3.01; N, 3.22; Found: C, 52.32; H, 3.00; N, 3.20.
4-(5-Chlorothiophen-2-yl)-2-(2,4-dimethylphenyl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5i): Yield 74%; m.p. 150-
152 ºC; IR (KBr disc, νmax, cm-1): 708, 1633, 2875; 1H NMR
(CDCl3, δ ppm): 2.282 (s, 6H, CH3), 2.574 (dd, 1H, J = 6.1,
16.5 Hz, C3-Ha), 2.950 (dd, 1H, J = 6.8, 12.3 Hz, C3-Hb), 4.380
(dd, 1H, J = 6.9, 12.6 Hz, C2-H), 6.971-7.106 (m, 4H, Ar-H),
7.166-7.388 (m, 6H, Ar-H); 13C NMR (CDCl3, δ ppm): 20.9
(2C, CH3), 40.4 (1C, C-3), 51.9 (1C, C-2), 116.6 (1C), 125.0 (1C),
125.6 (1C), 125.9 (1C), 127.8 (1C), 128.1 (2C), 128.4 (2C),
128.8 (1C), 129.9 (1C), 132.9 (1C), 134.0 (1C), 136.2 (1C),
137.5 (1C), 150.5 (1C), 161.5 (1C, C-4). MS (ES+) m/z: 383.01
(M+,35Cl, 100), 385.03 (M+2, 37Cl, 34); Anal. calcd. (found)
for C21H18NS2Cl (%): C, 65.69 (65.55); H, 4.73 (4.71); N, 3.65
(3.62).
4-(5-Chlorothiophen-2-yl)-2-(2,4-dichlorophenyl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5j): Yield 77%; m.p. 163-
1
164 ºC; IR (KBr disc, νmax, cm-1): 686, 744, 1650, 2906; H
4-(5-Chlorothiophen-2-yl)-2-(4-nitrophenyl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5f): Yield 61% (gummy
NMR (CDCl3, δ ppm): 2.590 (dd, 1H, J = 5.7, 16.0 Hz, C3-Ha),
2.998 (dd, 1H, J=6.3, 11.8 Hz, C3-Hb), 4.311 (dd, 1H, J=6.6,
12.2 Hz, C2-H), 6.914-6.952 (m, 2H, Ar-H), 7.100-7.467 (m,
7H,Ar-H); 13C NMR (CDCl3, δ ppm): 40.5 (1C, C-3), 53.7 (1C,
C-2), 116.6 (1C), 124.7 (1C), 125.1 (1C), 125.6 (1C), 126.3
(1C), 127.0 (1C), 127.8 (1C), 128.1 (1C), 129.7 (1C), 130.1
(1C), 130.5 (1C), 133.0 (1C), 134.4 (1C), 136.0 (1C), 137.8
(1C), 151.1 (1C), 163.3 (1C, C-4). MS (ES+) m/z: 423.06 (M+,
100), 425.01 (95), 427.02 (30), 429.06 (3);Anal. calcd. (found)
for C19H12NS2Cl3 (%): C, 53.72 (53.61); H, 2.85 (2.83); N,
3.30 (3.28).
Antimicrobial activity: The antimicrobial activities of
compounds 5a-jwere determined as minimum inhibitory concen-
trations (MIC) by serial dilution method [33]. Bacterial pathogens
Escherichia coli (MTCC 1687), Bacillus subtilis (MTCC 441)
and Staphylococcus aureus (MTCC 737) and fungal stains
Aspergillus niger, Aspergillus flavus and Candida albicans
(MTCC 227) used for the study. Ciprofloxacin and nystatin
were used as positive control against bacterial and fungal species,
respectively. Dimethyl sulfoxide was used as solvent control.
The experiments were carried out in triplicate; the results were
taken as a mean standard deviation (SD).
1
mass); IR (KBr disc, νmax, cm-1): 688, 1546, 1640, 2862; H
NMR (CDCl3, δ ppm): 2.561 (dd, 1H, J = 5.9, 17.4 Hz, C3-Ha),
2.990 (dd, 1H, J = 6.9, 12.7 Hz, C3-Hb), 4.380 (dd, 1H, J = 6.9,
13.0 Hz, C2-H), 6.990-7.031 (m, 2H, Ar-H), 7.210-7.355 (m,
6H,Ar-H), 8.026-8.190 (m, 2H,Ar-H); 13C NMR (CDCl3, δppm):
38.0 (1C, C-3), 50.7 (1C, C-2), 118.5 (1C), 123.7 (2C), 125.3
(1C), 125.7 (1C), 126.1 (1C), 127.6 (1C), 127.9 (1C), 128.6 (2C),
130.9 (1C), 133.0 (1C), 136.8 (1C), 145.3 (1C), 147.1 (1C), 152.2
(1C), 163.6 (1C, C-4). MS (ES+) m/z: 400.08 (M+, 37Cl, 100),
402.06 (M+2, 37Cl, 34);Anal. calcd. (found) for C19H13N2O2S2Cl
(%): C, 56.92 (56.80); H, 3.27 (3.25); N, 6.99 (6.96).
4-(4-(5-Chlorothiophen-2-yl)-2,3-dihydrobenzo[b]-
[1,4]thiazepin-2-yl)-N,N-dimethyl aniline (5g): Yield 60%,
m.p. 141-143 ºC; IR (KBr disc, νmax, cm-1): 700, 1112, 1652,
2899; 1H NMR (CDCl3, δ ppm): 2.698 (dd, 1H, J = 6.9, 17.7
Hz, C3-Ha), 2.930 (dd, 1H, J = 7.8, 13.9 Hz, C3-Hb), 3.012 (s, 6H,
N-CH3), 4.501 (dd, 1H, J = 7.5, 13.6 Hz, C2-H), 6.720-6.912
(m, 4H, Ar-H), 7.144-7.420 (m, 6H, Ar-H); 13C NMR (CDCl3,
δ ppm): 39.1 (1C, C-3), 40.6 (2C, N-CH3), 52.9 (1C, C-2), 113.6
(2C), 117.6 (1C), 125.1 (1C), 125.4 (1C), 125.7 (1C), 127.1 (1C),
127.9 (2C), 128.4 (2C), 128.7 (1C), 133.1 (1C), 136.8 (1C),
140.3 (1C), 151.7 (1C), 163.5 (1C, C-4). MS (ES+) m/z: 398.02
(M+, 35Cl, 100), 400.06 (M+2, 37Cl, 34); Anal. calcd. (found)
for C21H19N2S2Cl (%): C, 63.22 (63.10); H, 4.80 (4.78); N,
7.02 (7.00).
RESULTS AND DISCUSSION
IR spectra of the synthesized compounds 5a-j show
stretching frequencies in the region; strong bands at 712-675
cm-1 for thienyl C-Cl, weak bands at 1666-1623 cm-1 for C=N,
medium bands at 2906-2848 cm-1 for C-H functions. Other
important stretching bands shown by compounds being; 5b at
1230 cm-1 (C-F, str.), 5h at 643 cm-1 (C-Br, str.), 5g at 1112 cm-
1 (C-N, w), 5f at 1546 cm-1 (N-O, str.), 5c and 5i at 755 and 744
cm-1 (phenyl C-Cl, str.). The absorption bands at 1690-1660
cm-1 and 1640-1610 cm-1 due to α,β-unsaturated C=O and C=C
of compounds 3a-j; at 2600-2560, 1340-1270 and 3550-3410
cm-1 due to S-H, C-N and N-H groups of 2-aminobenezenethiol
(2) were absent.
2-(4-Bromophenyl)-4-(5-chlorothiophen-2-yl)-2,3-
dihydrobenzo[b][1,4]thiazepine (5h): Yield 66% (gummy
mass);IR (KBr disc, νmax, cm-1): 643, 712, 1666, 2890; 1H NMR
(CDCl3, δ ppm): 2.575 (dd, 1H, J = 6.1, 16.3 Hz, C3-Ha), 2.890
(dd, 1H, J = 6.9, 12.6 Hz, C3-Hb), 4.501 (dd, 1H, J = 6.7, 12.1
Hz, C2-H), 6.977-7.012 (m, 2H, Ar-H), 7.196-7.543 (m, 8H,
Ar-H); 13C NMR (CDCl3, δ ppm): 43.2 (1C, C-3), 52.7 (1C, C-2),
118.3 (1C), 120.2 (1C), 124.6 (1C), 125.1 (1C), 125.8 (1C),
126.8 (1C), 127.9 (1C), 129.0 (2C), 129.6 (1C), 130.9 (1C),

2604 Raghavendra et al.
Asian J. Chem.
TABLE-1
ANTIMICROBIAL ACTIVITY OF SYNTHESIZED SERIES OF COMPOUNDS 5(a-j)
Minimum inhibitory concentrations (MIC’s, µg/mL)
Compound
S. aureus
12.5
E. coli
12.5
P. aeruginosa
12.5
A. niger
25.0
A. flavus
25.0
C. albicans
50.0
5a
25.0
25.0
25.0
50.0
75.0
25.0
5b
12.5
12.5
12.5
25.0
25.0
50.0
5c
75.0
50.0
75.0
75.0
75.0
75.0
5d
100.0
>200.0
50.0
>200.0
50.0
>200.0
25.0
–
75.0
>200.0
50.0
>200.0
100.0
>200.0
25.0
62.5
>200.0
25.0
>200.0
50.0
>200.0
12.5
100.0
>200.0
>200.0
100.0
75.0
100.0
–
50.0
75.0
125.0
>200.0
>200.0
75.0
100.0
75.0
5e
5f
5g
5h
5i
>200.0
>200.0
100.0
75.0
100.0
–
5j
Ciprofloxacin
Nystatin
–
25.0
–
–
50.0
*Values are the mean of three determinations (n = 3)
1H NMR spectra shows a doublet of doublets at δ 2.561-2.698
(J = 5.7-6.9 Hz and 16.0-17.7 Hz) ppm for C3-Ha; δ 2.890-
3.010 (J = 6.3-7.8 Hz and 11.8-13.9 Hz) ppm for C3-Hb; and δ
4.303-4.501 (J = 6.3-7.5 Hz and 12.1-13.6 Hz) ppm for C2-H
protons, respectively. These three doublets of doublets show
that the C-3 atoms of benzothizepine ring are diastereotopic.
13C NMR spectra shows the resonance signals for C-2, C-3 and
C-4 carbons of benzothizepine rings at δ 50.4-54.9, 38.0-43.2
and 160.1-165.5 ppm, respectively. Besides these, all showed
the signals for aromatic and substituent proton and carbons in
the respective region. Further, the designed series of comp-
ounds shows base peak comparable to their molecular masses,
and also halogen isotopic mass peaks in the mass spectra and
comparable elemental analysis data.
of in vitro antimicrobial evaluation of newly synthesized comp-
ounds 5a-j shows that compounds 5a and 5c have excellent
antimicrobial inhibition in the range of 12.5-25.0 µg/mL against
bacteria S. aureus, E. coli, P. aeruginosa, and fungi A. niger,
A. flavus organisms comparable to ciprofloxacin and nystatin
and therefore, these compounds might acts as antimicrobial
agents.
ACKNOWLEDGEMENTS
The authors are grateful to IOE Instrumentation facility,
University of Mysore, Mysuru, India for providing the spectro-
scopic analysis.
CONFLICT OF INTEREST
Antimicrobial activity: The results show that amongst
the synthesized compounds 5a-j, compounds 5a and 5c exhibit
excellent activities against S. aureus (12.5 µg/mL), E. coli (12.5
µg/mL), P. aeruginosa (12.5 µg/mL), A. niger (25.0 µg/mL),
and A. flavus (25.0 µg/mL) species, but moderate activity
against C. albicans (50.0 µg/mL) comparable to positive
controls used. Compounds 5f, 5g, 5h and 5j were found to be
inactive against the tested organisms having MIC’s with (>200
µg/mL), which might be because of nitro, N,N-dimethylamino,
bromo and trichloro substitutions. However, compound 5g found
moderately active against bacterium S. aureus (50.0 µg/mL),
E. coli (50.0 µg/mL), P. aeruginosa (25.0 µg/mL); 5h and 5j
against fungi A. niger (100.0 µg/mL) and A. flavus (100.0 µg/
mL), C. albicans (75.0 µg/mL) species (Table-1).
The authors declare that there is no conflict of interests
regarding the publication of this article.
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