Synthesis, cytotoxic and antioxidant activities of azolyl benzothiazine carboxamides

Article abstract of DOI:10.1007/s11164-019-03778-4

Abstract: Azolyl benzothiazine carboxamides were prepared from benzothiazine carboxylate and azolyl amines in the presence of NaOMe under ultrasonication. 4-Bromothiophenylimidazolyl benzothiazine carboxamide (19b) and 4-bromopyrrolylimidazolyl benzothiazine carboxamide (22b) showed cytotoxic activity on HeLa cell lines (IC₅₀ 33.75, 47.52?μM) and MCF-7 cell lines (IC₅₀31.75, 34.35?μM). Furthermore, methyl-substituted furanyloxazolyl benzothiazine carboxamide (14a), furanylimidazolyl benzothiazine carboxamide (16a), thiophenyloxazolyl benzothiazine carboxamide (17a) and pyrrolyloxazolyl benzothiazine carboxamide (20a) exhibited antioxidant activity greater than ascorbic acid. Graphical abstract: Azolyl benzothiazine carboxamides are prepared from benzothiazine carboxylate and azolyl amines. Optimization of reaction conditions is established using different molar concentrations of NaOMe. Compounds 19b and 22b showed cytotoxic activity on HeLa cell lines and MCF-7 cell lines. Compounds 14a, 16a, 17a and 20a exhibited prominent antioxidant activity.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-019-03778-4

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03778-4
Synthesis, cytotoxic and antioxidant activities of azolyl
benzothiazine carboxamides
Siva Sankar Panga, et al. [full author details at the end of the article]
Received: 25 October 2018 / Accepted: 18 February 2019
© Springer Nature B.V. 2019
Abstract
Azolyl benzothiazine carboxamides were prepared from benzothiazine carboxylate
and azolyl amines in the presence of NaOMe under ultrasonication. 4-Bromothio-
phenylimidazolyl benzothiazine carboxamide (19b) and 4-bromopyrrolylimidazolyl
benzothiazine carboxamide (22b) showed cytotoxic activity on HeLa cell lines
(IC50 33.75, 47.52 µM) and MCF-7 cell lines (IC5031.75, 34.35 µM). Furthermore,
methyl-substituted furanyloxazolyl benzothiazine carboxamide (14a), furanylimida-
zolyl benzothiazine carboxamide (16a), thiophenyloxazolyl benzothiazine carboxa-
mide (17a) and pyrrolyloxazolyl benzothiazine carboxamide (20a) exhibited antioxi-
dant activity greater than ascorbic acid.
Graphical abstract Azolyl benzothiazine carboxamides are prepared from benzo-
thiazine carboxylate and azolyl amines. Optimization of reaction conditions is estab-
lished using diferent molar concentrations of NaOMe. Compounds 19b and 22b
showed cytotoxic activity on HeLa cell lines and MCF-7 cell lines. Compounds 14a,
16a, 17a and 20a exhibited prominent antioxidant activity.
Keywords Azole · Benzothiazine carboxamide · Cytotoxic activity · Antioxidant
activity
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-019-03778-4) contains supplementary material, which is available to authorized users.
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S. S. Panga et al.
Introduction
Cyclic sulfonamides (sultams) gained importance due to their potential pharmaceutical
activity. Amongst these, 1,2-benzothiazine-1,1-dioxide and its derivatives represent the
most familiar class of non-steroidal anti-infammatory drugs (NSAIDs) available in the
market. In fact, meloxicam and piroxicam are members of the oxicam family [1] and are
used as analgesic and anti-infammatory drugs [2]. Besides, the sulfonamide moiety is the
key functional unit in a number of drugs due to its stability and tolerance in living organ-
isms [3, 4]. Azoles are potential chemical entities with a wide range of pharmacological
activities such as anticancer, antibacterial, antifungal [5–9], antiviral and antiparasitic [10]
activities. Oxazole derivatives have been featured as drugs in the pharmaceutical arena viz.,
inthomycin C as an antineoplastic [11], oxaprozin as an NSAID [11] to relieve osteoarthri-
tis and rheumatoid arthritis, pemoline as a nervous system stimulant and bengazole A as an
antibiotic [11]. The thiazole scafold is found in many natural and synthetic molecules with
numerous applications in medicinal chemistry. Sulfathiazole (antimicrobial) and tiazofurin
(antineoplastic) are some of the drugs having a thiazole unit [12]. In addition to these, imi-
dazole derivatives such as econazole, miconazole and ketoconazole control fungal infec-
tions [7]. The imidazole ring is also an integral part of clinically used drugs: cimetidine,
omeprazole, lansoprazole to treat peptic ulcers [7], azomycine as an antibiotic, pilocarpine
in radiation therapy and methimazole as an antithyroid agent [6]. In continuation of our
eforts to develop potential multifunctional heterocycles [13–15], herein we report the syn-
thesis, cytotoxic and antioxidant activities of azolyl benzothiazine carboxamides.
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Synthesis, cytotoxic and antioxidant activities of azolyl…
Experimental
Apparatus and analysis
Melting points were determined in open capillaries on a Mel-Temp apparatus
and are uncorrected. The purity of the compounds was evaluated by TLC (sil-
ica gel H, BDH, ethyl acetate/hexane, 1:3). The IR spectra were recorded on a
Thermo Nicolet IR 200 FT-IR spectrometer as KBr pellets and the wave numbers
1
were given in cm−1. The H and 13C NMR spectra were recorded in DMSO-d6
on a Bruker spectrometer operating at 400 and 100 MHz. The chemical shifts
are reported in δ (ppm) using TMS as an internal standard. The high-resolution
mass spectra are recorded on a Q-TOF micromass spectrometer using electro-
spray ionization. Ultrasonication was performed in a Bandelinsonorex RK 10 2 H
ultrasonic bath operating at a frequency of 35 kHz. The microanalyses were per-
formed on a Perkin-Elmer 240C elemental analyzer. The progress of the reaction
was monitored by TLC using silica gel plates (silica gel 60 F254 0.25 mm), and
components were visualized by observation under UV light (254 and 365 nm).
General procedure for the synthesis of methyl 4‑methoxy‑2‑methyl‑2H‑benzo[e]
[1, 2]thiazine‑3‑carboxylate‑1,1‑dioxide (4)
To a solution of hydroxybenzothiazine carboxylate (3) (1.9 mmol) in ether, a two-
fold molar excess of ethereal diazomethane (3.80 mmol) was added under ice-cold
conditions. The reaction mixture was kept at 0 to −5 °C for 8 h. The yellow color
of diazomethane disappeared slowly. The solvent was evaporated and the resultant
solid was recrystallized from ethanol.
4-Methoxy-2-methyl-2H-benzo[e][1,2]thiazine-3-carboxylate-1,1-dioxide
(4).
Yield 85%; m.p.: 149–151 °C; IR (KBr): 1142, 1321 (SO2), 1588 (C=N), 1676
(C=O), 1681 (C=C) cm−1; 1H NMR (400 MHz, DMSO-d6):δ 2.58 (s, 3H, N–CH3),
3.49 (s, 3H, O–CH3), 3.65 (s, 3H, COO–CH3), 7.41–7.73 (m, 4H, Ar–H) ppm; 13
C
NMR (100 MHz, DMSO-d6): δ 38.4 (N–CH3), 50.6 (COO–CH3), 55.1 (O–CH3),
99.8 (C-3), 139.2 (C-4), 165.7 (C=O), 121.0, 124.3, 126.1, 129.6, 130.5, 132.9 (aro-
matic carbons) ppm; HRMS (m/z): 306.2871 [M+Na]; anal. calcd. for C12H13NO5S:
C, 50.88; H, 4.63; N, 4.94%; found: C, 50.81; H, 4.71; N, 4.87%.
General procedure for the synthesis of heteroarylazolyl benzothiazine
carboxamides (14–22)
Benzothiazine carboxylate (4) (1 mmol), azolyl amine (5–13) (1 mmol) and 5 mol%
sodium methoxide (5 ml) in toluene were taken and sonicated at a frequency of 35
kHz for 3–5 h. The solvent was removed on a rotary evaporator and the resultant
solid was recrystallized from ethanol.
4-Methoxy-2-methyl-N-(4-(5-methylfuran-2-yl)oxazol-2-yl)-2H-benzo[e][1,2]
thiazine-3-carboxamide-1,1-dioxide (14a). White solid (0.278 g, 76%); m.p.
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S. S. Panga et al.
137–139 °C. IR (KBr): 3363 (NH), 1680 (C=O), 1624 (C=C), 1561 (C=N),
1327–1133 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.36 (s, 3H, C5″-CH3),
2.59 (s, 3H, N–CH3), 3.47 (s, 3H, O–CH3), 6.05 (d, 1H, C4″-H), 6.54 (d, 1H,
C3″-H), 7.28–7.57 (m, 5H, Ar–H, and C5′-H), 10.66 (bs, 1H, CONH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 13.6 (C5″-CH3), 38.0 (N–CH3), 55.2 (O–CH3),
105.4 (C4″), 106.1 (C3), 108.0 (C3″), 141.1 (C4), 150.3 (C2′), 153.1 (C5″), 155.0
(C2″), 166.1 (C=O), 122.3, 124.6, 125.2, 126.0, 131.6, 133.4, 135.3, 138.7 (aro-
matic carbons, C4′ and C5′) ppm. HRMS (m/z): 438.4095 [M+Na]+; anal. calcd. for
C19H17N3O6S: C, 50.88; H, 4.63; N, 4.94%; found: C, 54.79; H, 4.66; N, 5.03%.
N-(4-(5-Bromofuran-2-yl)oxazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e][1,2]
thiazine-3-carboxamide-1,1-dioxide (14b). White solid (0.321 g, 65%); m.p.
145–147 °C. IR (KBr): 3377 (NH), 1691 (C=O), 1637 (C=C), 1570 (C=N),
1336–1146 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.55 (s, 3H, N–CH3),
3.46 (s, 3H, O–CH3), 6.34 (d, 1H, C4″-H), 6.87 (d, 1H, C3″-H), 7.34–7.69 (m, 5H,
Ar–H, and C5′-H), 10.69 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 38.7 (N–CH3), 55.4 (O–CH3), 104.6 (C4″), 105.8 (C3), 107.9 (C3″), 118.7 (C5″),
142.4 (C4), 149.4 (C2′), 158.3 (C2″), 165.6 (C=O), 122.7, 125.4, 126.6, 127.2, 131.6,
132.9, 133.8, 136.2 (aromatic carbons, C4′ and C5′) ppm. HRMS (m/z): 503.2789
[M+Na]+; anal. calcd. for C18H14BrN3O6S: C, 45.01; H, 2.94; N, 8.75%; found: C,
45.08; H, 2.89; N, 8.70%.
4-Methoxy-2-methyl-N-(4-(5-nitrofuran-2-yl)oxazol-2-yl)-2H-benzo[e][1,2]
thiazine-3-carboxamide-1,1-dioxide (14c). White solid (0.303 g, 73%); m.p.
148–150 °C. IR (KBr): 3381 (NH), 1648 (C=O), 1644 (C=C), 1576 (C=N),
1328–1138 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.63 (s, 3H, N–CH3),
3.49 (s, 3H, O–CH3), 7.10 (d, 1H, C4″-H), 7.33 (d, 1H, C3″-H), 7.46–7.75 (m, 5H,
Ar–H, and C5′-H), 10.70 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 37.6 (N–CH3), 56.8 (O–CH3), 107.5 (C3), 109.8 (C4″), 111.6 (C3″), 140.3 (C4),
151.5 (C2′), 154.8 (C5″), 159.6 (C2″), 166.6 (C=O), 122.4, 125.5, 126.9, 128.0,
130.8, 132.4, 133.7, 135.6 (aromatic carbons, C4′ and C5′) ppm. HRMS (m/z):
469.3742 [M+Na]+; anal. calcd. for C18H14N4O8S: C, 48.43; H, 3.16; N, 12.55%;
found: C, 48.47; H, 3.10; N, 12.49%.
4-Methoxy-2-methyl-N-(4-(5-methylfuran-2-yl)thiazol-2-yl)-2H-benzo[e][1,2]
thiazine-3-carboxamide-1,1-dioxide (15a). White solid (0.312 g, 70%); m.p.
133–135 °C. IR (KBr): 3, 362 (NH), 1676 (C=O), 1630 (C=C), 1569 (C=N),
1322–1129 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H, C5″-CH3),
2.72 (s, 3H, N–CH3), 3.56 (s, 3H, O–CH3), 6.07 (d, 1H, C4″-H), 6.90 (d, 1H,
C3″-H), 7.28–7.64 (m, 5H, Ar–H, and C5′-H), 10.56 (bs, 1H, CONH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 13.8 (C5″-CH3), 39.8 (N–CH3), 56.8 (O–CH3),
103.7 (C5′), 107.0 (C4″), 108.1 (C3), 108.9 (C3″), 139.9 (C4′), 143.6 (C4), 152.2
(C5″), 156.9 (C2″), 162.4 (C2′),168.1 (C=O), 124.8, 125.7, 131.9, 132.4, 134.1,
135.0 (aromatic carbons) ppm. HRMS (m/z): 454.4711 [M+Na]+; anal. calcd. for
C19H17N3O5S2: C, 52.89; H, 3.97; N, 9.74%; found: C, 52.96; H, 3.93; N, 9.81%.
N-(4-(5-Bromofuran-2-yl)thiazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e][1,2]
thiazine-3-carboxamide-1,1-dioxide (15b). White solid (0.342 g, 75%); m.p.
138–140 °C. IR (KBr): 3355 (NH), 1663 (C=O), 1684 (C=C), 1563 (C=N),
1330–1134 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.68 (s, 3H, N–CH3),
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Synthesis, cytotoxic and antioxidant activities of azolyl…
3.52 (s, 3H, O–CH3), 6.49 (d, 1H, C4″-H), 7.06 (d, 1H, C3″-H), 7.42–7.74 (m, 5H,
Ar–H, and C5′-H), 11.59 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 40.1 (N–CH3), 56.4 (O–CH3), 104.6 (C5′), 105.2 (C4″), 107.3 (C3), 108.4 (C3″),
117.4 (C5″), 140.0 (C4′), 143.9 (C4), 156.3 (C2″), 161.6 (C2′), 168.3 (C=O), 124.3,
126.1, 132.0, 132.7, 134.4, 135.2 (aromatic carbons) ppm. HRMS (m/z): 519.3394
[M+Na]+; anal. calcd. for C18H14BrN3O5S2: C, 43.56; H, 2.84; N, 2.84%; found: C,
43.64; H, 2.79; N, 8.40%.
4-Methoxy-2-methyl-N-(4-(5-nitrofuran-2-yl)thiazol-2-yl)-2H-benzo[e][1,2]
thiazine-3-carboxamide-1,1-dioxide (15c). White solid (0.309 g, 76%); m.p.
144–146 °C. IR (KBr): 3373 (NH), 1684 (C=O), 1665 (C=C), 1570 (C=N),
1338–1140 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.71 (s, 3H, N–CH3),
3.60 (s, 3H, O–CH3), 7.14 (d, 1H, C4″-H), 7.28 (d, 1H, C3″-H), 7.36–7.72 (m, 5H,
Ar–H, and C5′-H), 12.62 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 40.3 (N–CH3), 57.3 (O–CH3), 103.9 (C5′), 107.7 (C3), 108.5 (C4″), 109.6 (C3″),
140.6 (C4′), 144.2 (C4), 152.7 (C5″), 158.6 (C2″), 162.9 (C2′), 168.7 (C=O), 124.1,
126.7, 132.3, 133.6, 134.2, 136.5 (aromatic carbons) ppm. HRMS (m/z): 485.4406
[M+Na]+; anal. calcd. for C18H14N4O7S2: C, 46.75; H, 3.05; N, 12.12%; found: C,
46.81; H, 3.08; N, 12.02%.
4-Methoxy-2-methyl-N-(4-(5-methylfuran-2-yl)-1H-imidazol-2-yl)-2H-
benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (16a). White solid (0.273 g,
74%); m.p. 141–143 °C. IR (KBr): 3566 (NH), 1667 (C=O), 1621 (C=C), 1566
(C=N), 1320–1132 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.34 (s, 3H,
C5″-CH3), 2.58 (s, 3H, N–CH3), 3.46 (s, 3H, O–CH3), 5.94 (d, 1H, C4″-H), 6.53
(d, 1H, C3″-H), 7.19–7.56 (m, 5H, Ar–H, and C5′-H), 11.18 (bs, 1H, CONH),
12.04 (bs, 1H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 13.4
(C5″-CH3), 37.6 (N–CH3), 54.5 (O–CH3), 103.9 (C5′), 105.1 (C3), 106.3 (C4″),
108.4 (C3″), 137.2 (C4′), 140.9 (C4), 149.2 (C2′), 150.1 (C5″), 154.2 (C2″), 165.1
(C=O), 124.5, 127.1, 130.4, 132.2, 133.7, 134.3 (aromatic carbons) ppm. HRMS
(m/z): 437.4254 [M + Na]+; anal. calcd. for C19H18N4O5S: C, 55.06; H, 4.38; N,
13.52%; found: C, 55.14; H, 4.24; N, 13.43%.
N-(4-(5-Bromofuran-2-yl)-1H-imidazol-2-yl)-4-methoxy-2-methyl-2H-
benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (16b). White solid (0.325 g,
78%); m.p. 149–151 °C. IR (KBr): 3358 (NH), 1674 (C=O), 1646 (C=C), 1577
1
(C=N), 1331–1143 (SO2) (cm−1); H NMR (400 MHz, DMSO-d6): δ 2.49 (s,
3H, N–CH3), 3.39 (s, 3H, O–CH3), 6.32 (d, 1H, C4″-H), 6.88 (d, 1H, C3″-H),
7.25–7.53 (m, 5H, Ar–H, and C5′-H), 11.22 (bs, 1H, CONH), 12.34 (bs, 1H,
imidazole NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 36.9 (N–CH3), 54.6
(O–CH3), 105.6 (C4″), 106.2 (C3), 108.6 (C3″), 117.2 (C5′), 120.6 (C5″), 137.4
(C4′), 141.6 (C4), 150.5 (C2′), 158.4 (C2″), 165.6 (C=O), 125.2, 128.6, 129.9,
132.1, 134.6, 135.7 (aromatic carbons) ppm. HRMS (m/z): 502.3052 [M + Na]+;
anal. calcd. for C18H15BrN4O5S: C, 45.11; H, 3.15; N, 11.69%; found: C, 45.07;
H, 3.18; N, 11.76%.
4-Methoxy-2-methyl-N-(4-(5-nitrofuran-2-yl)-1H-imidazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (16c). White solid (0.289 g, 75%); m.p.
162–164 °C. IR (KBr): 3379 (NH), 1635 (C=O), 1671 (C=C), 1561 (C=N),
1323–1129 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.60 (s, 3H, N–CH3),
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S. S. Panga et al.
3.49 (s, 3H, O–CH3), 6.74 (d, 1H, C4″-H), 7.05 (d, 1H, C3″-H), 7.27–7.59 (m, 5H,
Ar–H, and C5′-H), 11.03 (bs, 1H, CONH), 11.95 (bs, 1H, imidazole-NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 38.1 (N–CH3), 54.9 (O–CH3), 105.4 (C3), 107.9
(C4″), 109.9 (C3″), 118.6 (C5′), 135.7 (C4′), 140.5 (C4), 149.8 (C2′), 150.9 (C5″),
160.7 (C2″), 167.6 (C=O), 123.6, 126.9, 131.4, 131.8, 132.7, 134.3 (aromatic car-
bons) ppm. HRMS (m/z): 468.3961 [M+Na]+; anal. calcd. for C18H15N5O7S: C,
48.54; H, 3.39; N, 15.72%; found: C, 48.63; H, 3.33; N, 15.65%.
4-Methoxy-2-methyl-N-(4-(5-methylthiophen-2-yl)oxazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (17a). White solid (0.306 g, 71%);
m.p. 132–134 °C. IR (KBr): 3365 (NH), 1695 (C=O), 1633 (C=C), 1569 (C=N),
1328–1136 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.40 (s, 3H, C5″-CH3),
2.70 (s, 3H, N–CH3), 3.51 (s, 3H, O–CH3), 6.94 (d, 1H, C4″-H), 7.25 (d, 1H,
C3″-H), 7.33–7.62 (m, 5H, Ar–H, and C5′-H), 10.72 (bs, 1H, CONH) ppm; 13C NMR
(100 MHz, DMSO-d6): δ 15.0 (C5″-CH3), 38.9 (N–CH3), 56.0 (O–CH3), 108.2 (C3),
120.8 (C4′), 142.0 (C4), 153.3 (C2′), 167.1 (C=O), 123.9, 124.2, 124.6, 125.4, 126.8,
127.8, 133.0, 134.7, 135.1135.5, 136.4 (aromatic carbons, C2″, C3″, C4″ and C5″)
ppm. HRMS (m/z): 454.4705 [M+Na]+; anal. calcd. for C19H17N3O5S2: C, 52.89;
H, 3.97; N, 9.74%; found: C, 52.80; H, 3.92; N, 9.87%.
N-(4-(5-Bromothiophen-2-yl)oxazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (17b). White solid (0.357 g, 72%);
m.p. 140–142 °C. IR (KBr): 3357 (NH), 1643 (C=O), 1685 (C=C), 1575 (C=N),
1339–1131 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.73 (s, 3H, N–CH3),
3.55 (s, 3H, O–CH3), 6.98 (d, 1H, C4″-H), 7.15 (d, 1H, C3″-H), 7.38–7.68 (m, 5H,
Ar–H, and C5′-H), 10.76 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 37.6 (N–CH3), 56.3 (O–CH3), 107.2 (C3), 114.5 (C5″), 121.6 (C4′), 142.5 (C4),
145.2 (C2″), 154.6 (C2′), 167.2 (C=O), 123.2, 125.3, 127.4, 129.6, 132.5, 133.8,
135.4, 136.7, 137.1 (aromatic carbons, C3″ and C4″) ppm. HRMS (m/z): 519.3396
[M+Na]+; anal. calcd. for C18H14BrN3O5S2: C, 43.56; H, 2.84; N, 8.47%; found: C,
43.50; H, 2.88; N, 8.53%.
4-Methoxy-2-methyl-N-(4-(5-nitrothiophen-2-yl)oxazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (17c). White solid (0.314 g, 70%); m.p.
146–148 °C. IR (KBr): 3384 (NH), 1654 (C=O), 1685 (C=C), 1580 (C=N),
1340–1148 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.75 (s, 3H, N–CH3),
3.54 (s, 3H, O–CH3), 7.40–7.73 (m, 5H, Ar–H, and C5′-H), 8.24 (d, 1H, C3″-H),
8.48 (d, 1H, C4″-H),10.78 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 39.2 (N–CH3), 56.7 (O–CH3), 107.5 (C3), 110.5 (C4″), 121.5 (C4′), 142.4 (C4),
149.7 (C2″), 152.5 (C5″), 153.8 (C2′), 167.5 (C=O), 124.6, 125.7, 127.1, 131.4,
132.3, 133.4, 135.7, 138.2 (aromatic carbons, C5′ and C3″) ppm. HRMS (m/z):
485.4412 [M+Na]+; anal. calcd. for C18H14N4O7S2: C, 46.75; H, 3.05; N, 12.12%;
found: C, 46.70; H, 3.01; N, 12.21%.
4-Methoxy-2-methyl-N-(4-(5-methylthiophen-2-yl)thiazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (18a). White solid (0.312 g, 70%);
m.p. 139–141 °C. IR (KBr): 3363 (NH), 1667 (C=O), 1669 (C=C), 1561 (C=N),
1324–1127 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.42 (s, 3H, C5″-CH3),
2.72 (s, 3H, N–CH3), 3.66 (s, 3H, O–CH3), 7.12 (d, 1H, C4″-H), 7.36 (d, 1H,
C3″-H), 7.45–7.86 (m, 5H, Ar–H, and C5′-H), 11.58 (bs, 1H, CONH) ppm; 13C
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
NMR (100 MHz, DMSO-d6): δ 15.4 (C5″-CH3), 40.0 (N–CH3), 57.2 (O–CH3),
103.9 (C5′), 108.3 (C3), 140.3 (C4′), 144.0 (C4), 164.5 (C2′), 168.1 (C=O), 125.4,
126.3, 127.5, 128.4, 132.7, 133.2, 134.5, 136.1136.6, 137.9 (aromatic carbons,
C2″, C3″, C4″ and C5″) ppm. HRMS (m/z): 470.5322 [M+Na]+; anal. calcd. for
C19H17N3O4S3: C, 50.99; H, 3.83; N, 9.39%; found: C, 51.06; H, 3.76; N, 9.46%.
N-(4-(5-Bromothiophen-2-yl)thiazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (18b). White solid (0.368 g, 72%);
m.p. 146–148 °C. IR (KBr): 3365 (NH), 1672 (C=O), 1651 (C=C), 1560 (C=N),
1336–1138 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.69 (s, 3H, N–CH3),
3.58 (s, 3H, O–CH3), 7.18 (d, 1H, C4″-H), 7.29 (d, 1H, C3″-H), 7.48–7.80 (m, 5H,
Ar–H, and C5′-H), 11.45 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 40.5 (N–CH3), 56.8 (O–CH3), 104.7 (C5′), 107.6 (C3), 114.6 (C5″), 138.4 (C2″),
139.5 (C4′), 143.4 (C4), 162.1 (C2′), 168.5 (C=O), 124.5, 125.8, 126.3, 128.4, 132.1,
133.8, 134.2, 136.4 (aromatic carbons, C3″ and C4″) ppm. HRMS (m/z): 535.4005
[M+Na]+; anal. calcd. for C18H14BrN3O4S3: C, 42.19; H, 2.75; N, 8.20%; found: C,
42.26; H, 2.80; N, 8.28%.
4-Methoxy-2-methyl-N-(4-(5-nitrothiophen-2-yl)thiazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (18c). White solid (0.329 g, 74%); m.p.
155–157 °C. IR (KBr): 3387 (NH), 1668 (C=O), 1672 (C=C), 1583 (C=N),
1343–1142 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.76 (s, 3H, N–CH3),
3.61 (s, 3H, O–CH3), 7.49–7.75 (m, 5H, Ar–H, and C5′-H), 7.94 (d, 1H, C3″-H),
8.16 (d, 1H, C4″-H),11.63 (bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6):
δ 39.4 (N–CH3), 57.6 (O–CH3), 103.9 (C5′), 108.8 (C3), 110.8 (C4″), 140.6 (C4′),
144.6 (C4), 146.7 (C2″), 153.8 (C5″), 164.4 (C2′), 168.8 (C=O), 124.3, 127.5, 128.9,
132.5, 133.0, 134.6, 136.7 (aromatic carbons and C3″) ppm. HRMS (m/z): 501.5021
[M+Na]+; anal. calcd. for C18H14N4O6S3: C, 45.18; H, 2.95; N, 11.71%; found: C,
45.11; H, 2.99; N, 11.80%.
4-Methoxy-2-methyl-N-(4-(5-methylthiophen-2-yl)-1H-imidazol-2-yl)-2H-
benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (19a). White solid (0.283 g,
76%); m.p. 152–154 °C. IR (KBr): 3365 (NH), 1670 (C=O), 1639 (C=C), 1572
1
(C=N), 1324–1129 (SO2) (cm−1); H NMR (400 MHz, DMSO-d6): δ 2.38 (s,
3H, C5″-CH3), 2.62 (s, 3H, N–CH3), 3.61 (s, 3H, O–CH3), 6.80 (d, 1H, C4″-H),
7.28–7.47 (m, 6H, Ar–H, C5′-H and C3″-H), 11.20 (bs, 1H, CONH), 11.96 (bs,
1H, imidazole NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 14.8 (C5″-CH3),
38.0 (N–CH3), 54.8 (O–CH3), 106.6 (C3), 115.8 (C5′), 141.2 (C4), 150.3 (C2′),
165.9 (C=O), 125.0, 126.2, 127.2, 129.4, 132.1, 133.5, 134.1, 135.7, 136.0, 137.6,
138.2 (aromatic carbons, C4′, C2″, C3″, C4″ and C5″) ppm. HRMS (m/z): 453.4870
[M+Na]+; anal. calcd. for C19H18N4O4S2: C, 53.01; H, 4.21; N, 13.01%; found: C,
52.95; H, 4.24; N, 13.15%.
N-(4-(5-Bromothiophen-2-yl)-1H-imidazol-2-yl)-4-methoxy-2-methyl-2H-
benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (19b). White solid (0.336 g, 74%);
m.p. 166–168 °C. IR (KBr): 3380 (NH), 1677 (C=O), 1642 (C=C), 1566 (C=N),
1337–1140 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.58 (s, 3H, N–CH3),
3.63 (s, 3H, O–CH3), 6.94 (d, 1H, C4″-H), 7.25 (d, 1H, C3″-H), 7.41–7.59 (m, 5H,
Ar–H, and C5′-H), 11.22 (bs, 1H, CONH), 12.15 (bs, 1H, imidazole NH) ppm; 13
C
NMR (100 MHz, DMSO-d6): δ 37.3 (N–CH3), 55.0 (O–CH3), 105.7 (C3), 110.5
1 3

S. S. Panga et al.
(C5″), 117.6 (C5′), 120.3 (C3″), 122.3 (C4″), 139.5 (C2″), 140.4 (C4), 153.2 (C2′),
166.2 (C=O), 125.6, 127.8, 131.7, 132.2, 134.5, 137.3, 138.2 (aromatic carbons and
C4′) ppm. HRMS (m/z): 518.3563 [M+Na]+; anal. calcd. for C18H15BrN4O4S2: C,
43.64; H, 3.05; N, 11.31%; found: C, 43.60; H, 3.11; N, 11.24%.
4-Methoxy-2-methyl-N-(4-(5-nitrothiophen-2-yl)-1H-imidazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (19c). White solid (0.327 g, 71%); m.p.
173–175 °C. IR (KBr): 3376 (NH), 1662 (C=O), 1669 (C=C), 1578 (C=N),
1340–1149 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.66 (s, 3H, N–CH3),
3.65 (s, 3H, O–CH3), 7.45–7.60 (m, 5H, Ar–H, and C5′-H), 11.24 (bs, 1H, CONH),
7.83 (d, 1H, C3″-H), 8.64 (d, 1H, C4″-H), 11.99 (bs, 1H, imidazole-NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 38.5 (N–CH3), 55.3 (O–CH3), 106.9 (C3), 110.5
(C4″), 116.9 (C5′), 139.1 (C4′), 141.6 (C4), 146.9 (C2″), 151.4 (C2′), 151.7 (C5″),
165.5 (C=O), 127.5, 129.1, 131.8, 132.0, 132.9, 134.3, 137.6 (aromatic carbons
and C3′) ppm. HRMS (m/z): 484.4564 [M+Na]+; anal. calcd. for C18H15N5O6S2: C,
46.85; H, 3.28; N, 15.18%; found: C, 46.94; H, 3.24; N, 15.26%.
4-Methoxy-2-methyl-N-(4-(5-methyl-1H-pyrrol-2-yl)oxazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (20a). White solid (0.285 g, 70%);
m.p. 143–145 °C. IR (KBr): 3359 (NH), 1696 (C=O), 1638 (C=C), 1581 (C=N),
1329–1136 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H, C5″-CH3),
2.59 (s, 3H, N–CH3), 3.56 (s, 3H, O–CH3), 5.72 (d, 1H, C4″-H), 6.29 (d, 1H,
C3″-H), 7.45–7.78 (m, 5H, Ar–H, and C5′-H), 10.73 (bs, 1H, CONH), 11.23 (bs,
1H, pyrrole-NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 16.9 (C5″-CH3), 38.6
(N–CH3), 55.5 (O–CH3), 105.4 (C3″), 106.7 (C4″), 107.4 (C3), 139.4 (C4′), 142.2
(C4), 150.4 (C2′), 167.4 (C=O), 125.3, 126.9 128.5, 131.2, 133.4, 133.7, 135.5,
137.4, 138.1 (aromatic carbons, C5″, C2″ and C5″) ppm. HRMS (m/z): 437.4266
[M+Na]+; anal. calcd. for C19H18N4O5S: C, 55.06; H, 4.38; N, 13.52%; found: C,
55.12; H, 4.41; N, 13.63%.
N-(4-(5-Bromo-1H-pyrrol-2-yl)oxazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (20b). White solid (0.313 g, 75%);
m.p. 157–159 °C. IR (KBr): 3361 (NH), 1665 (C=O), 1650 (C=C), 1561 (C=N),
1336–1131 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.66 (s, 3H, N–CH3),
3.54 (s, 3H, O–CH3), 6.29 (d, 1H, C4″-H), 6.36 (d, 1H, C3″-H), 7.42–7.68 (m, 5H,
Ar–H, and C5′-H), 10.74 (bs, 1H, CONH), 11.52 (bs, 1H, pyrrole-NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 38.8 (N–CH3), 56.3 (O–CH3), 106.6 (C3″), 108.7
(C3), 114.9 (C4″), 142.5 (C4), 148.6 (C2′), 166.8 (C=O), 125.5, 127.5, 129.2, 131.6,
132.8, 135.5, 135.7, 138.4, 138.7139.6 (aromatic carbons, C4′, C5′, C2″ and C5″)
ppm. HRMS (m/z): 502.2950 [M+Na]+; anal. calcd. for C18H15BrN4O5S: C, 45.11;
H, 3.15; N, 11.69%; found: C, 45.18; H, 3.18; N, 11.45%.
4-Methoxy-2-methyl-N-(4-(5-nitro-1H-pyrrol-2-yl)oxazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (20c). White solid (0.311 g, 70%); m.p.
165–167 °C. IR (KBr): 3370 (NH), 1672 (C=O), 1679 (C=C), 1570 (C=N),
1341–1128 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.69 (s, 3H, N–CH3),
3.52 (s, 3H, O–CH3), 6.78 (d, 1H, C3″-H), 7.15 (d, 1H, C4″-H), 7.49–7.70 (m, 5H,
Ar–H, and C5′-H), 10.77 (bs, 1H, CONH), 11.98 (bs, 1H, pyrrole-NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 39.3 (N–CH3), 56.8 (O–CH3), 106.6 (C3″), 107.9
(C3), 108.3 (C4″), 138.9 (C4′), 142.8 (C4), 150.9 (C2′), 167.0 (C=O), 122.7, 127.2,
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
129.3, 131.9, 132.8, 134.8, 135.1, 135.6, 136.7 (aromatic carbons C5′, C2″ and C5″)
ppm. HRMS (m/z): 468.3961 [M+Na]+; anal. calcd. for C18H15N5O7S: C, 48.54; H,
3.39; N, 15.72%; found: C, 48.59; H, 3.36; N, 15.80%.
4-Methoxy-2-methyl-N-(4-(5-methyl-1H-pyrrol-2-yl)thiazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (21a). White solid (0.288 g, 75%);
m.p. 156–158 °C. IR (KBr): 3364 (NH), 1639 (C=O), 1655 (C=C), 1563 (C=N),
1322–1141 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.44 (s, 3H, C5″-CH3),
2.60 (s, 3H, N–CH3), 3.49 (s, 3H, O–CH3), 5.69 (d, 1H, C4″-H), 6.27 (d, 1H,
C3″-H), 7.43–7.69 (m, 5H, Ar–H, and C5′-H), 11.09 (bs, 1H, pyrrole-NH), 12.02
(bs, 1H, CONH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 17.2 (C5″-CH3), 39.4
(N–CH3), 57.4 (O–CH3), 103.7 (C5′), 105.9 (C3″), 107.4 (C4″), 108.3 (C3), 139.2
(C4′), 143.1 (C4), 160.6 (C2′), 167.3 (C=O), 125.4, 126.9, 128.1, 132.0, 132.4,
133.2, 134.7, 135.4, (aromatic carbons C2″ and C5″) ppm. HRMS (m/z): 453.4862
[M+Na]+; anal. calcd. for C19H18N4O4S2: C, 53.01; H, 4.21; N, 13.01%; found: C,
53.10; H, 4.26; N, 13.12%.
N-(4-(5-Bromo-1H-pyrrol-2-yl)thiazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (21b). White solid (0.341 g, 76%);
m.p. 163–165 °C. IR (KBr): 3373 (NH), 1648 (C=O), 1634 (C=C), 1667 (C=N),
1340–1135 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.58 (s, 3H, N–CH3),
3.54 (s, 3H, O–CH3), 6.36 (d, 1H, C3″-H), 6.45 (d, 1H, C4″-H), 7.40–7.73 (m, 5H,
Ar–H, and C5′-H), 11.57 (bs, 1H, CONH), 11.83 (bs, 1H, pyrrole-NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 38.6 (N–CH3), 56.4 (O–CH3), 102.6 (C4′), 107.1
(C3″), 108.6 (C3), 114.7 (C4″), 123.0 (C5″), 139.4 (C4′), 143.3 (C4), 155.6 (C2″),
162.9 (C2′), 165.7 (C=O), 127.4, 130.6, 131.2, 132.5, 134.0, 135.7 (aromatic car-
bons) ppm. HRMS (m/z): 518.3560 [M+Na]+; anal. calcd. for C18H15BrN4O4S2: C,
43.64; H, 3.05; N, 11.31%; found: C, 43.58; H, 3.02; N, 11.39%.
4-Methoxy-2-methyl-N-(4-(5-nitro-1H-pyrrol-2-yl)thiazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (21c). White solid (0.331 g, 72%); m.p.
178–180 °C. IR (KBr): 3379 (NH), 1645 (C=O), 1673 (C=C), 1571 (C=N),
1345–1146 (SO2) (cm−1); 1H NMR (400 MHz, DMSO-d6): δ 2.64 (s, 3H, N–CH3),
3.53 (s, 3H, O–CH3), 6.68 (d, 1H, C3″-H), 7.42 (d, 1H, C4″-H), 7.49–7.73 (m, 5H,
Ar–H, and C5′-H), 11.61 (bs, 1H, CONH), 11.97 (bs, 1H, pyrazole-NH) ppm; 13C
NMR (100 MHz, DMSO-d6): δ 37.9 (N–CH3), 57.9 (O–CH3), 107.3 (C3″), 108.8
(C3), 109.9 (C4″), 139.6 (C4′), 141.7 (C4), 163.2 (C2′), 166.9 (C=O), 123.5, 128.4,
132.3, 132.6, 133.3, 134.8, 136.2, 137.5 (aromatic carbons and C2″ and C5″) ppm.
HRMS (m/z): 484.4567 [M+Na]+; anal. calcd. for C18H15N5O6S2: C, 46.85; H,
3.28; N, 15.18%; found: C, 46.93; H, 3.25; N, 15.24%.
4-Methoxy-2-methyl-N-(4-(5-methyl-1H-pyrrol-2-yl)-1H-imidazol-2-yl)-2H-
benzo[e][1,2] thiazine-3-carboxamide-1,1-dioxide (22a). White solid (0.289 g,
70%); m.p. 182–184 °C. IR (KBr): 3371 (NH), 1690 (C=O), 1647 (C=C), 1560
1
(C=N), 1332–1128 (SO2) (cm−1); H NMR (400 MHz, DMSO-d6): δ 2.32 (s, 3H,
C5″-CH3), 2.65 (s, 3H, N–CH3), 3.46 (s, 3H, O–CH3), 5.75 (d, 1H, C4″-H), 6.30
(d, 1H, C3″-H), 7.30–7.74 (m, 5H, Ar–H, and C5′-H), 11.02 (bs, 1H, pyrazole-NH),
11.24 (bs, 1H, CONH), 12.18 (bs, 1H, imidazole-NH) ppm; 13C NMR (100 MHz,
DMSO-d6): δ 16.6 (C5″-CH3), 37.4 (N–CH3), 54.3 (O–CH3), 105.3 (C3″), 106.6
(C3), 107.2 (C4″), 117.6 (C5′), 139.2 (C4′), 140.2 (C4), 149.3 (C2′), 165.0 (C=O),
1 3

S. S. Panga et al.
124.4, 125.6, 126.3, 127.8, 130.2, 130.7, 133.4, 134.9 (aromatic carbons C2″ and
C5″) ppm. HRMS (m/z): 436.4423 [M+Na]+; anal. calcd. for C19H19N5O4S: C,
55.20; H, 4.63; N, 16.94%; found: C, 55.13; H, 4.59; N, 16.82%.
N-(4-(5-Bromo-1H-pyrrol-2-yl)-1H-imidazol-2-yl)-4-methoxy-2-methyl-2H-
benzo[e][1,2] thiazine-3-carboxamide-1,1-dioxide (22b). White solid (0.325 g, 73%);
m.p. 196–198 °C. IR (KBr): 3360 (NH), 1715 (C=O), 1659 (C=C), 1573 (C=N),
1
1327–1132 (SO2) (cm−1); H NMR (400 MHz, DMSO-d6): δ 2.50 (s, 3H, N–CH3),
3.44 (s, 3H, O–CH3), 6.14 (d, 1H, C3″-H), 6.28 (d, 1H, C4″-H), 7.29–7.58 (m, 5H,
Ar–H, and C5′-H), 11.16 (bs, 1H, CONH), 11.65 (bs, 1H, pyrazole-NH), 12.16 (bs,
1H, imidazole-NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 36.7 (N–CH3), 54.8
(O–CH3), 104.8 (C3), 105.2 (C3″), 114.5 (C4″), 118.4 (C5′), 139.3 (C4′), 140.5 (C4),
149.1 (C2′), 165.2 (C=O), 125.2, 126.9, 127.4, 130.0, 131.7, 133.6, 135.1, 137.7 (aro-
matic carbons C2″ and C5″) ppm. HRMS (m/z): 501.3102 [M+Na]+; anal. calcd. for
C18H16BrN5O4S: C, 45.20; H, 3.37; N, 14.64%; found: C, 45.26; H, 3.32; N, 14.58%.
4-Methoxy-2-methyl-N-(4-(5-nitro-1H-pyrrol-2-yl)-1H-imidazol-2-yl)-2H-
benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (22c). White solid (0.324 g, 73%);
m.p. 205–207 °C. IR (KBr): 3366 (NH), 1718 (C=O), 1682 (C=C), 1580 (C=N),
1
1338–1139 (SO2) (cm−1); H NMR (400 MHz, DMSO-d6): δ 2.56 (s, 3H, N–CH3),
3.55 (s, 3H, O–CH3), 6.52 (d, 1H, C3″-H), 7.09 (d, 1H, C4″-H), 7.46–7.75 (m, 5H,
Ar–H, and C5′-H), 11.17 (bs, 1H, CONH), 11.75 (bs, 1H, pyrazole-NH), 12.92 (bs,
1H, imidazole-NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ 37.8 (N–CH3), 55.2
(O–CH3), 106.7 (C3″), 107.9 (C3), 110.7 (C4″), 117.6 (C5′), 139.5 (C4′), 140.8 (C4),
149.3 (C2′), 166.7 (C=O), 122.5, 127.0, 131.2, 131.6, 134.1, 135.4, 136.7, 137.8 (aro-
matic carbons C2″ and C5″) ppm. HRMS (m/z): 467.4121 [M+Na]+; anal. calcd. for
C18H16N6O6S: C, 48.65; H, 3.63; N, 18.91%; found: C, 48.71; H, 3.60; N, 18.79%.
Experimental procedure for cytotoxic activity
Compounds 14–22 were dissolved in DMSO at diferent concentrations of
12.5–200 µM.
Cells
MCF-7 (breast cancer) cells and HeLa cervical carcinoma cells were maintained
in Dulbecco’s modifed Eagle’s medium (DMEM), 10% fetal bovine serum and 1%
penicillin and streptomycin. The cells were plated in T-25 tissue culture fasks and
incubated at 37 °C in a 5% CO2 atmosphere with 90% humidity.
MTT assay for cell viability
The cytotoxicity of the compounds was tested using MCF-7 (breast cancer) cells and
HeLa cervical carcinoma cells. 5×104 cells were plated in each well of a 96-well tissue
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
culture cluster (Nunc, Inc., Germany) and incubated at 37 °C in the culture medium
containing DMEM, 10% fetal bovine serum and antibiotics (Invitrogen, USA), in 5%
CO2 atmosphere. Compounds were dissolved in DMSO. Serial dilutions were made for
the active compounds 19b and 22b from stock solution of 10 mg/mL (43,800 µM) in
DMSO and diluted with culture medium to make a concentration of 200 µM, which
was further used for serial dilutions. After attachment of the cells (usually 3–4 h), dif-
ferent concentrations of dilutions were added to cells in 96-well plates and incubated
for 20 h. MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide] solution
(20 mL of 5 mg/mL) was added to each well and the incubation continued for an addi-
tional 3 h. The dark blue formazan crystals formed within the healthy cells were solu-
bilized with DMSO, and the absorbance was estimated in an ELISA plate reader (7520
microplate reader, Cambridge Technologies, Inc.) at 550 nm and correlated with the
cell number. Experiments were performed in triplicate, and the values of the average of
three (n=3) independent experiments were considered for interpretation. The inhibi-
tory concentration (IC50) of the compound was assessed by Graph Pad Prism software.
Experimental procedure for antioxidant activity
The compounds 14–22 were tested for antioxidant activity by DPPH and nitric oxide
(NO) methods.
DPPH radical scavenging activity
The hydrogen atom or electron donation ability of the compounds was measured from
the bleaching of the purple-colored methanol solution of 2,2,-diphenyl-1-picrylhydrazyl
(DPPH) radical. The spectrophotometric assay uses the stable radical DPPH as a rea-
gent. To 4 mL of 0.004% (w/v) methanol solution of DPPH 1 mL of various concentra-
tions of the test compounds (50, 75 and 100 µg/mL) in methanol were added. After a
30-min incubation period at room temperature, the absorbance was read against a blank
at 517 nm. Ascorbic acid was used as the standard. The percent of inhibition (I %) of
free radical production from DPPH was calculated by the following equation:
[(
)
]
I% = Acontrol − Asample ∕Ablank × 100
where Acontrol is the absorbance of the control reaction (containing methanolic DPPH
and ascorbic acid), Asample is the absorbance of the test compound (containing meth-
anolic DPPH and test compound) and Ablank is the absorbance of the blank (contain-
ing only methanolic DPPH). Tests were carried out in triplicate.
Nitric oxide (NO) scavenging activity
Nitric oxide scavenging activity was measured by slightly modifed methods of
Green et al. [16] and Marcocci et al. [17] Nitric oxide (NO) radicals were generated
1 3

S. S. Panga et al.
from sodium nitroprusside. 1 mL of sodium nitroprusside (10 mM) and 1.5 mL of
phosphate bufer saline (0.2 M, pH 7.4) were added to diferent concentrations (50,
75 and 100 µg/mL) of the test compounds and incubated for 150 min at 25 °C. After
incubation, 1 mL of the reaction mixture was treated with 1 mL of Griess reagent
(1% sulfanilamide, 2% H3PO4 and 0.1% naphthylethylenediamine dihydrochloride).
The absorbance of the chromatophore was measured at 546 nm. Ascorbic acid was
used as standard. Nitric oxide scavenging activity was calculated by the following
equation:
[(
)
]
% of scavenging = Acontrol − Asample ∕Ablank × 100
where Acontrol is the absorbance of the control reaction (containing all reagents and
ascorbic acid), Asample is the absorbance of the test compound (containing all rea-
gents and test compound) and Ablank is the absorbance of the blank (containing only
reagents). Tests were carried out in triplicate.
Results and discussion
N-Alkylation of sodium saccharin with methyl chloroacetate in DMF resulted
in methyl 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)acetate (2). Gabriel-
Colman intramolecular rearrangement of 2 in the presence of sodium methoxide
under nitrogen atmosphere aforded methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-
3-carboxylate-1,1-dioxide [1, 18] (3). Treatment of 3 with excess diazomethane
under nitrogen atmosphere produced methyl 4-hydroxy-2-methyl-2H-benzo[e][1,2]
thiazine-3-carboxylate-1,1-dioxide (4). It was observed that the reaction took place
with the formation of N- and O-methylated product: methyl 4-methoxy-2-methyl-
2H-benzo[e][1,2]thiazine-3-carboxylate-1,1-dioxide (4) in the presence of two-fold
excess diazomethane at −10 °C in 8 h (Scheme 1).
The amidation of esters with amines was reported using diferent catalysts viz,
DBU [19], triazabicyclo[4.4.0]dec-5-ene [20] and 1,2,4-triazole-DBU [21]. Inor-
ganic catalysts like Sb(OEt)3 [22, 23] and Zr(OtBu)4-HoAt [24] have also been used
for direct amidation. Besides, these sodium and potassium alkoxides have proved to
possess high catalytic activity for direct amidation reactions [25]. In fact, Takastri
et al. [25] reported NaOMe catalyzed amidation of various alkyl and aryl esters and
Scheme 1 Synthesis of methyl 4-methoxy-2-methyl-2H-benzo[e][1,2]thiazine-3-carboxylate-1,1-dioxide
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
Table 1 Reaction of 4 with
Sample no.
NaOMe (mol%)
Yield (%)
5a in the presence of diferent
molar concentrations of NaOMe
1
2.0
3.0
4.0
5.0
6.0
42
48
57
76
73
2
3
4
5
examined that methyl benzoates with electron-withdrawing substituents were good
substrates for the synthesis of amides [25]. Under these conditions, amidation of
methyl cinnamate also proceeded efectively, leading to amides [25]. Recently, we
have reported amidation of heteroaryl esters with heteroaryl amines in the presence
of potassium tertiary butoxide in THF [26]. As such, we have carried out amidation
of methyl 4-methoxy-2-methyl-2H-benzo[e][1,2]thiazine-3-carboxylate-1,1-dioxide
(4) with 4-(5-methylfuran-2-yl)oxazol-2-amine (5a) in the presence of two molar
equivalents of potassium tertiary butoxide in THF where in the product 4-methoxy-
2-methyl-N-(4-(5-methylfuran-2-yl)oxazol-2-yl)-2H-benzo[e][1,2]thiazine-3-car-
boxamide 1,1-dioxide (14a) was obtained in low yield (28%). It was observed that
there was not much diference in the yield of 14a at higher molar concentration of
potassium tertiary butoxide. However, when the reaction was repeated with two
molar equivalents of sodium methoxide, the yield of 14a was increased to 42%. In
order to increase the yield, the reaction between 4 and 5a was carried out with dif-
ferent molar concentrations of sodium methoxide. The reaction proceeded well in
the presence of 5.0 mol% sodium methoxide, leading to the formation of product
14a in excellent yield (Table 1).
Then, the reaction of 4 was carried out with 4-(5-substituted furan-2-yl)oxazol-
2-amine (5)/4-(5-substituted furan-2-yl)thiazol-2-amine (6)/4-(5-substituted furan-
2-yl)-1H-imidazol-2-amine (7) in the presence of 5.0 mol% sodium methoxide to
get 4-methoxy-2-methyl-N-(4-(5-substituted furan-2-yl)oxazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide
(14)/4-methoxy-2-methyl-N-(4-(5-substi-
tuted furan-2-yl)thiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide
(15)/4-methoxy-2-methyl-N-(4-(5-substituted furan-2-yl)-1H-imidazol-2-yl)-2H-
benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (16). Adopting similar methodol-
ogy, 4-methoxy-2-methyl-N-(4-(5-substituted thiophen-2-yl)oxazol-2-yl)-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (17), 4-methoxy-2-methyl-N-(4-(5-substi-
tuted thiophen-2-yl)thiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-diox-
ide (18) and 4-methoxy-2-methyl-N-(4-(5-substituted thiophen-2-yl)-1H-imidazol-
2-yl)-2H-benzo[e][1,2] thiazine-3-carboxamide-1,1-dioxide (19) were prepared by
the treatment of 4 with 4-(5-substituted thiophen-2-yl)oxazol-2-amine (8), 4-(5-sub-
stituted thiophen-2-yl)thiazol-2-amine (9) and 4-(5-substituted thiophen-2-yl)-
1H-imidazol-2-amine (10). Similar reaction of 4 with 4-(5-substituted 1H-pyrrol-
2-yl)oxazol-2-amine (11), 4-(5-substituted 1H-pyrrol-2-yl)thiazol-2-amine (12)
and 4-(5-substituted 1H-pyrrol-2-yl)-1H-imidazol-2-amine (13) resulted in 4-meth-
oxy-2-methyl-N-(4-(5-substituted
1H-pyrrol-2-yl)oxazol-2-yl)-2H-benzo[e][1,2]
1 3

S. S. Panga et al.
Scheme 2 Synthesis of heteroarylazolyl benzothiazine carboxamides
thiazine-3-carboxamide-1,1-dioxide (20), 4-methoxy-2-methyl-N-(4-(5-substituted
1H-pyrrol-2-yl)thiazol-2-yl)-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide
(21) and 4-methoxy-2-methyl-N-(4-(5-substituted 1H-pyrrol-2-yl)-1H-imidazol-2-yl)-
2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (22) (Scheme 2). The structures
of all the new molecules were established by IR, NMR, mass and elemental analyses
and the data is incorporated in the experimental section.
Entry
Ester
Amine
Product
1
2
3
4
4
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
Entry
Ester
Amine
Product
4
4
5
6
4
4
4
7
8
4
9
4
1 3

S. S. Panga et al.
Biological evaluation
Cytotoxic activity
Compounds 14–22 were subjected to MTT assay to determine growth inhibitory
activity against HeLa and MCF-7 cell lines. HeLa cells are an immortalized cer-
vical cancer cell line. These cells grow rapidly compared to normal cells. HeLa
cells become cancerous due to infection with human papillomavirus 18 (HPV18).
These cells are also used to develop polio vaccine. Currently, these cells are in
use in the study cancer and HIV/AIDS to grow viruses and to test antitumor
medicines [27]. MCF-7 is an epithelial cancer cell line derived from breast ade-
nocarcinoma. It has both estrogen and progesterone receptors, whereas human
epidermal growth receptor 2 (HER2) amplifcation is absent in these cells. Tumo-
rigenecity of MCF-7 cells in mice occurs only after supplementation of estrogen
[28]. HeLa and MCF-7 cells are two diferent types of cancer cells of distinct ori-
gin, and hence we used them for evaluating the cytotoxicity of compounds 14–22.
Compounds 19b and 22b and the reference drug doxorubicin showed cytotoxic
activity with IC50 values 33.75 2.20, 47.52 1.51 and 7.975 0.638 µM on
HeLa cell lines, and 31.75 3.13, 34.35 1.09 and 8.013 0.38 µM on MCF-7
cell lines. The remaining compounds did not display cytotoxicity when used up to
a concentration of 100 µM.
Figures 1 and 2 show the results of cytotoxicity of reference drug using MTT
assay on HeLa and MCF-7 cell lines. Figures 3 and 4 indicate the results of
cytotoxicity of N-(4-(5-bromothiophen-2-yl)-1H-imidazol-2-yl)-4-methoxy-2-
methyl-2H-benzo[e][1,2]thiazine-3-carboxamide-1,1-dioxide (19b) on HeLa and
MCF-7 cell lines. Figures 5 and 6 indicate the results of cytotoxicity of N-(4-
(5-bromo-1H-pyrrol-2-yl)-1H-imidazol-2-yl)-4-methoxy-2-methyl-2H-benzo[e]
[1,2]thiazine-3-carboxamide-1,1-dioxide (22b) on HeLa and MCF-7 cell lines.
The cytotoxic activity observed in these compounds is concentration-dependent.
The activity increases with higher concentration. Interestingly, compound 19b is
more potent on HeLa and MCF-7 cell lines than 22b. Hence, compound 19b is a
potential lead molecule for cytotoxic activity against HeLa and MCF-7 cell lines.
Further modifcations of 19b may lead to a more potent molecule that in turn
paves the way to developing a new drug.
Antioxidant activity
Compounds 14–22 were assayed for antioxidant activity by DPPH and NO meth-
ods, and the results are presented in Tables 2 and 3 and Figs. 7 and 8, respectively.
Amongst all the tested compounds, furanyloxazolyl benzothiazine carboxamide
(14), furanylimidazolyl benzothiazine carboxamide (16), thiophenyloxazolyl ben-
zothiazine carboxamide (17) and pyrrolyloxazolyl benzothiazine carboxamide (20)
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
Fig. 1 The dose–response curve
of doxorubicin measured by
MTT assay on HeLa cells. The
X axis shows the concentration
of the compound and the Y axis
shows the cell viability
Fig. 2 The dose–response curve
of doxorubicin measured by
MTT assay on MCF-7 cells. The
X axis shows the concentration
of the compound and the Y axis
shows the cell viability
Fig. 3 The dose–response curve
of 19b measured by MTT assay
on HeLa cells. The X axis
shows the concentration of the
compound and the Y axis shows
the cell viability
exhibited good antioxidant activity when compared with other compounds. It was
noticed that the presence of an electron-donating methyl substituent on the hetero-
cyclic ring enhanced the activity when compared with those having electron-with-
drawing bromo and nitro substituents in the respective series. In fact, compounds
1 3

S. S. Panga et al.
Fig. 4 The dose–response curve
of 19b measured by MTT assay
on MCF-7 cells. The X axis
shows the concentration of the
compound and the Y axis shows
the cell viability
Fig. 5 The dose–response curve
of 22b measured by MTT assay
on HeLa cells. The X axis
shows the concentration of the
compound and the Y axis shows
the cell viability
Fig. 6 The dose–response curve
of 22b measured by MTT assay
on MCF-7 cells. The X axis
shows the concentration of the
compound and the Y axis shows
the cell viability
14a, 16a, 17a and 20a exhibited excellent antioxidant activity greater than the stand-
ard ascorbic acid.
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
Table 2 The in vitro antioxidant activity of compounds 14–22 by DPPH method
Compd. No.
Concentration (µg/ml)
IC50 (µg/ml) mean SD
50 Mean SD
75 Mean SD
100 Mean SD
14a
14b
14c
78.31 0.29
65.43 0.51
58.64 0.48
60.34 0.24
48.19 0.43
37.41 0.32
75.68 0.31
61.28 0.12
59.82 0.58
76.42 0.14
62.87 0.76
55.35 0.54
47.78 0.65
31.39 0.21
22.21 0.39
52.14 0.41
38.40 0.35
27.32 0.71
77.95 0.79
63.30 0.25
57.61 0.46
50.25 0.18
35.73 0.74
25.12 0.37
56.72 0.16
42.27 0.62
33.56 0.23
74.89 0.64
–
80.36 0.81
66.25 0.86
60.71 0.35
62.82 0.38
49.45 0.27
38.28 0.49
77.73 0.74
63.14 0.89
55.39 0.16
78.51 0.95
64.18 0.32
56.64 0.72
48.21 0.24
33.98 1.03
23.60 0.56
54.93 0.98
39.57 0.68
28.95 0.42
79.54 0.14
65.12 0.84
59.68 0.77
51.32 0.21
37.97 0.53
27.43 0.64
58.86 0.52
43.61 0.19
35.19 0.46
76.73 0.72
–
82.18 0.79
68.88 0.73
62.49 0.38
63.41 0.26
51.15 0.42
39.67 0.66
78.45 0.28
65.72 0.84
57.50 0.67
79.47 0.32
66.74 0.82
58.82 0.69
50.38 0.19
35.58 0.64
25.27 0.59
56.69 0.45
41.21 0.14
30.55 0.53
81.92 0.76
67.16 0.72
61.86 0.36
53.34 0.98
38.61 0.51
29.24 0.62
60.53 0.49
44.32 0.24
36.63 0.96
78.38 0.81
–
31.92 0.18
38.20 0.47
42.63 0.69
41.43 0.72
97.75 0.26
126.03 0.62
33.03 0.24
40.79 0.49
67.70 0.63
32.71 0.48
39.76 0.12
45.16 0.42
99.24 0.81
140.52 0.37
197.86 0.79
47.94 0.28
121.32 0.76
163.66 0.61
32.07 0.15
39.49 0.46
43.39 0.65
49.75 0.32
129.50 0.83
170.99 0.78
44.07 0.34
112.81 0.60
136.50 0.74
33.38 0.84
–
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
21c
22a
22b
22c
Ascorbic acid
Blank
The free radical scavenging activity of the compounds 14a, 16a, 17a and 20a was
measured at diferent concentrations, and the change in absorbance at 10, 20 and
30 min in the DPPH method is listed in Table 4. It was observed at these 10-min
intervals, the values are very close, and the results indicated that the antioxidant
activity is independent of time.
1 3

S. S. Panga et al.
Table 3 The in vitro antioxidant
activity of compounds 14–22 by
NO method
Compound
Concentration (µg/ml)
50 Mean SD 75 Mean SD 100 Mean SD
14a
14b
14c
15a
15b
15c
16a
16b
16c
17a
17b
17c
18a
18b
18c
19a
19b
19c
20a
20b
20c
21a
21b
21c
22a
22b
22c
85.54 0.63
67.32 0.69
59.71 0.18
61.89 0.28
50.25 0.76
39.60 0.33
78.56 0.41
62.13 0.72
55.65 0.45
79.69 0.32
65.27 0.16
56.45 0.56
48.92 0.51
33.22 0.37
25.44 0.26
54.18 0.46
39.84 0.21
30.73 0.83
80.52 0.61
64.15 0.43
58.48 0.59
53.79 0.35
37.41 0.49
26.19 0.24
57.85 0.78
44.38 0.14
34.62 0.52
88.74 0.19
69.81 0.64
60.30 0.43
63.60 0.52
52.44 0.72
40.37 0.39
80.12 0.37
64.42 0.62
57.26 0.20
81.15 0.34
66.64 0.45
58.28 0.67
49.53 0.89
34.24 0.55
27.35 0.31
55.19 0.53
41.48 0.26
32.32 0.79
81.16 0.69
65.73 0.14
59.40 0.61
54.51 0.58
39.24 0.48
28.62 0.28
58.58 0.23
46.46 0.74
35.94 0.46
80.21 0.74
–
89.33 0.58
70.69 1.04
61.82 0.34
65.84 0.64
54.16 0.83
42.62 0.18
81.64 0.84
66.81 0.27
59.38 0.54
83.74 0.56
68.36 0.92
60.25 0.36
51.89 0.47
36.53 0.78
29.23 0.51
57.55 0.67
42.45 0.12
34.14 0.72
83.31 0.62
67.72 1.02
60.66 0.30
56.86 0.44
40.47 0.74
30.58 0.69
59.30 0.53
48.41 0.42
37.19 0.24
82.23 0.83
–
Ascorbic acid 78.84 0.69
Blank
–
Conclusion
A new class of azolyl benzothiazine carboxamides was prepared from benzothia-
zine carboxylate and azolyl amines in the presence of NaOMe under ultrasonica-
tion and tested for their cytotoxic and antioxidant activities. Optimization of reaction
conditions was established using diferent molar concentrations of NaOMe. 4-Bro-
mothiophenylimidazolyl benzothiazine carboxamide (19b) and 4-bromopyrrolylimi-
dazolyl benzothiazine carboxamide (22b) showed cytotoxic activity on HeLa cell
lines (IC50 33.75, 47.52 µM) and MCF-7 cell lines (IC5031.75, 34.35 µM) and found
that 19b is more potent than 22b on both cell lines. Furthermore, methyl-substituted
furanyloxazolyl benzothiazine carboxamide (14a), furanylimidazolyl benzothiazine
1 3

Synthesis, cytotoxic and antioxidant activities of azolyl…
90
80
70
60
50
40
30
20
10
0
Concentraꢀon 50
µg/ml
Concentraꢀon 75
µg/ml
Concentraꢀon 100
µg/ml
Fig. 7 The in vitro antioxidant activity of 14–22 by DPPH method
100
90
80
70
60
50
40
30
20
10
0
Concentraꢀon 50
µg/ml
Concentraꢀon 75
µg/ml
Concentraꢀon
100 µg/ml
Fig. 8 The in vitro antioxidant activity of 14–22 by NO method
Table 4 Antioxidant activity of
Compound
10 min
20 min
30 min
compounds 14a, 16a, 17a and
20a at 10-min intervals by the
DPPH scavenging method
14a
16a
17a
20a
82.18
78.45
79.47
81.92
82.32
78.61
79.79
82.16
82.74
78.87
79.96
82.42
carboxamide (16a), thiophenyloxazolyl benzothiazine carboxamide (17a) and pyr-
rolyloxazolyl benzothiazine carboxamide (20a) exhibited antioxidant activity greater
than ascorbic acid.
1 3

S. S. Panga et al.
Acknowledgements The authors are grateful to the Council of Scientifc and Industrial Research (CSIR),
New Delhi for fnancial assistance under a major research project.
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Synthesis, cytotoxic and antioxidant activities of azolyl…
Afliations
Siva Sankar Panga1 · Rekha Tamatam1 · Padmaja Adivireddy1 ·
Padmavathi Venkatapuram1 · Siva Krishna Narra2 · Kondaiah Paturu2
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Padmavathi Venkatapuram
vkpuram2001@yahoo.com
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2
Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh 517 502,
India
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science,
Bangalore, Karnataka 560 012, India
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