Anticancer activity of some newly synthesized pyrano[2,3-d][1,2,3]triazine derivatives using 1-(7-hydroxy-2,2-dimethylchroman-6-yl)ethanone as synthon

Article abstract of DOI:10.1007/s00044-014-1229-0

A series of the newly substituted pyrano[1,2,3]triazine derivatives 3-14 were synthesized using compounds 1 and 2 as starting materials. Compound 2 was methylated using methyl iodide to compound 3, which was treated with aromatic aldehydes to give acryloyl derivatives 4a-c. Compounds 4a,b were reacted with ethyl cyano-acetate to give pyran-3-carboxylates 5a,b which were reacted with ethyl glycinate hydrochloride to give 6a,b. Treatment of 6a,b with hydrazine hydrate gives acid hydrazides 7a,b, which were reacted with 5,5-dimethyl-1,3-cyclohexanedione to give acetohydrazides 8a,b. Cyclization of 8b with 2-(4-nitrobenzylidene)malononitrile afforded hexahydroquinoline 9. However, the acridindione 10 was synthesized by heating of 8b with 2-(4-nitrobenzylidene)malononitrile in acetic acid containing few drops of triethylamine. Treatment of 7a,b with phenyl isothiocyanate or 2,5-hexanedione or phthalic anhydride gave compounds 11a,b, 13a,b and 14a,b, respectively. In the present work, all the selected pyrano[1,2,3]trizine derivatives were soluble in DMSO at concentrations high enough to allow cell experiments, and the in vitro biological activity of these compounds was evaluated by their growth inhibitory potency in liver HEPG2 cancer cell lines. The cytotoxic potency of compounds 3-14 was studied in comparison to the known anticancer drugs 5-fluorouracil and doxorubicin.

Full text of DOI:10.1007/s00044-014-1229-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2015) 24:1514–1526
DOI 10.1007/s00044-014-1229-0
ORIGINAL RESEARCH
Anticancer activity of some newly synthesized pyrano
[2,3-d][1,2,3]triazine derivatives using 1-(7-hydroxy-2,
2-dimethylchroman-6-yl)ethanone as synthon
•
Nabil H. Ouf Abd El-Galil E. Amr
•
Mohamed I. Sakran
Received: 3 October 2013 / Accepted: 11 August 2014 / Published online: 26 August 2014
Ó Springer Science+Business Media New York 2014
Abstract
A
series of the newly substituted pyr-
In the present work, all the selected pyrano[1,2,3]trizine
derivatives were soluble in DMSO at concentrations high
enough to allow cell experiments, and the in vitro biological
activity of these compounds was evaluated by their growth
inhibitory potency in liver HEPG2 cancer cell lines. The
cytotoxic potency of compounds 3–14 was studied in com-
parison to the known anticancer drugs 5-fluorouracil and
doxorubicin.
ano[1,2,3]triazine derivatives 3–14 were synthesized using
compounds 1 and 2 as starting materials. Compound 2 was
methylated using methyl iodide to compound 3, which was
treated with aromatic aldehydes to give acryloyl derivatives
4a–c. Compounds 4a,b were reacted with ethyl cyano-acetate
to give pyran-3-carboxylates 5a,b which were reacted with
ethyl glycinate hydrochloride to give 6a,b. Treatment of
6a,b with hydrazine hydrate gives acid hydrazides 7a,b,
which were reacted with 5,5-dimethyl-1,3-cyclohexanedione
to give acetohydrazides 8a,b. Cyclization of 8b with 2-(4-
nitrobenzylidene)malononitrile afforded hexahydroquinoline
9. However, the acridindione 10 was synthesized by heating
of 8b with 2-(4-nitrobenzylidene)malononitrile in acetic acid
containing few drops of triethylamine. Treatment of7a,b with
phenyl isothiocyanate or 2,5-hexanedione or phthalic anhy-
dride gave compounds 11a,b, 13a,b and 14a,b, respectively.
Keywords 1-(2,4-Dihydroxyphenyl)ethanone ꢀ
Acryloyl derivatives ꢀ Pyrano[1,2,3]triazine ꢀ
Anticancer and cytotoxic activities
Introduction
A number of derivatives containing s-triazine nucleus have
been reported as heterocyclic compounds (Smith et al., 1980).
They are applicable as reactive dyes and also are used as
polymers and drugs (Chaudhari and Patel, 2010; Halverson
and Hirt, 1951). Among the compound having good antimi-
crobial properties, s-triazine derivatives constitute an impor-
tant class of compounds possessing diverse pharmacological
activities including broadly active as herbicidal (Gamez et al.,
2003) and antimicrobial (Jain et al., 2007). Some are alsoused
for the treatment of HIV infection (Patel et al., 2007). Several
workers investigated the s-triazine nucleus in the scope of
potential therapeutic agents for diseases due to bacteria
(Srinivas et al., 2006), cancer (Kaswala et al., 2009), and
antitumor (Shin-ichi et al., 2006). As pyrimidine is basic
nucleus in DNA and RNA, it has been found to associate with
diverse pharmacological activities such as anticancer (Patel
et al., 2001), anti-inflammatory (Vanderhoek et al., 1973),
antiviral (Patel et al., 2012), antibacterial (Karci et al., 2009;
Modha et al., 2001), antioxidant (Sharma and Reddy, 1993),
N. H. Ouf (&) ꢀ M. I. Sakran
Department of Chemistry and Biochemistry, Faculty of Science,
Tabuk University, Tabuk, Saudi Arabia
e-mail: ouf.nabil@yahoo.com
N. H. Ouf
Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt
A. E.-G. E. Amr
Pharmaceutical Chemistry Department, College of Pharmacy,
King Saud University, Riyadh 11451, Saudi Arabia
A. E.-G. E. Amr
Applied Organic Chemistry Department, National Research
Center, Dokki, Cairo, Egypt
M. I. Sakran
Department of Chemistry, Faculty of Science, Tanta University,
Tanta 31527, Egypt
123

Med Chem Res (2015) 24:1514–1526
1515
antiulcer (Laneri et al., 1998), and anti-HIV/AIDS (Patel
et al., 2007) activities. Additionally, in our previous work, we
reported the synthesis of substituted heterocyclic derivatives
as anti-inflammatory (Amr et al., 2005) and antitumor (Abo-
Ghalia and Amr, 2004 and Hammam et al., 2003) agents. On
the other hand, pyrimidine and thiazolopyrimidine derivatives
have promising biological and anticancer activities (Girgis
and Ahmed-Farag, 2003 and Flefel et al., 2007). Also, the
newly substituted heterocyclic candidates exhibited antian-
drogenic (Amr and Abdalla, 2006), analgesic, antiparkinso-
nian, anti-inflammatory (Amr and Abdalla, 2006; Ouf et al.,
2008 and Ouf and Amr, 2008), anticancer (Amr et al., 2006a,
2006b), anticonvulsant (Nehad et al., 2007), and antiar-
rhythmic (Ahmed et al., 2007) activities. In view of these
observations and in continuation of our previous work in
heterocyclic chemistry, we synthesized some new pyr-
ano[2,3-d][1,2,3]triazine derivatives and tested their anti-
cancer activities with 5-fluorouracil (5-FU) and doxorubicin
(DOX) as anticancer drugs.
67.5 MHz): d = 13C-NMR (DMSOd6, ppm): d = 27.45,
28.15 (3CH3), 55.65 (OCH3), 198.45 (C=O), 76.32 (C-1),
32.05 (C-2), 22.98 (C-3), 116.68 (C-4), 128.92 (C-5),
110.75 (C-6), 156.96 (C-7), 100.01 (C-8), 159.48 (C-9);
MS (EI, 70 eV): m/z = 234 [M?, 100]. Anal. calcd. for
C14H18O3 (234.29):C, 71.77; H, 7.74. Found: C, 71.74; H,
7.70.
(E)-3-(Aryl)-1-(7-methoxy-2,2-dimethylchroman-6-
yl)prop-2-en-1-one 4a–c
A mixture of compound 3 (0.01 mol) and aromatic alde-
hydes, namely, vanillin, benzaldehyde, or 3-anisaldehyde,
in the presence of two drops of piperidine was heated under
reflux for 2–4 h. The reaction mixture was cooled and
triturated with ethanol then filtered off, dried, and then
crystallized from propan-2-ol to give compounds (4a–c),
respectively.
(E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(7-methoxy-2,2-
dimethylchroman-6-yl)prop-2-en-1-one (4a)
Materials and methods
Brown powder, yield 70 %, m.p. 197 °C; IR (KBr, cm-1):
1667 (C=O), 3433 (OH); 1H-NMR (DMSO-d6, ppm):
d = 1.52 (d, 6H, 2CH3), 1.98–2.38 (m, 4H, 2CH2), 3.71,
4.03 (2 s, 6H, 2OCH3), 5.36 (s, 1H, OH, exchangeable with
D2O), 6.84–7.39 (m, 7H, 5H Ar–H ? CH=CH); 13C-NMR
(DMSOd6, ppm): d = 27.42 (2CH3), 55.85, 56.02
(2OCH3), 76.42 (C-1), 31.93 (C-2), 22.65 (C-3), 117.24 (C-
4), 129.18 (C-5), 111.64 (C-6), 157.96 (C-7), 100.45 (C-8),
159.68 (C-9), 189.22 (C-10), 120.88 (C-11), 144.35 (C-12),
128.45 (C-13), 119.78 (C-14), 115.98 (C-15), 144.15 (C-
16), 151.05 (C-17), 111.95 (C-18); MS (EI, 70 eV): m/
z = 368 [M?, 8] and at 178 (100, base peak). Anal. calcd.
for C22H24O5 (368.42): C, 71.72; H, 6.57. Found: C, 71.65;
H, 6.52.
Chemistry
All melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. Elemental analysis
data were obtained from the microanalytical unit, Cairo
University, Cairo, Egypt, and the results were in favorable
agreements with the calculated values. The IR spectra
(KBr) were recorded on a PYEUNICAM spectrophotom-
eter. The 1H- and 13C-NMR spectra were recorded at
300 MHz on a Perkin Elmer R12B Spectrometer using
TMS as an internal standard. The mass spectra were per-
formed using VG 2AB-3F spectrometer (70 eV). All
reactions were followed by TLC (silica gel, aluminum
sheets 60F254, Merck). The starting materials 1 and 2 were
prepared according to the reported procedures (Kumar
et al., 2011).
(E)-1-(7-Methoxy-2,2-dimethylchroman-6-yl)-3-
phenylprop-2-en-1-one (4b)
1-(7-Methoxy-2,2-dimethylchroman-6-yl)ethanone (3)
Brown powder, yield 70 %, m.p. 220 °C; IR (KBr, cm-1):
1680 (C=O), 2990 (CH-aliphatic), 3090 (CH aro-
matic),1220(C–O ether); 1H-NMR (DMSO-d6, ppm):
d = 1.48 (d, 6H, 2CH3), 2.05–2.48 (m, 4H, 2CH2), 3.92 (s,
3H, OCH3), 7.33–8.06 (m, 9H, 7H Ar–H ? CH=CH); 13C-
NMR (DMSOd6, ppm): d = 27.36 (2CH3), 55.864
(OCH3), 76.45 (C-1), 32.04 (C-2), 22.58 (C-3), 118.22 (C-
4), 129.32 (C-5), 112.05 (C-6), 158.54 (C-7), 101.00 (C-8),
160.64 (C-9), 189.45 (C-10), 120.82 (C-11), 144.48 (C-12),
135.15 (C-13), 127.03 (C-14, C-18), 127.98 (C-15, C-17),
127.68 (C-16); MS (EI, 70 eV): m/z = 322 [M?, 12] and at
132 (100, base peak). Anal. calcd. for C21H22O3 (322.40):
C, 78.23; H, 6.88. Found: C, 78.18; H, 6.82.
A mixture of compound 2 (2 g), methyl iodide (7 mL), and
anhydrous potassium carbonate (7 g) in acetone (100 mL)
was refluxed for 12 h and then filtered while hot. The fil-
trate solution was evaporated under reduced pressure to
dryness, and the obtained residue was crystallized from
ethanol to give compound 3 as yellow powder. Yield 75 %,
m.p. 117 °C; IR (KBr, cm-1): 1667 (C=O), 2995 (CH-
Aliph.), 3080 (CH-Ar), 1223 (C–O ether); 1H-NMR
(DMSO-d6, 300 MHz): d = 1.50 (d, 6H, 2CH3), 2.00–2.42
(m, 4H, 2CH2), 2.50 (s, 3H, COCH3), 3.84 (s, 3H, OCH3),
6.65, 7.58 (2 s, 2H, Ar–H); 1H-NMR (DMSO-d6,
123

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Med Chem Res (2015) 24:1514–1526
(E)-1-(7-Methoxy-2,2-dimethylchroman-6-yl)-3-(3-
methoxyphenyl)prop-2-en-1-one (4c)
Ethyl 2-amino-6-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
phenyl-4H-pyran-3-carboxylate (5b)
Crystallized from pale yellow powder, yield 80 %, m.p.
302 °C; IR (KBr, cm-1): 1670 (C=O), 2992 (CH-ali-
phatic), 3090 (CH aromatic),1225 (C–O ether); H-NMR
Pale yellow powder, yield 70 %, m.p. 113 °C; IR (KBr,
cm-1): 1732 (CO, ester), 3132, 3389 (NH2). 1H-NMR
(DMSO-d6, ppm): d = 1.26 (t, 3H, CH3), 1.50 (d, 6H,
2CH3), 1.98–2.40 (m, 4H, 2CH2), 3.83 (s, 3H, OCH3), 4.23
(q, 2H, CH2), 4.46 (s, 1H, CH-pyrane), 6.99–7.50 (m, 8H,
Ar–H ? CH-pyrane), 7.95 (s, 2H, NH2, exchangeable with
D2O); 13C-NMR (DMSOd6, ppm): d = 14.07 (CH3-ester),
27.10 (2CH3), 56.12 (OCH3), 61.36 (CH2-ester), 166.84
(C=O, ester), 76.38 (C-1), 32.10 (C-2), 23.15 (C-3), 117.36
(C-4), 127.18 (C-5), 101.48 (C-6), 155.16 (C-7), 99.99 (C-
8), 154.82 (C-9), 140.24 (C-10), 91.00 (C-11), 39.75 (C-
12), 75.60 (C-13), 162.08 (C-14), 142.01 (C-15), 122.65
(C-16), 116.02 (C-17), 142.20 (C-18), 151.10 (C-19),
114.01 (C-20); MS (EI, 70 eV): m/z = 435 [M?, 24] and at
390 (100, base peak). Anal. calcd. for C26H29NO5 (435.51):
C, 71.70; H, 6.71; N; 3.22, Found: C, 71.65; H, 6.67; N;
3.15.
1
(DMSO-d6, ppm): d = 1.48 (d, 6H, 2CH3), 1.96–2.42 (m,
4H, 2CH2), 3.75, 3.92, (2 s, 6H, 2OCH3), 7.61–8.06 (m,
8H, 6H Ar–H ? CH=CH); 13C-NMR (DMSOd6, ppm):
d = 27.35 (2CH3), 55.76, 56.05 (2OCH3), 76.45 (C-1),
31.92 (C-2), 22.54 (C-3), 117.32 (C-4), 130.02 (C-5),
111.72 (C-6), 158.65 (C-7), 100.32 (C-8), 160.38 (C-9),
188.99 (C-10), 121.18 (C-11), 144.65 (C-12), 136.01 (C-
13), 118.02 (C-14), 129.06 (C-15), 113.12 (C-16), 160.22
(C-17), 110.08 (C-18); MS (EI, 70 eV): m/z = 352 [M?,
18] and at 162 (100, base peak). Anal. calcd. for C22H24O4
(352.44): C, 74.98; H, 6.86. Found: C, 74.95; H, 6.80.
Ethyl 2-amino-4-(aryl)-6-(7-methoxy-2,2-
dimethylchroman-6-yl)-4H-pyran-3-carboxylate (5a,b)
Ethyl 2-(aryl)-7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
oxo-4H-pyrano[2,3-d][1,2,3]-triazin-3(5H)-yl)acetate
(6a,b)
A mixture of compound 4a or 4b (1 mmol) and ethyl cy-
anoacetate (1 mmol) in pyridine (50 mL) was refluxed for
12 h. The reaction mixture was poured into ice water and
neutralized with hydrochloric acid, and the obtained pre-
cipitate was filtered off, washed with water, dried, and
crystallized from propan-2-ol to give compounds 5a,b,
respectively.
To a solution of ethyl carboxylate 5a or 5b (6 g,
0.039 mol) cooled solution of dilute hydrochloric acid, a
solution of sodium nitrite (4.25 g) in water (10 ml) was
added to form diazonium salt. A solution of ethyl glycinate
hydrochloride (5.54 g, 0.039 mol) was added to the stirred
solution of the diazonium salt with subsequent neutraliza-
tion by sodium carbonate. After 1 h stirring, the obtained
precipitate was separated by filtration, and the formed solid
was washed with water, air-dried, and crystallized from
absolute ethanol to give compounds 6a or 6b.
Ethyl 2-amino-4-(4-hydroxy-3-methoxyphenyl)-6-(7-
methoxy-2,2-dimethylchroman-6-yl)-4H-pyran-3-
carboxylate (5a)
Pale yellow powder, yield 85 %, m.p. 106 °C; IR (KBr,
cm-1): 1735 (CO, ester), 3375 (OH), 3129, 3153 (NH2);
1H-NMR (DMSO-d6, ppm): d = 1.37 (t, 3H, CH3), 1.52 (d,
6H, 2CH3), 2.00–2.52 (m, 4H, 2CH2), 3.88, 3.98 (2 s, 6H,
2OCH3), 4.33 (q, 2H, CH2), 4.46 (s, 1H, pyrane-CH), 5.72
(s, 1H, OH, exchangeable with D2O), 6.98–7.85 (m, 6H,
Ar–H ? CH-pyrane), 8.14 (s, 2H, NH2, exchangeable with
D2O); 13C-NMR (DMSOd6, ppm): d = 14.05 (CH3-ester),
27.05 (2CH3), 56.10, 56.18 (2OCH3), 61.45 (CH2-ester),
166.86 (C=O, ester), 76.32 (C-1), 32.06 (C-2), 23.16 (C-3),
117.25 (C-4), 127.22 (C-5), 101.52 (C-6), 155.18 (C-7),
99.98 (C-8), 154.86 (C-9), 140.26 (C-10), 91.08 (C-11),
39.76 (C-12), 75.62 (C-13), 162.05 (C-14), 135.72 (C-15),
122.65 (C-16), 116.02 (C-17), 142.20 (C-18), 151.10 (C-
19), 114.01 (C-20); MS (EI, 70 eV): m/z = 481 [M?, 22]
and at 246 (100, base peak). Anal. calcd. for C27H31NO7
(481.53): C, 67.34; H, 6.49; N; 2.91. Found: C, 67.28; H,
6.40; N; 2.89.
Ethyl 2-(5-(4-hydroxy-3-methoxyphenyl)-7-(7-methoxy-
2,2-dimethylchroman-6-yl)-4-oxo-4H-pyrano[2,3-d]
[1,2,3]triazin-3(5H)-yl)acetate (6a)
Yield: 86 %, m.p. 226 °C; IR (KBr, cm-1): 3380 (OH),
3050 (C–H Ar.), 2965 (C–H aliph.), 1739 (C=O, ester),
1
1680 (C=O, amidic), 1233 (C–O); H-NMR (DMSO-d6,
ppm): d = 1.36 (t, 3H, CH3), 1.54 (d, 6H, 2CH3),
2.02–2.46 (m, 4H, 2CH2), 3.80, 3.86 (2 s, 6H, OCH3), 4.30
(q, 2H, CH2), 4.38 (s, 1H, CH-pyrane), 4.68 (s, 2H, CH2),
5.70 (s, 1H, OH exchangeable with D2O), 6.86–7.72 (m,
6H, Ar–H ? CH-pyrane); 13C-NMR (DMSOd6, ppm):
d = 14.05 (CH3-ester), 27.48 (2CH3), 56.15, 56.28
(2OCH3), 61.45 (CH2-ester), 168.65 (C=O, ester), 76.32
(C-1), 31.92 (C-2), 23.18 (C-3), 116.52 (C-4), 127.26 (C-
5), 100.96 (C-6), 154.95 (C-7), 100.18 (C-8), 154.64 (C-9),
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Med Chem Res (2015) 24:1514–1526
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140.32 (C-10), 91.36 (C-11), 40.34 (C-12), 114.75 (C-13),
147.56 (C-14), 135.35 (C-15), 121.86 (C-16), 116.08 (C-
17), 142.22 (C-18), 151.12 (C-19), 114.16 (C-20), 158.72
(C-21), 48.55 (C-22); MS (EI, 70 eV): m/z = 550 [M?, 4]
and at 192 (100, base peak). Anal. calcd. for C29H31N3O8
(549.57): C, 63.38; H, 5.69; N; 7.65. Found: C, 63.30; H,
5.65; N; 7.60.
(s, 1H, NH exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 27.12 (2CH3), 56.25, 56.42 (2OCH3), 169.48
(C=O, hydrazide), 76.18 (C-1), 32.08 (C-2), 23.24 (C-3),
117.62 (C-4), 127.32 (C-5), 101.05 (C-6), 155.02 (C-7),
100.12 (C-8), 154.52 (C-9), 140.30 (C-10), 92.00 (C-11),
40.32 (C-12), 115.05 (C-13), 146.98 (C-14), 135.42 (C-15),
122.16 (C-16), 115.58 (C-17), 142.02 (C-18), 151.18 (C-
19), 114.26 (C-20), 159.02 (C-21), 48.55 (C-22); MS (EI,
70 eV): m/z = 536 [M?, 16] and at 314 (100, base peak).
Anal. calcd. for C27H29N5O7 (535.54): C, 60.55; H, 5.46;
N; 13.08. Found: C, 60.48; H, 5.40; N; 13.00.
Ethyl 2-(7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-oxo-5-
phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)acetate
(6b)
Yield: 65 %, m.p. 205 °C; IR (KBr, cm-1): 3050 (C–H
Ar.), 2965 (C–H aliph.), 1739 (C=O, ester), 1680 (C=O,
2-(7-(7-Methoxy-2,2-dimethylchroman-6-yl)-4-oxo-5-
phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)
acetohydrazide (7b)
1
amidic), 1233 (C–O); H-NMR (DMSO-d6, ppm): d 1.38
(t, 3H, CH3), 1.48 (d, 6H, 2CH3), 1.98–2.42 (m, 4H, 2CH2),
3.92 (s, 3H, OCH3), 4.32 (q, 2H, CH2), 4.45 (s, 1H, CH-
pyrane), 4.70 (s, 2H, CH2), 6.82–7.76 (m, 8H, Ar–
H ? CH-pyrane); 13C-NMR (DMSOd6, ppm): d = 14.05
(CH3-ester), 27.48 (2CH3), 56.15 (OCH3), 61.45 (CH2-
ester), 168.65 (C=O, ester), 76.36 (C-1), 31.94 (C-2), 23.16
(C-3), 116.50 (C-4), 127.25 (C-5), 100.98 (C-6), 154.92
(C-7), 100.16 (C-8), 154.65 (C-9), 140.34 (C-10), 91.35
(C-11), 40.35 (C-12), 114.75 (C-13), 147.56 (C-14), 142.32
(C-15), 128.86 (C-16, C-20), 128.08 (C-17, C-19), 125.46
(C-18), 158.80 (C-21), 48.56 (C-22); MS (EI, 70 eV): m/
z = 504 [M?, 8] and at 191 (100, base peak). Anal. calcd.
for C28H29N3O6 (503.54): C, 66.79; H, 5.80; N; 8.34.
Found: C, 66.72; H, 5.74; N; 8.30.
Yield: 80 %, m.p. 228 °C; IR (KBr, cm-1): 3311–3300
(N–H str), 3070 (CH Ar.), 2957 (C–H aliph.), 1680, 1662
(C=O), 1577 (N–H bending scissoring); 1H-NMR (DMSO-
d6, ppm): d = 1.50 (d, 6H, 2CH3), 2.00–2.44 (m, 4H,
2CH2), 3.90 (s, 3H, OCH3), 4.36 (s, 2H, NH2, exchange-
able with D2O), 4.45 (s, 1H, CH-pyrane), 4.78 (s, 2H,
CH2), 6.85–7.76 (m, 8H, Ar–H ? CH-pyrane), 10.30 (s,
1H, NH exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 27.48 (2CH3), 56.15 (OCH3), 169.64 (C=O,
hydrazide), 76.42 (C-1), 31.95 (C-2), 23.15 (C-3), 116.52
(C-4), 127.22 (C-5), 106.00 (C-6), 154.95 (C-7), 100.18
(C-8), 154.63 (C-9), 140.33 (C-10), 92.12 (C-11), 40.32
(C-12), 114.78 (C-13), 147.56 (C-14), 142.35 (C-15),
129.08 (C-16, C-20), 128.34 (C-17, C-19), 125.52 (C-18),
169.80 (C-21), 52.56 (C-22); MS (EI, 70 eV): m/z = 490
[M?, 12] and at 184 (100, base peak). Anal. calcd. for
C26H27N5O5 (489.52): C, 63.79, H, 5.56; N; 14.31. Found:
C, 63.74, H, 5.50; N; 14.24.
2-(5-(Aryl)-7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-
acetohydrazides (7a,b)
A mixture of the ester 6a or 6b (0.05 mol) and hydrazine
hydrate (2.5 g, 0.05 mol) in ethanol (20 ml) was stirred for
2 h at room temperature. Excess ethanol was evaporated
under vacuum, and the obtained precipitate product was
filtered off, dried, and crystallized from ethanol to give
compounds 7a,b.
2-(5-(Aryl)-7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N0-(5,5-
dimethyl-3-oxocyclohex-1-enyl)acetohydrazides (8a,b)
A mixture of equimolar amounts of 5,5-dimethyl-l, 3-cy-
clohexadione (dimedone) and hydrazides 7a,b (0.05 mol)
in toluene (15 ml) was heated under reflux for 4 h. using
Dean-Stark water separator. After cooling, the obtained
crystalline product was filtered off, dried, and recrystal-
lized from toluene to give compounds 8a,b, respectively.
2-(5-(4-Hydroxy-3-methoxyphenyl)-7-(7-methoxy-2,2-
dimethylchroman-6-yl)-4-oxo-4H-pyrano[2,3-d]
[1,2,3]triazin-3(5H)-yl)acetohydrazide (7a)
Yield 77 %, m.p. 231 °C; IR (KBr, cm-1): 3380 (OH),
3311–3300 (N–H str), 3070 (CH Ar.), 2957 (C–H aliph.),
1
1680, 1662 (C=O), 1577 (N–H bending scissoring). H-
2-(5-(4-Hydroxy-3-methoxyphenyl)-7-(7-methoxy-2,2-
dimethylchroman-6-yl)-4-oxo-4H-pyrano[2,3-d]-
[1,2,3]triazin-3(5H)-yl)-N0-(5,5-dimethyl-3-oxocyclohex-1-
enyl)acetohydrazide (8a)
NMR (DMSO-d6, ppm): d = 1.46 (d, 6H, 2CH3),
1.96–2.43 (m, 4H, 2CH2), 3.80, 3.92 (2s, 6H, 2OCH3), 4.32
(s, 2H, NH2, exchangeable with D2O), 4.45 (s, 1H, CH-
pyrane), 4.86 (s, 2H, CH2), 5.70 (s, 1H, OH exchangeable
with D2O), 6.88–7.72 (m, 6H, Ar–H ? CH-pyrane), 10.30
Yield: 70 %, m.p. 248 °C; IR (KBr, cm-1): 3380 (OH),
3197 (2N–H str), 3010 (CH-Ar), 2957 (C–H Aliph.), 1710,
123

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Med Chem Res (2015) 24:1514–1526
1
1750, 1690 (C=O), 1583 (N–H bending scissoring); H-
NMR (DMSO-d6, ppm): d = 0.97, 1.02 (2s, 6H, 2CH3),
1.48 (d, 6H, 2CH3), 1.88–2.44 (m, 8H, 4CH2), 3.80, 4.10
(2s, 6H, 2OCH3), 4.42 (s, 1H, CH-pyrane), 5.84 (s, 1H, OH
exchangeable with D2O), 5.20 (s, 2H, N–CH2), 5.42 (s, 1H,
CH cyclohexene), 7.40–7.72 (m, 6H, Ar–H ? CH-pyrane),
8.80 (s, 1H, NH exchangeable with D2O), 10.30 (s, 1H,
NH, NH exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 26.85 (2CH3), 27.50 (2CH3), 56.10, 56.15
(2OCH3), 76.35 (C-1), 31.95 (C-2), 23.15 (C-3), 116.86 (C-
4), 127.18 (C-5), 100.86 (C-6), 154.98 (C-7), 100.20 (C-8),
154.62 (C-9), 140.30 (C-10), 91.32 (C-11), 40.31 (C-12),
115.75 (C-13), 146.56 (C-14), 135.00 (C-15), 119.80 (C-
16), 116.08 (C-17), 142.15 (C-18), 151.05 (C-19), 113.85
(C-20), 158.60 (C-21), 54.50 (C-22), 169.65 (C-23), 162.80
(C-24), 101.80 (C-25), 197.90 (C-26), 53.82 (C-27), 32.67
(C-28), 40.08 (C-29); MS (EI, 70 eV): m/z = 658 [M?, 32]
and at 286 (100, base peak). Anal. calcd. for C35H39N5O8
(657.71): C, 63.91; H, 5.98; N, 10.65. Found: C, 63.86; H,
5.92; N, 10.60.
ethanol (15 ml) containing four drops of trimethylamine
was heated under reflux for 12 h. The reaction mixture was
cooled, and the separated solid product was filtered off,
washed with water, and crystallized from ethanol to give
compound 9. Yield: 65 %, m.p. 278 °C; IR (KBr, cm-1):
3446–3341 (NH2, str), 3020 (C–H Ar.), 2958 (C–H Aliph.),
1750, 1690 (C=O), 1650 (C=C conj), 2184 (CN); 1H-NMR
(DMSO-d6, ppm): d = 0.80, 1.06 (2s, 6H, 2CH3), 1.52 (d,
6H, 2CH3), 2.02–2.45 (m, 8H, 4CH2), 3.90 (s, 3H, OCH3),
4.48 (s, 1H, CH-pyrane), 4.56 (s, 1H, pyridine-H), 5.20 (s,
2H, N-CH2), 6.63 (s, 2H, NH2, exchangeable with D2O),
6.78 (d, 1H, pyrane-H), 7.05–8.10 (m, 11H, Ar–H), 11.20
(s, 1H, NH, exchangeable with D2O); 13C-NMR (DMSO-
d6, ppm): d = 26.95 (2CH3), 27.45 (2 CH3), 56.18 (OCH3),
115.04 (C:N), 76.45 (C-1), 32.00 (C-2), 23.15 (C-3),
116.84 (C-4), 127.14 (C-5), 100.95 (C-6), 155.00 (C-7),
100.10 (C-8), 154.54 (C-9), 140.32 (C-10), 91.32 (C-11),
40.20 (C-12), 115.71 (C-13), 146.51 (C-14), 142.01 (C-15),
129.07 (C-16, C-16‘), 128.14 (C-17, C-17‘), 125.15 (C-18),
158.58 (C-19), 53.95 (C-20), 169.68 (C-21), 81.01 (C-22),
136.70 (C-23), 35.88 (C-24), 111.80 (C-25), 198.78 (C-26),
52.00 (C-27), 31.95 (C-28), 38.52 (C-29), 145.44 (C-30),
147.65 (C-31), 129.18 (C-32, C-32‘), 120.76 (C-33, C-33‘),
145.05 (C-34); MS (EI, 70 eV): m/z = 811 [M?, 14] and at
458 (100, base peak). Anal. calcd. for C44H42N8O8
(810.85): C, 65.17; H, 5.22; N, 13.82. Found: C, 65.14; H,
5.18; N, 13.80.
2-(7-(7-Methoxy-2,2-dimethylchroman-6-yl)-4-oxo-5-
phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N0-(5,5-
dimethyl-3-oxocyclohex-1-enyl)acetohydrazide (8b)
Yield: 75 %, m.p. 253 °C; IR (KBr, cm-1): 3197 (2 N–H
str), 3010 (CH-Ar), 2957 (C–H aliph.), 1710, 1750, 1690
(C=O), 1583 (N–H bending scissoring); 1H-NMR (DMSO-
d6, ppm): d = 0.97, 1.04 (2s, 6H, 2CH3), 1.55 (d, 6H,
2CH3), 1.95–2.50 (m, 8H, 4CH2), 3.90 (s, 3H, OCH3), 4.46
(s, 1H, CH-pyrane), 5.18 (s, 2H, N-CH2), 5.46 (s, 1H, CH
cyclohexene), 7.40–7.72 (m, 8H, Ar–H ? CH-pyrane),
8.80 (s, 1H, NH, exchangeable with D2O), 10.30 (s, 1H,
NH, exchangeable with D2O); 13C-NMR (DMSOd6, ppm):
d = 26.86 (2CH3), 27.44 (2CH3), 56.14 (OCH3), 76.42 (C-
1), 31.94 (C-2), 23.18 (C-3), 116.84 (C-4), 127.20 (C-5),
100.90 (C-6), 154.96 (C-7), 100.15 (C-8), 154.60 (C-9),
140.33 (C-10), 91.36 (C-11), 40.30 (C-12), 115.70 (C-13),
146.50 (C-14), 142.00 (C-15), 129.09 (C-16, C-20), 128.12
(C-17, C-19), 125.15 (C-18), 158.56 (C-21), 53.96 (C-22),
169.72 (C-23), 162.88 (C-24), 101.84 (C-25), 197.85 (C-
26), 53.65 (C-27), 32.12 (C-28), 40.15 (C-29); MS (EI,
70 eV): m/z = 612 [M?, 24] and at 181 (100, base peak).
Anal. calcd. for C34H37N5O6 (611.68): C, 66.76; H, 6.10;
N; 11.45. Found: C, 66.72; H, 6.05; N; 11.40.
N-(1,2,3,4,5,6,7,8-Octahydro-3,3,6,6-tetramethyl-9-(4-
nitrophenyl)-1,8-dioxoacridin-10(9H)-yl)-2-(7-(7-methoxy-
2,2-dimethylchroman-6-yl)-4-oxo-5-phenyl-4H-pyrano[2,3-
d][1,2,3]triazin-3(5H)-yl)acetamide (10)
A mixture of two molar amounts of enaminone 8b and
2-(4-nitrobenzylidene) malononitrile (0.001 mol) was
refluxed in glacial acetic acid (20 ml) for 3 h with few
drops of trimethylamine. The reaction mixture was con-
centrated under vacuum, and the solid formed after cooling
was collected by filtration, dried, and crystallized from
aqueous ethanol to give compound 10. Yield: 60 %, m.p.
288 °C; IR (KBr, cm-1): 3020 (C–H Ar.), 2958 (C–H
aliph), 1750, 1690 (C=O), 1650 (C=C conj). 1H-NMR
(DMSO-d6, ppm): d = 0.82, 1.06 (2s, 6H, 2CH3), 1.52 (d,
6H, 2CH3), 1.98–2.52 (m, 12H, 6CH2), 3.90 (s, 3H, OCH3),
4.42 (s, 1H, CH-pyrane), 4.62 (s, 1H, pyridine-H), 5.16 (s,
2H, N–CH2), 6.64 (d, 1H, pyrane-H), 7.15–8.04 (m, 11H,
Ar–H), 11.20 (s, 1H, NH, exchangeable with D2O); 13C-
NMR (DMSO-d6, ppm): d = 26.88 (2CH3), 27.42 (4CH3),
56.34 (OCH3), 76.44 (C-1), 32.01 (C-2), 23.16 (C-3),
116.85 (C-4), 127.13 (C-5), 100.90 (C-6), 155.02 (C-7),
100.13 (C-8), 154.55 (C-9), 140.34 (C-10), 91.32 (C-11),
40.24 (C-12), 115.70 (C-13), 146.50 (C-14), 142.04 (C-15),
129.08 (C-16, C-16‘), 128.15 (C-17, C-17‘), 125.18 (C-18),
N-(3-Amino-2-cyano-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4-
nitrophenyl)-5-oxoquinolin-1(4H)-yl)-2-(7-(7-methoxy-2,2-
dimethylchroman-6-yl)-4-oxo-5-phenyl-4H-pyrano[2,3-
d][1,2,3]triazin-3(5H)-yl)acetamide (9)
A mixture of equimolar amounts of enaminones 8b and
2-(4-nitrobenzylidene)malononitrile
(0.00 l mol)
in
123

Med Chem Res (2015) 24:1514–1526
1519
158.60 (C-19), 53.92 (C-20), 169.64 (C-21), 145.52 (C-22,
C-34), 38.74 (C-23, C-33), 31.65 (C-24, C-32), 51.32 (C-
25, C-31), 198.82 (C-26, C-30), 111.45 (C-27, C-29), 41.02
(C-28), 148.13 (C-35), 129.76 (C-36, C-36‘), 120.65 (C-37,
C-37‘), 145.30 (C-38); MS (EI, 70 eV): m/z = 867 [M?,
10] and at 436 (100, base peak). Anal. calcd. for
C49H50N6O9 (866.95): C, 67.88; H, 5.81; N; 9.69. Found:
C, 67.82; H, 5.80; N; 9.64.
1H-NMR (DMSO-d6, ppm): d = 1.50 (d, 6H, 2CH3),
2.02–2.48 (m, 4H, 2CH2), 3.86 (s, 1H, OCH3), 4.44 (s, 1H,
CH-pyrane), 5.12 (s, 2H, N–CH2), 6.74 (s, 1H, CH-pyra-
ne), 7.25–8.05 (m, 12H, Ar–H), 9.80, 10.05, 10.45 (3s, 3H,
3NH, exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 27.48 (2CH3), 56.15 (OCH3), 179.45 (C=S),
76.36 (C-1), 31.98 (C-2), 23.16 (C-3), 116.54 (C-4), 127.26
(C-5), 106.05 (C-6), 154.92 (C-7), 100.13 (C-8), 154.65
(C-9), 140.35 (C-10), 92.13 (C-11), 40.34 (C-12), 114.76
(C-13), 147.58 (C-14), 142.31 (C-15), 129.01 (C-16, C-20),
128.31 (C-17, C-19), 125.51 (C-18), 169.81 (C-21), 52.51
(C-22), 169.00 (C-23), 136.92 (C-24), 126.37 (C-25,
C-25‘), 128.76 (C-26, C-26‘), 124.12 (C-27); MS (EI,
70 eV): m/z = 624 [M?, 18] and at 194 (100, base peak).
Anal. calcd. for C33H32N6O5S (624.70): C, 63.45; H, 5.16;
N, 13.45; S, 5.13. Found: C, 63.40; H, 5.10; N, 13.40; S,
5.90.
1-(2-(5-(Aryl)-7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)acetyl)-4-
phenylthiosemicarbazide (11a,b)
A mixture of compound 7a or 7 b (0.012 mol) and phen-
ylisothiocyanate (0.012 mol, 1.62 g) in ethanol (15 ml)
was refluxed for 1 h. After cooling, the obtained precipitate
was filtered off, dried, and crystallized from ethanol to give
compounds 11a or 11b.
(30Z)-2-(5-(Aryl)-7-(7-methoxy-2,2-dimethylchroman-6-
yl)-4-oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N0-
(3,4-diphenylthiazol-2(3H)-ylidene)acetohydrazides
(12a,b)
1-(2-(5-(4-Hydroxy-3-methoxyphenyl)-7-(7-methoxy-2,2-
dimethylchroman-6-yl)-4-oxo-4H-pyrano[2,3-d]
[1,2,3]triazin-3(5H)-yl)acetyl)-4-phenylthiosemicarbazide
(11a)
A mixture of compound 11a or 11b (0.001 mol), phen-
acylbromide (0.233 g, 0.001 mol), and fused sodium ace-
tate (0.238 g, 0.004 mol) in absolute ethanol (10 ml) was
heated under reflux for 10 h with stirring. The reaction
mixture was cooled and diluted with water, and the sepa-
rated product was filtered off, dried, and crystallized from
ethanol to give compounds 12a or 12b.
Yield: 76 %, m.p. 261 °C; IR (KBr, cm-1): 3380 (OH),
3331, 3227, 3219 (N–H str), 3050 (CH-Ar.), 2931 (C–H
aliph), 1740, 1684 (C=O), 1570 (N–H bending scissoring),
1
1300 (C=S). H-NMR (DMSO-d6, ppm): d = 1.52 (d, 6H,
2CH3), 1.94–2.45 (m, 4H, 2CH2), 3.80, 4.10 (2s, 6H,
2OCH3), 4.45 (s, 1H, CH-pyrane), 5.12 (s, 2H, N–CH2),
5.70 (s, 1H, OH exchangeable with D2O), 6.65 (d, 1H, CH-
pyrane), 7.72–8.00 (m, 10H, Ar–H), 9.76, 10.01, 10.50 (3s,
3H, 3NH, exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 27.12 (2CH3), 56.25, 56.42 (2OCH3), 179.48
(C=S), 76.18 (C-1), 32.10 (C-2), 23.24 (C-3), 117.63 (C-4),
127.30 (C-5), 101.08 (C-6), 155.00 (C-7), 100.12 (C-8),
154.50 (C-9), 140.30 (C-10), 92.00 (C-11), 40.32 (C-12),
115.07 (C-13), 146.94 (C-14), 135.43 (C-15), 121.96 (C-
16), 116.08 (C-17), 142.12 (C-18), 151.18 (C-19), 114.26
(C-20), 159.02 (C-21), 48.55 (C-22), 169.10 (C-23), 136.96
(C-24), 126.36 (C-25, C-250), 128.75 (C-26, C-260), 124.10
(C-27); MS (EI, 70 eV): m/z = 670 [M?, 26] and at 194
(100, base peak). Anal. calcd. for C34H34N6O7S (670.73):
C, 60.85; H, 5.11; N, 12.53, S, 4.78; Found: C, 60.80; H,
5.06; N, 12.48; S, 4.73.
(30Z)-2-(5-(4-Hydroxy-3-methoxyphenyl)-7-(7-methoxy-
2,2-dimethylchroman-6-yl)-4-oxo-4H-pyrano [2,3-d]
[1,2,3]triazin-3(5H)-yl)-N0-(3,4-diphenylthiazol-2(3H)-
ylidene)acetohydrazide (12a)
Yield: 72 %, m.p. 283 °C; IR (KBr, cm-1): 3380 (OH),
3242 (N–H str), 1715, 1750, 1680 (C=O), 3050 (CH Ar.);
1H-NMR (DMSO-d6, ppm): d = 1.54 (d, 6H, 2CH3),
1.96–2.44 (m, 4H, 2CH2), 3.78, 4.08 (s, 6H, 2OCH3), 4.46
(s, 1H, CH-pyrane), 5.13 (s, 2H, N–CH2), 5.76 (s, 1H, OH
exchangeable with D2O), 6.52 (s, lH, CH thiazole),
6.72–7.55 (m, 16H, Ar–H ? CH-pyrane), 10.50 (s, lH, NH
exchangeable with D2O); 13C-NMR (DMSOd6, ppm):
d = 27.24 (2CH3), 56.18, 56.28 (2OCH3), 76.34 (C-1),
31.93 (C-2), 23.22 (C-3), 116.54 (C-4), 127.28 (C-5),
101.06 (C-6), 155.08 (C-7), 99.98 (C-8), 154.60 (C-9),
140.30 (C-10), 91.44 (C-11), 40.42 (C-12), 114.74 (C-13),
147.56 (C-14), 135.36 (C-15), 121.86 (C-16), 116.12 (C-
17), 142.24 (C-18), 151.16 (C-19), 114.24 (C-20), 158.75
(C-21), 48.56 (C-22), 168.68 (C-23), 156.70 (C-24), 148.05
(C-25), 106.65 (C-26), 141.60 (C-27), 116.02 (C-28,
C-28‘), 129.52 (C-29, C-29‘), 118.95 (C-30), 135.01
1-(2-(7-(7-Methoxy-2,2-dimethylchroman-6-yl)-4-oxo-5-
phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)acetyl)-4-
phenylthiosemicarbazide (11b)
Yield: 70 %, m.p. 266 °C; IR (KBr, cm-1): 3331, 3227,
3219 (N–H str), 3050 (CH-Ar.), 2931 (C–H Aliph.), 1740,
1684 (C=O), 1570 (N–H bending scissoring), 1300 (C=S);
123

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Med Chem Res (2015) 24:1514–1526
(C-31), 126.68 (C-32, C-32‘), 128.78 (C-33, C-33‘), 127.82
(C-34); MS (EI, 70 eV): m/z = 771 [M?, 22] and at 266
(100, base peak). Anal. calcd. for C42H38N6O7S (770.85):
C, 65.44; H, 4.97; N, 10.90; S, 4.16. Found: C, 65.40; H,
4.92; N, 10.86; S, 4.12.
2OCH3), 4.42 (s, 1H, CH-pyrane), 5.18 (s, 2H, N–CH2),
5.74 (s, 1H, OH exchangeable with D2O), 6.56 (d, 2H, 2CH
pyrole), 6.68–7.72 (m, 6H, Ar–H ? CH-pyrane), 11.14 (s,
1H, NH exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 12.54 (2CH3), 27.32 (2CH3), 56.13, 56.16
(2OCH3), 76.42 (C-1), 31.90 (C-2), 23.12 (C-3), 116.82 (C-
4), 127.19 (C-5), 100.85 (C-6), 154.95 (C-7), 100.23 (C-8),
154.63 (C-9), 140.29 (C-10), 91.35 (C-11), 40.34 (C-12),
115.71 (C-13), 146.51 (C-14), 135.01 (C-15), 119.81 (C-
16), 116.08 (C-17), 142.15 (C-18), 151.06 (C-19), 113.86
(C-20), 158.62 (C-21), 54.51 (C-22), 170.65 (C-23), 132.80
(C-24, C-24‘), 105.80 (C-25, C-25‘); MS (EI, 70 eV): m/
z = 614 [M?, 12] and at 138 (100, base peak). Anal. calcd.
for C33H35N5O7 (613.66): C, 64.59, H, 5.75; N, 11.41.
Found: C, 64.56; H, 5.71; N, 11.36.
(30Z)-2-(7-(7-Methoxy-2,2-dimethylchroman-6-yl)-4-oxo-
5-phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N0-
(3,4-diphenylthiazol-2(3H)-ylidene)acetohydrazide (12b)
Yield: 75 %, m.p. 270 °C; IR (KBr, cm-1): 3242 (N–H
str), 1715, 1750, 1680 (C=O), 3050 (CH Ar); H-NMR
1
(DMSO-d6, ppm): d = 1.49 (d, 6H, 2CH3), 2.04–2.46 (m,
4H, 2CH2), 3.86 (s, 3H, OCH3), 4.48 (s, 1H, CH-pyrane),
5.16 (s, 2H, N–CH2), 6.45 (s, lH, CH thiazole), 6.78–7.58
(m, 18H, Ar–H ? CH-pyrane), 10.46 (s, lH, NH,
exchangeable with D2O); 13C-NMR (DMSOd6, ppm):
d = 27.52 (2CH3), 56.18 (OCH3), 76.38 (C-1), 31.94 (C-
2), 23.18 (C-3), 116.50 (C-4), 127.25 (C-5), 100.96 (C-6),
154.92 (C-7), 100.16 (C-8), 154.65 (C-9), 140.30 (C-10),
91.33 (C-11), 40.35 (C-12), 114.75 (C-13), 147.56 (C-14),
142.32 (C-15), 128.86 (C-16, C-20), 128.05 (C-17, C-19),
125.42 (C-18), 158.82 (C-21), 48.54 (C-22), 168.65 (C-23),
156.68 (C-24), 148.00 (C-25), 106.60 (C-26), 141.55 (C-
27), 116.00 (C-28, C-28‘), 129.50 (C-29, C-29‘), 118.92
(C-30), 135.00 (C-31), 126.64 (C-32, C-32‘), 128.75 (C-33,
C-33‘), 127.85 (C-34); MS (EI, 70 eV): m/z = 725 [M?,
28] and at 268 (100, base peak). Anal. calcd. for
C41H36N6O5S (724.82): C, 67.90; H, 5.05; N, 11.59; S,
4.42. Found: C, 67.85; H, 5.00; N, 11.54; S, 4.38.
2-(7-(7-Methoxy-2,2-dimethylchroman-6-yl)-4-oxo-5-
phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N-(2,5-
dimethyl-1H-pyrrol-1-yl)acetamide (13b)
Yield: 80 %, m.p. 263 °C; IR (KBr, cm-1): 3284 (N–H
str), 3067 (C–H Ar), 2978 (C–H aliph.), 1750, 1681 (C=O),
1582 (N–H bending scissoring); 1H-NMR (DMSO-d6,
ppm): d = 1.50 (d, 6H, 2CH3), 1.94 (s, 6H, 2CH3),
2.05–2.46 (m, 4H, 2CH2), 3.86 (s, 3H, OCH3), 4.48 (s, 1H,
CH-pyrane), 5.10 (s, 2H, N-CH2), 6.58 (d, 2H, 2CH py-
role), 6.64–7.78 (m, 8H, Ar–H ? CH-pyrane), 10.50 (s,
1H, NH exchangeable with D2O); 13C-NMR (DMSOd6,
ppm): d = 13.08 (2CH3), 27.44 (2CH3), 56.14 (OCH3),
76.44 (C-1), 31.95 (C-2), 23.19 (C-3), 116.84 (C-4), 127.20
(C-5), 100.90 (C-6), 154.96 (C-7), 99.96 (C-8), 154.61 (C-
9), 140.33 (C-10), 91.35 (C-11), 40.31 (C-12), 115.71 (C-
13), 146.51 (C-14), 142.01 (C-15), 129.05 (C-16, C-20),
128.15 (C-17, C-19), 125.17 (C-18), 158.59 (C-21), 53.93
(C-22), 170.68 (C-23), 132.77 (C-24, C-24‘), 106.09 (C-25,
C-25‘); MS (EI, 70 eV): m/z = 568 [M?, 16] and at 137
(100, base peak). Anal. calcd. for C32H33N5O5 (567.63): C,
67.71, H, 5.86; N, 12.34. Found: C, 67.65; H, 5.82; N;
12.28.
2-(5-(Aryl)-7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N-(2,5-
dimethyl-1H-pyrrol-1-yl)acetamide (13a,b)
A mixture of hydrazide 7a or 7b (0.002 mol) and 2,5-
hexanedione (0.25 ml, 0.002 mol) in glacial acetic acid
(5 ml) was stirred at room temperature overnight. The
reaction mixture was poured onto water, and the separated
solid was filtered off, dried, and crystallized from ethanol
to give compounds 13a,b, respectively.
2-(5-(Aryl)-7-(7-methoxy-2,2-dimethylchroman-6-yl)-4-
oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N-(1,3-
dioxoisoindolin-2-yl)acetamide (14a,b)
2-(5-(4-Hydroxy-3-methoxyphenyl)-7-(7-methoxy-2,2-
dimethylchroman-6-yl)-4-oxo-4H-pyrano[2,3-d]
[1,2,3]triazin-3(5H)-yl)-N-(2,5-dimethyl-1H-pyrrol-1-
yl)acetamide (13a)
A mixture of hydrazides 7a,b (0.002 mol) and phthalic
anhydride (0.296 g, 0.002 mol) in absolute ethanol (10 ml)
with a few drops of glacial acetic acid was refluxed for 6 h.
The reaction mixture was concentrated under reduced
pressure, and the obtained solid was filtered off, dried, and
crystallized from ethanol to give compounds 14a,b,
respectively.
Yield: 82 %, m.p. 268 °C; IR (KBr, cm-1): 3380 (OH),
3284 (N–H str), 3067 (C–H Ar), 2978 (C–H aliph.), 1750,
1681 (C=O), 1582 (N–H bending scissoring); 1H-NMR
(DMSO-d6, ppm): d = 1.48 (d, 6H, 2CH3), 1.95 (s, 6H,
2CH3), 2.08–2.42 (m, 4H, 2CH2), 3.80, 4.10 (2s, 6H,
123

Med Chem Res (2015) 24:1514–1526
1521
2-(5-(4-Hydroxy-3-methoxyphenyl)-7-(7-methoxy-2,2-
dimethylchroman-6-yl)-4-oxo-4H-pyrano[2,3-d]
[1,2,3]triazin-3(5H)-yl)-N-(1,3-dioxoisoindolin-2-
yl)acetamide (14a)
Anticancer activity
Measurement of cytotoxicity by sulforhodamine B
(SRB) assay
Yield: 75 %, m.p. 297 °C; IR (KBr, cm-1): 3380 (OH),
3197 (N–H str), 3093 (C–H Ar), 1750, 1727, 1694, 1672
(C=O), 1574 (N–H bending scissoring); 1H-NMR
(DMSO-d6, ppm): d = 1.54 (d, 6H, 2CH3), 1.99–2.42 (m,
4H, 2CH2), 3.80, 4.10 (2s, 6H, 2OCH3), 4.45 (s, 1H, CH-
pyrane), 5.20 (s, 2H, N–CH2), 5.72 (s, 1H, OH
exchangeable with D2O), 6.64 (d, 1H, CH-pyrane),
7.05–8.30 (m, 9H, Ar–H), 11.20 (s, 1H, NH exchangeable
with D2O); 13C-NMR (DMSOd6, ppm): d = 27.34
(2CH3), 56.28, 56.30 (2OCH3), 76.35 (C-1), 31.95 (C-2),
23.23 (C-3), 116.54 (C-4), 127.25 (C-5), 101.08 (C-6),
155.04 (C-7), 99.92 (C-8), 154.61 (C-9), 140.31 (C-10),
91.46 (C-11), 40.40 (C-12), 114.73 (C-13), 147.59 (C-14),
135.39 (C-15), 121.85 (C-16), 116.13 (C-17), 142.22 (C-
18), 151.15 (C-19), 114.26 (C-20), 158.76 (C-21), 48.55
(C-22), 168.65 (C-23), 164.56 (C-24, C-24‘), 131.75 (C-
25, C-25‘), 127.56 (C-26, C-26‘), 123.12 (C-27, C-270);
MS (EI, 70 eV): m/z = 666 [M?, 36] and at 190 (100,
base peak). Anal. calcd. for C35H31N5O9 (665.64): C,
63.15; H, 4.69; N, 10.52. Found: C, 63.10; H, 4.65; N,
10.46.
Compounds were subjected to a screening system for
evaluation of their antitumor activity against liver HEPG2
cancer cell lines in comparison to the known anticancer
drugs: 5-FU and DOX. Potential cytotoxicity of the
selected derivatives was tested using the method of Skehan
et al. (1990) as follows: Cells were plated in 96-multiwell
plate (104 cells/well) for 24 h before treatment with the
compound(s) to allow attachment of cells to the wall of the
plate. Different concentrations of the compounds under test
(0, 1, 2.5, 5, 10 lg/mL) were added to the cell monolayer.
Triplicate wells were prepared for each individual dose.
Monolayer cells were incubated with the compound(s) for
48 h at 37 °C and in an atmosphere of 5 % CO2. Cultures
were then fixed with trichloroacetic acid and stained for
30 min with 0.4 % (w/v) sulforhodamine B (SRB) dis-
solved in 1 % acetic acid. Unbound dye was removed by
four washes with 1 % acetic acid, and protein-bound dye
was extracted with 10 mM-unbuffered Tris base
[tris(hydroxymethyl)amino-methane] for determination of
optical density in a computer-interfaced, 96-well microtiter
plate reader. The SRB assay results were linear with the
number of cells and with values for cellular protein mea-
sured by both the Lowry and Bradford assays at densities
ranging from sparse subconfluence to multilayered supra-
confluence. The signal-to-noise ratio at 564 nm was
approximately 1.5 with 1,000 cells/well. The relation
between surviving fraction and drug concentration was
plotted to get the survival curve of both cancer cell lines
after the specified compound.
2-(7-(7-Methoxy-2,2-dimethylchroman-6-yl)-4-oxo-5-
phenyl-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N-(1,3-
dioxoisoindolin-2-yl)acetamide (14b)
Yield: 78 %, m.p. 307 °C; IR (KBr, cm-1): 3197 (N–H
str), 3093 (C–H Ar), 1750, 1727, 1694, 1672 (C=O), 1574
(N–H bending scissoring). 1H-NMR (DMSO-d6, ppm):
d = 1.54 (d, 6H, 2CH3), 2.00–2.48 (m, 4H, 2CH2), 3.90
(s, 3H, OCH3), 4.42 (s, 1H, CH-pyrane), 5.14 (s, 2H,
N-CH2), 6.68 (d, 1H, CH-pyrane), 7.15–8.32 (m, 11H,
Ar–H), 11.18 (s, 1H, NH exchangeable with D2O); 13C-
NMR (DMSOd6, ppm): d = 27.48 (2 CH3), 56.18
(OCH3), 76.40 (C-1), 31.95 (C-2), 23.18 (C-3), 116.50
(C-4), 127.25 (C-5), 100.96 (C-6), 154.92 (C-7), 100.18
(C-8), 154.65 (C-9), 140.36 (C-10), 91.33 (C-11), 40.36
(C-12), 114.75 (C-13), 147.56 (C-14), 142.30 (C-15),
128.85 (C-16, C-20), 128.06 (C-17, C-19), 125.45 (C-18),
158.81 (C-21), 48.55 (C-22), 168.61 (C-23), 164.55 (C-
24, C-24‘), 131.72 (C-25, C-25‘), 127.50 (C-26, C-26‘),
123.12 (C-27, C-27‘); MS (EI, 70 eV): m/z = 620 [M?,
24] and at 190 (100, base peak). Anal. calcd. for
C34H29N5O7 (619.62): C, 65.91; H, 4.72; N, 11.30.
Found: C, 65.88; H, 4.70; N, 11.26.
Result and discussion
Chemistry
The newly substituted pyrano[1,2,3]triazine derivatives were
synthesized by using 1-(2,4-dihydroxyphenyl) ethanone1 and
1-(7-hydroxy-2,2-dimethylchroman-6-yl)ethanone
2
as
starting materials, which were synthesized by reported
method(Kumar etal., 2011). The derivative 2 was methylated
using methyl iodide in acetone to give 1-(7-methoxy-2,2-
dimethylchroman-6-yl)ethanone (3), which was treated with
aromatic aldehydes in the presence of piperidine to give the
corresponding acryloyl derivatives (4a–c). Compounds
4a,b were reacted with ethyl cyanoacetate in pyridine and
123

1522
Med Chem Res (2015) 24:1514–1526
Scheme 1 Synthetic route to
compounds 3–7
O
CH3COOH/ZnCl2
145oC
CH3
HO
OH
HO
OH
1
O
O
3
5
8
6
7
4
9
2
CH3I/CH3COCH3
CH3
CH3
CH3
1
O
O
O
OH
3
2
X
X
ArCHO
pipredine
16
18
15
Y
Y
15
17
17
16
19
20
14
18
13
12
COOEt
NH2
NCCH2COOEt
11
10
11
10
12
O
13
3
5
5
8
3
4
9
6
7
4
6
2
2
14
O
1
7
1
CH3
CH3
O
O
O
9
O
8
X
4a-c
5a,b
X
Y
18
Y
NaNO2/HCl
17
16
19
20
O
COOEt
COOEt
15
12
22
13
H2NCH2COOEt
11
10
N
N
21
N
O
N
N Cl
5
3
6
4
2
1
O
14
CH3
O
O
7
CH3
[A]
O
O
9
X
8
6a,b
18
Y
19
17
16
20
O
CONHNH2
22
15
12
NH2NH2
13
14
11
10
21
N
N
N
5
3
6
4
2
1
O
7
CH3
O
O
9
8
7a,b
a, X = OH, Y = OCH3; b, X = Y = H; c, X = H, Y = OCH3
gave the corresponding ethyl 2-amino-4-(aryl)-6-(7-meth-
oxy-2,2-dimethylchroman-6-yl)-4H-pyran-3-carboxylates
(5a,b). The diazotization of compounds 5a,b with sodium
nitrite and hydrochloric acid gives unseparated intermediate
[A], which was converted to the corresponding esters 6a,b by
reacting with ethyl glycinate hydrochloride. Treatment of
ester derivatives 6a,b with hydrazine hydrate gives the cor-
responding acid hydrazide derivatives 7a,b (Scheme 1).
The reaction of compounds 7a,b with 5,5-dimethyl-1,3-
cyclohexanedione afforded the corresponding pyrano[2,3-d]
1,2,3]triazin-3(5H)-yl)-N’-(5,5-dimethyl-3-oxocyclohex-
1-enyl)acetohydrazide derivatives 8a,b, respectively.
Cyclization of 8b with 2-(4-nitrobenzylidene)malono-
nitrile (Yao et al., 2008) in ethanol in the presence of few
drops of TMA afforded hexahydroquinoline derivative 9.
However, the acridindione 10 was synthesized by heating
123

Med Chem Res (2015) 24:1514–1526
1523
7a,b
O
X
18
OH
Y
19
O
17
16
26
20
27
25
24
O
21
N
15
12
H
22
23
O
N
13
11
10
N
N
N
28
29
H
3
5
8
4
9
6
2
1
O
14
a, X = OH, Y = OCH3;
b, X = Y = H
CH3
8a,b
O
O
7
NC
CN
O2N
EtOH/TMA
AcOH/TMA
8b
NO2
8b
NO2
34
38
37`
36`
33`
32`
33
37
36
32
O
O
O
31
24
35
27
18
18
26
26`
27`
22`
H2N
25
30
27
25`
26
29
25
17
16
17`
16`
28
17
16
17`
16`
23
23`
23
20
28
22
O
NC
N
15
12
O
N
22
24`
15
12
24
20
21
21
13
NH
NH
13
11
10
19
N
11
10
19
N
N
N
N
3
5
8
3
5
8
4
9
6
O
N
O
4
9
6
2
1
2
1
O
O
14
14
CH3
CH3
10
9
7
O
O
O
O
7
Scheme 2 Synthetic route to compounds 8–10
Anticancer activity
of 8b with 2-(4-nitrobenzylidene)malono-nitrile in acetic
acid containing few drops of TMA (Scheme 2).
The selected compounds showed reasonable antitumor
activity in comparison to 5-FU and DOX. Cytotoxic drugs
remain the main stay of cancer chemotherapy and are being
administered with novel ways of therapy such as inhibitors
of signals (Guilbaud et al., 2001). It is therefore important
to discover novel cytotoxic agents with spectra of activity
and toxicity that differ from those current agents (El-
Nakkady et al., 2012). It is well known that chemotherapy
aims to destroy the cancer cells with various types of
chemicals (Pautus et al., 2006). The substances used are
supposed to target mainly the cancer cells and doses are
calculated to minimize the collateral damage to surrounding
tissues, which nevertheless occurs (Hayakawa et al., 2004).
Treatment of compounds 7a,b with phenyl isothiocyanate
in ethanol gave the corresponding thiosemicarbazide deriva-
tives 11a,b, respectively, which were cyclized with phenacyl
bromide in the present of sodium acetate to give the corre-
sponding 1,3-thiazole derivatives 12a,b, respectively. Cycli-
zation of compounds 7a,b with 2,5-hexanedione in acetic acid
affords 2-(5-(aryl)-7-(7-methoxy-2,2-dimethylchroman-6-
yl)-4-oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N-(2,5-
dimethyl-1H-pyrrol-1-yl)acetamide 13a,b. Also, the reac-
tion of compounds 7a,b with phthalic anhydride in acetic
acid gave 2-(5-(aryl)-7-(7-methoxy-2,2-dimethylchroman-
6-yl)-4-oxo-4H-pyrano[2,3-d][1,2,3]triazin-3(5H)-yl)-N-
(1,3-dioxoisoindolin-2-yl)acetamide 14a,b (Scheme 3).
123

1524
Med Chem Res (2015) 24:1514–1526
X
18
19
Y
17
16
20
O
21
N
15
12
H
22
29
28
PhCOCH2Br/
AcONa/EtOH
13
23
O
N
11
10
N
N
N
30
29
5
8
3
27
24
6
4
`
2
1
N
14
O
S
X
28`
32
CH3
18
Y
31
19
25
26
O
7
O
9
17
16
12a,b
33
34
32`
20
O
15
12
33`
H
22
13
23 N
11
10
N
N
NH
21
N
5
8
3
6
O
4
2
1
O
14
S
NH
24
CH3
25`
25
26
O
O
7
9
11a,b
26`
27
X
18
19
Y
17
16
20
PhNCS
EtOH
O
15
12
CH3
O
O
H
22
24
13
14
23
O
N
11
10
21
N
N
N
N
25
5
3
27
6
4
9
7a,b
7a,b
2
1
O
AcOH/r.t
H3C
26
CH3
O
7
O
8
13a,b
X
18
19
Y
O
17
16
O
O
20
O
21
N
15
12
O
H
22
24
13
14
23
N
11
10
N
N
N
25
26
5
8
3
24`
6
4
9
O
AcOH
2
O
27
O
25`
261
1
CH3
27`
7
O
O
14a,b
a, X = OH, Y = H; b, X = Y = H
Scheme 3 Synthetic route to compounds 11–14
This kind of treatment increases the entropy of the
organism, suppresses the immune system, and forms a
toxic cell environment which may destroy surrounding
healthy cells. It is important to use minimum effective
doses in a hope to minimize the side effects of chemo-
therapeutic drugs.
growth inhibition activity on the tested cell line between 1
and 10 lg/mL concentrations in comparison to the known
anticancer drugs: 5-FU and DOX. The results in Table 1
indicated the cytotoxic activity of the newly synthesized
derivatives (compounds 3, 4a, 4b, 4c, 5, 6, 7, 8a,b, 9, 10
11, 12, 13, 14a,b) on liver HEPG2 cancer cell lines in
comparison to the traditional anticancer drugs: 5-FU and
DOX. It can be deduced from the results that compounds
Preliminary screening of the selected derivatives
showed that compounds exhibited a moderate to strong
123

Med Chem Res (2015) 24:1514–1526
1525
anticancer activity. Novel derivatives of pyrano[1,2,3]tri-
zine possessing a broader spectrum of antitumor activity
and fewer toxic side effects than 5-FU and DOX have been
sought. The antitumor activities of such compounds were
assessed against HEPG2 cancer cell line in comparison to
the traditional anticancer drugs: 5-FU and DOX.
Table 1 Cytotoxicity of the prepared compounds against liver
HEPG2 cancer cell lines
Comp. no.
IC50 [lM]
5-Fluorouracil
0.0380
0.00620
0.0365
0.0060
0.0075
0.0068
0.0105
0.0112
0.0122
0.0135
0.0272
0.0280
0.0252
0.0270
0.0178
0.0239
0.0182
0.0195
0.0285
0.0295
0.0442
0.0480
0.0297
0.0350
Doxorubicin
3
4a
Structure–activity relationship (SAR)
4b
4c
It appeared from analysis of the structure of the most
strongly active anticancer compounds that compounds 4a–
c have a strong anticancer activities due to the conjugation
of enone with aromatic moities; 4a is the most active due to
the presence of OH in para-position (it may be anti-oxi-
dant) then 4c due to the presence of OCH3 group. Com-
pounds 5a,b are active due to the presence of ester
(COOEt) and amino (NH2) groups, and compounds
6a,b are active due to the presence of ester group, the
activity of 9 due to the presence of amino group and 11b
has C=S and NH-groups. Compound 10 is less active than
9 due to the cyclization of the CN and NH2 group in 9 and
compound 7 is less reactive than 6 due to the changing of
the ester group to aceto-hydrazide. Also compound 12 is
less active than 11 due to the formation of thiazole ring.
And also compound 13 is weak due to the formation of
pyrrole ring. Additionally, the difference in activities
between the compounds which were due to the indicated
substituents in the molecule.
5a
5b
6a
6b
7a
7b
8a
8b
9
10
11a
11b
12a
12b
13a
13b
14a
14b
4a–c, 5a,b, 6a,b, 9, and 11a,b were the most active and
induced a reasonable growth inhibition, in a dose-depen-
dent manner against HEPG2 when compared to 5-FU and
DOX (IC50 equals 0.0060, 0.0075, 0.0068, 0.0105, 0.0112,
0.0122, 0.0135, 0.0178, 0.0182, and 0.0195 lM, while for
5-FU and DOX were 0.0380 and 0.00620 lM). Also
compounds 11b, 8a,b, 7a,b, 12a,b, 14a,b, and 3 were the
moderately active and induced a moderate growth inhibi-
tion, in a dose-dependent manner against HEPG2 when
compared to 5-FU and DOX (IC50 equals 0.0239, 0.0252,
0.0270, 0.0272, 0.0280, 0.0285, 0.0295, 0.0297, 0.0350,
and 0.0365 lM, while for 5-FU and DOX were 0.0380 and
0.00620 lM). Also compounds 13a,b were the weakly
active and induced a little growth inhibition, in a dose-
dependent manner against HEPG2 when compared to 5-FU
and DOX (IC50 equals 0.0442 and 0.0480 lM, while for
5-FU and DOX were 0.0380 and 0.00620 lM). From these
results, it appeared that compounds 4a–c [5a,b [
6a,b [ 9 [ 11a,b have a strong anticancer activity. Also,
compounds 10 > 8a,b > 7a,b > 12a,b > 14a,b > 3 have a
moderate anticancer activity, whereas 13a,b has weak
Conclusion
A series of the newly substituted pyrano[1,2,3]triazine
derivatives 3–14 were synthesized using compounds 1 and
2 as starting materials. Some of the synthesized compounds
were screened as anticancer agents. All the selected pyr-
ano[1,2,3]trizine derivatives were soluble in DMSO at
concentrations high enough to allow cell experiments, and
the in vitro biological activity of these compounds was
evaluated by their growth inhibitory potency in liver
HEPG2 cancer cell lines. The cytotoxic potency of com-
pounds 3–14 was studied in comparison to the known
anticancer drugs 5-FU and DOX. The derivatives 4a–c,
5a,b, 6a,b, 9, and 11a,b have a strong cytotoxic activity.
Also, compounds 10, 8a,b, 7a,b, 12a,b, 14a,b [ 3 have a
moderate cytotoxic activity, whereas compounds
13a,b have weak cytotoxic activity.
Acknowledgments The Authors extend their appreciation to the
Deanship of Scientific Research at King Saud University for funding
the work through the research group Project No. RGP-VPP-0172.
123

1526
Med Chem Res (2015) 24:1514–1526
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Kumar SK, Kanth AV, Reddy KT, Omprakash G (2011) Synthesis
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