Synthesis of novel 1,2,3-triazole/isoxazole functionalized 2H-Chromene derivatives and their cytotoxic activity

Article abstract of DOI:10.1016/j.bmcl.2014.02.069

A series of novel 2-(1,2,3-triazolylmethoxy) 5a-q and isoxazole tagged 6a-g 2H-Chromene derivatives were prepared starting from salicylaldehyde and ethyl-4,4,4-trifluoroacetoacetate via cyclization to form ethyl 2-hydroxy-2-(trifluoromethyl)-2H-Chromene-3-carboxylate 3. Compound 3 on reaction with propargyl bromide resulted compound 4 and was independently reacted with aryl/alkyl azides and aryl aldoximes obtained 2-(1,2,3- triazolylmethoxy) and isoxazole tagged 2H-Chromene derivatives 5a-q, 6a-i, respectively. Compounds 6 were further hydrolysed to acid derivatives 7a-g. All the products 5a-q, 6a-i, 7a-g were screened for cytotoxic activity against four human cancer cell lines and among all the compounds, 5f, 5g, 5l, 5q showed promising activity at <20 μM concentration.

Full text of DOI:10.1016/j.bmcl.2014.02.069

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1661–1663
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel 1,2,3-triazole/isoxazole functionalized
2H-Chromene derivatives and their cytotoxic activity
K. Ratnakar Reddy a, P. Sambasiva Rao a, G. Jitender Dev a, Y. Poornachandra b, C. Ganesh Kumar b,
P. Shanthan Rao a, B. Narsaiah a,
⇑
a Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
b Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2-(1,2,3-triazolylmethoxy) 5a–q and isoxazole tagged 6a–g 2H-Chromene derivatives
were prepared starting from salicylaldehyde and ethyl-4,4,4-trifluoroacetoacetate via cyclization to form
ethyl 2-hydroxy-2-(trifluoromethyl)-2H-Chromene-3-carboxylate 3. Compound 3 on reaction with prop-
argyl bromide resulted compound 4 and was independently reacted with aryl/alkyl azides and aryl aldox-
imes obtained 2-(1,2,3-triazolylmethoxy) and isoxazole tagged 2H-Chromene derivatives 5a–q, 6a–i,
respectively. Compounds 6 were further hydrolysed to acid derivatives 7a–g. All the products 5a–q,
6a–i, 7a–g were screened for cytotoxic activity against four human cancer cell lines and among all the
Received 23 December 2013
Revised 19 February 2014
Accepted 25 February 2014
Available online 6 March 2014
Keywords:
Salicylaldehyde
2H-Chromene
Propargylation
1,2,3-Triazole
Isoxazole
compounds, 5f, 5g, 5l, 5q showed promising activity at <20
l
M concentration.
Ó 2014 Elsevier Ltd. All rights reserved.
Anticancer activity
2H-Chromene derivatives are an important class of heterocyclic
compounds1 used as substrates for the synthesis of antitumor,2,3
antimicrobial,4 fungicidal,5 insecticidal6 and anti HIV agents.7 The
2H-Chromene nucleus also present in health promoting agents like
antioxidants,8 polyphenols,9 and is a privileged scaffold found in
many biologically active molecules,10–12 including natural
products.13,14 Several reports are available on synthesis of
Chromene derivatives and efficient strategies are based on
salicylaldehyde.15–19 Recent reports on synthesis of 2H-Chromene
derivatives are mainly from salicylaldehyde and ethyl-4,4,4-triflu-
medicinal chemistry.23–28 In order to construct 1,2,3-triazole and
isoxazole ring systems, several synthetic methods have been
developed.29–32 Based on the importance of 2H-Chromenes,
1,2,3-triazole and isoxazole, it was envisaged that hybrid
molecules would display promising activity.
In continuation of our efforts on the synthesis of potential
molecules,33–35 we have prepared a series of novel 1,2,3-triazole
and isoxazole functionalized chromene derivatives. Thus, the
salicylaldehyde
1 on reaction with ethyl-4,4,4-trifluoroaceto
acetate 2 in dichloromethane using piperidine as a base yielded
2-hydroxy-2-trifluoromethyl chromene-3-carboxylate ethyl ester 3.
Compound 3 was reacted with propargyl bromide in acetone using
K2CO3 as a base and obtained O-propargylated chromene deriva-
tive 4 which was further reacted with diverse substituted azides
oroacetoacetate,20
a
,b-unsaturated cyclic ketones,21 1H-indene-
1,3(2H)dione.22 Similarly, 1,2,3-triazoles and isoxazoles due to
their unique chemical and structural properties received much
attention over the past decade and found wide application in
CO Et
2
CO Et
2
CHO
ii
O
O
i
+
O
OH
O
O
F C
3
OEt
OH
CF
CF
3
3
4
1
2
3
Scheme 1. Preparation of ethyl-2-(prop-2-ynyloxy)-2(trifluoromethyl)-2H-Chromene-3-carboxylate (4). Reagents and conditions: (i) piperidine/ethanol, reflux, 5 h. (ii)
Propargyl bromide (1.0 equiv)/acetone, K2CO3 (1.0 equiv), KI (5 mol %), 4 h, reflux.
⇑
Corresponding author. Tel.: +91 40 27193630; fax: +91 40 27160387.
E-mail address: narsaiah@iict.res.in (B. Narsaiah).
http://dx.doi.org/10.1016/j.bmcl.2014.02.069
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1662
K. Ratnakar Reddy et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1661–1663
like aryl azides or alkyl amide azides37,38 in THF using CuI as cata-
lyst under Sharpless conditions yielded 5a–i and 5j–q, respectively,
Table 2
Cytotoxic activity of compounds 5a–q, 6a–i and 7a–ga
Compound
IC50 valuesb (in
lM)
in high yield. Similarly, compound
4 on reaction with aryl
A549
DU145
HeLa
MCF7
5a
5b
19.7 0.11
—
30.2 0.21
—
25.1 0.32
—
26.7 0.22
—
CO Et
2
iii
5c
—
—
—
—
5d
5e
5f
5g
5h
5i
26.3 0.22
—
7.3 0.14
11.9 0.16
—
—
21.5 0.28
—
8.9 0.09
13.2 0.11
—
22.7 0.18
—
8.4 0.20
15.6 0.14
—
—
25.3 0.16
—
9.1 0.15
16.2 0.21
—
—
R
O
O
N
N
CF
3
N
5a-i
CO Et
CO Et
2
2
—
iii
5j
5k
5l
5m
54.3 0.36
29.4 0.24
12.8 0.18
—
—
67.4 0.48
31.9 0.28
12.3 0.12
—
—
H
N
O
O
O
O
O
32.7 0.36
10.1 0.42
—
28.1 0.16
11.6 0.23
—
N
N
CF
CF
5j-3q
3
N
4
R
O
5n
5o
5p
5q
6a
6b
6c
6d
50.1 0.48
—
22.3 0.11
9.9 0.14
35.5 0.24
48.6 0.32
—
—
33.9 0.37
—
49.9 0.34
—
26.1 0.31
11.4 0.22
42.3 0.21
21.4 0.11
—
—
42.1 0.21
—
28.1 0.14
12.1 019
48.2 0.14
22.1 0.22
65.4 0.48
—
CO Et
2
24.4 0.23
10.2 0.08
53.5 0.36
57.3 0.33
71.8 0.48
—
—
—
—
iv
R
O
CF
3
O
N
6a-i
Scheme 2. Synthesis of 1,2,3-triazole/isoxazole functionalized 2H-Chromene deriv-
atives. Reagents and conditions: (iii). Aryl or alkyl amide azide/CuI, THF, rt, 15–20 h,
(iv) R–CH@NOH/NaOCl, DCM, rt, 6–8 h.
6e
6f
6g
—
—
—
—
—
—
—
—
—
6h
6i
7a
7b
—
71.7 0.42
18.2 0.30
41.4 0.32
—
52.3 0.32
12.3 0.35
33.4 0.23
—
—
19.1 0.18
51.2 0.24
—
18.2 0.12
30.1 0.16
—
CO Et
2
CO2H
O
v
R
O
O
7c
7d
7e
7f
—
—
—
168.0 0.41
155.0 0.52
140.5 0.35
42.0 0.48
100.2 0.28
1.9 0.17
—
—
—
—
64.2 0.32
—
—
35.2 0.25
—
1.8 0.17
O
R
CF
CF3
7a-g
3
O
6a-g
N
O
N
36.2 0.24
—
1.9 0.09
Scheme 3. 2-((3-Arylisoxazole-5-yl)methoxy)-2-trifluoromethyl)-2H-Chromene-
3-carboxylic acid (7a–g). Reagents and conditions: (v) 10% NaOH/EtOH, reflux 1 h.
7g
—
5-Fluoro uracilc
1.8 0.08
a
Exponentially growing cells were treated with different concentrations of
compounds 5a–q, 6a–i and 7a–g for 24 h and cell growth inhibition was analyzed
Table 1
through MTT assay.
Preparation of compounds 5a–q, 6a–i and 7a–g
b
IC50 is defined as the concentration, which results in a 50% decrease in cell
number as compared with that of the control cultures in the absence of an inhibitor.
Compound
R
Yielda
Mp (°C)
The values represent the mean SE of three individual observations.
5a
5b
5c
5d
5e0
5f
5g
5h
5i
4-CH3C6H4
4-NO2C6H4
C6H5
3,4-ClF-C6H3
3-CF3C6H4
4-FC6H4
3,4-NO2FC6H3
3-OCH3C6H4
–(CH2)7–CH3
4-CH3C6H4
4-OCH3C6H4
3-ClC6H5
3-FC6H4
2-FC6H4
2-BrC6H4
2-Cl,4-IC6H3
3-C6H11
4-FC6H4
3-CF3C6H4
2-C9H8
4-CH3C6H4
4-NO2C6H4
2,4-DiFC6H4
4-OCH3C6H4
4-BrC6H4
85
83
90
80
82
83
82
84
85
75
78
80
81
75
70
80
70
87
85
90
80
82
83
84
85
82
76
75
80
81
80
60
65
155–157
122–124
136–138
103–105
102–104
125–127
92–93
74–75
Liquid
86–88
84–86
68–70
83–85
92–93
120–122
67–69
c
5-Fluorouracil was employed as positive control,
M.
— indicates IC50 value
>150
l
aldoximes39,40 yielded isoxazole functionalized 2H-Chromene
derivatives 6a–i. Compounds 6a–i were further hydrolyzed to acid
derivatives 7a–g. All the products 5a–q, 6a–i, 7a–g were screened
for anticancer activity against four human cancer cell lines using
5-Fluorouracil as control. Compounds 5f, 5g, 5l, 5q, 6a, 6b, 6i, 7a
and 7f which showed promising activity at micro molar concentra-
tion have been identified. The sequence of reactions outlined in
Schemes 1–3 and the resulting products are tabulated in Table 1.
Compounds 5a–q, 6a–i and 7a–g were screened against four
human cancer cell lines namely A549-Lung Cancer (CCL-185),
MCF7—Breast cancer (HTB-22), DU145—Prostate cancer (HTB-81),
HeLa—Cervical cancer (CCL-2) using 5-Fluorouracil as positive
control by MTT assay.36 The IC50 values of the test compounds
for 24 h were calculated and presented in Table 2. It is evident from
the results that, most of the compounds showed significant
decrease in cell viability in all the tested cell lines in a concentra-
tion-dependent manner. Among all the compounds, 5f, 5g, 5l, 5q
5j
5k
5l
5m
5n
5o
5p
5q
6a
6b
6c
6d
6e0
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
75–76
119–122
108–109
123–124
115–116
135–136
117–118
118–120
122–123
132–135
137–138
166–167
157–158
158–159
160–161
154–156
162–163
4-ClC6H4
found to show promising activity at <20
lines whereas compounds 6a, 6b, 6i, 7a and 7f showed moderate
activity at <50 M concentration. The activity is attributed to the
lM against all the cell
4-CH3C6H4
2,4-DiFC6H4
4-FC6H4
3-CF3C6H4
2-C9H8
l
presence of fluorine or chlorine or nitro group on phenyl at fourth
position of triazole ring, whereas in presence of chlorine along with
fluorine on phenyl of triazole ring reducing activity. Isoxazole func-
tionalized 2H-Chromene derivatives 6a–i and 7a–g showed minute
4-OCH3C6H4
4-NO2C6H4
7g
a
Isolated yields.
decrease in cell viability of the tested cell lines even after 100 lM

K. Ratnakar Reddy et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1661–1663
1663
9. Jankun, J.; Selman, S. H.; Swierez, R. Nature 1997, 387, 561.
10. Skommer, J.; Wlodkowic, D.; MVtt, M., et al Leukemia Res. 2006, 30, 322.
11. Kemnitzer, W.; Drewe, J.; Jiang, S., et al J. Med. Chem. 2004, 47, 6299.
concentration. Slight structural modification of these active deriv-
atives may yield prospective anticancer drugs.
In conclusion, A series of novel 2H-Chromene derivatives were
prepared and screened for cytotoxic activity against four human
cancer cell lines and triazole tagged 2H-Chromene derivatives
showed better cytotoxic activity than isoxazole tagged 2H-Chro-
mene derivatives. Among all the compounds 5f, 5g, 5l and 5q are
identified as promising compounds.
12. Kasibhatla, S.; Gourdeau, H.; Meerovitch, K., et al Mol. Cancer Ther. 2004, 3,
1365.
13. Parmar, V. S.; Jain, S. C.; Bisht, K. S., et al Phytochemistry 1997, 46, 597.
14. Gill, M. Aust. J. Chem. 1995, 48, 1.
15. Wang, X. S.; Zhou, J.; Yang, K., et al Synth. Commun. 2010, 40, 873.
16. Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M., et al Adv. Synth. Catal. 2008,
350, 591.
17. Ilia, M.; Caecilia, M. M.; Irina, N., et al Arch. Pharm. Chem. Life Sci. 2006, 33, 319.
18. Chen, W.; Cai, Y. F.; Fu, X., et al Org. Lett. 2011, 13, 4910.
19. Cao, S. S. T.; Fang, D.; Gong, K., et al Yingyong Huaxue 2009, 26, 1123.
20. Li, Hongqi; Cai, Li; Li, Jinxing; Hu, Yixin; Zhou, Pingping; Zhang, Jiming Dyes
Pigm. 2011, 91, 309.
Acknowledgments
Authors are thankful to the Council of Scientific & Industrial Re-
search (CSIR), New Delhi, India for funding through a XII five year
plan project DITSF code: CSC-0204. Authors, K. Ratnakar Reddy, P.
Sambasiva Rao, G. Jitender Dev, Y. Poornachandra are also thankful
to the CSIR, India for providing financial assistance in the form of
Research Fellowship and contingency grant.
21. Ravichandran, S.; Subramanl, K.; Arunkumar, R. Int. J. Chem. Technol. Res. 2009,
1, 329.
22. Zeng, Li Yan; Lv, Mei Fang; Cai, Chun Chin. Chem. Lett. 2012, 23, 1347.
23. Comprehensive Heterocyclic Chemistry 11; Fan, W. Q., Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Elsevier: Oxford, UK, 1996; Vol. 4, pp 1–126.
24. Whiting, M.; Olson, A. J.; Kolb, H. C.; Finn, M. G.; Sharpless, K. B.; Elder, J. H.;
Fokin, V. V. Angew. Chem. 2006, 45, 1435.
25. Borne, Y.; Kolb, H. C.; Radiac, Z.; Sharpless, K. B.; Taylor, P.; Marchot, P. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 1449.
Supplementary data
26. Cosimelli, Barbara; Simorini, Francesca; Taliani, Sabrina; La Motta, Concettina;
Da Settimo, Federico; Severi, Elda; Greco, Giovanni; Novellino, Ettore; Costa,
Barbara; Da Pozzo, Eleonora; Bendinelli, Sara; Martini, Claudia Eur. J. Med.
Chem. 2011, 46, 4506.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.02.
069.
27. Zhang, Datong; Jia, Jiong; Meng, Lijuan; Xu, Weiren; Tang, Lida; Wang, Jianwu
Arch. Pharmacol. Res. 2010, 33, 831.
28. Ratcliffe, Paul et al Bioorg. Med. Chem. Lett. 2011, 21, 4652.
29. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn,
M. G.; Sharpless, K. B. Angew. Chem. 2002, 41, 1053.
References and notes
30. Krivopalov, V. P.; Shurko, O. P. Russ. Chem. Rev. 2005, 74, 1053.
31. Aicher, Thomas D.; Balkan, Bork; Bell, Philip A.; Brand, Leonard J.; Cheon, S. H.,
et al J. Med. Chem. 1998, 41, 4556.
32. De Luca, Lidia; Giacomelli, Giampaolo; Riu, Antonella J. Org. Chem 2001, 66,
6823.
33. Manichanrika, P.; Yakaiah, T.; Gayatri, G.; Pranay Kumar, K.; Narsaiah, B.;
Murthy, U. S. N.; Raghuram Rao, A. Eur. J. Med. Chem. 2010, 45, 78.
34. Sirisha, B.; Narsaiah, B.; Yakaiah, T.; Gayatri, G.; Narahari Sastry, G.; Raghu
Prasad, M.; Raghuram Rao, A. Eur. J. Med. Chem. 2010, 45, 1739.
35. Kurumurthy, C.; Sambasiva Rao, P.; Veeraswamy, B.; Santhosh kumar, G.;
Shanthan Rao, P.; Narsaiah, B.; Velatooru, L. R.; Pamanji, R.; Venkateshwar rao,
J. Eur. J. Med. Chem. 2011, 46, 3462.
1. (a) Kharrat, S. E.; Laurent, P.; Blancou, H. J. Org. Chem. 2006, 71, 863; (b) Bera, K.;
Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. J. Org. Chem. 2011, 76, 3539.
2. Subba reddy, B. V.; Divya, B.; Swain, M.; Rao, T. P.; Yadav, J. S.; Vishnu Vardhan,
M. V. P. S. Bioorg. Med. Chem. Lett. 2012, 22, 1995.
3. Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A. L.; Tillequin, F.; Koch, M.;
Pierre, A.; Guilbaud, N.; Leonce, S.; Kraus-Berthier, L.; Rolland, Y.; Atassi, G. J.
Med. Chem. 1996, 39, 4762.
4. (a) Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S. Bioorg. Med. Chem. Lett.
2005, 15, 4295; (b) Tahtaoui, C.; Demailly, A.; Guidemann, C.; Joyeux, C.;
Schneider, P. J. Org. Chem. 2010, 75, 3781.
5. Lago, J. H. G.; Ramos, C. S.; Casanova, D. C. C.; Morandim, A. A.; Bergamo, D. C.
B.; Cavalheiro, A. J.; Bolzani, V. S.; Furlan, M.; Guilharaes, E. F.; Young, M. C. M.;
Kato, M. J. J. Nat. Prod. 2004, 67, 1783.
6. Bernard, C. B.; Krishnamurty, H. G.; Chauret, D.; Durst, T.; Philogene, B. J. R.;
Sanchez Vindas, P.; Hasbun, C.; Poveda, L.; San Roman, L.; Arnason, J. T. J. Chem.
Ecol. 1995, 21, 801.
7. (a) Engler, T. A.; La Tessa, K. O.; Iyengar, R.; Chai, W.; Agrios, K. Bioorg. Med.
Chem. 1996, 4, 1755; (b) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi,
T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino, L. M.; Fowke, K.; Morris-
Natschke, S.; Lee, K. H. Tetrahedron 2001, 57, 1559.
36. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
37. Alliston, Kevin R.; Dou, Dengfeng; Groutas, William C.; Tiew, Kok-Chuan; Lai,
Huiguo; Padmanabhan; Teramoto, Tadahisa; Lushington, Gerald H. Bioorg. Med.
Chem. 2012, 20, 1213.
38. Cwiklicki, Anke; Rehse, Klaus Arch. Pharm. 2004, 337, 156.
39. Wardrop, Duncan J.; Yermolina, Maria V.; Caffrey, Michael; Rong, Lijun L.;
Wang, Jizhen J. Med. Chem. 2011, 54, 765.
40. Fokin, Valery V.; Hansen, Trond V.; Wu, Peng J. Org. Chem. 2005, 70, 7761.
8. Mukai, K.; Okabe, K.; Hosose, H. J. Org. Chem. 1989, 54, 557.