Synthesis and biological evaluation of 3-amino-2-pyrones as selective cyclooxygenase-1 (COX-1) inhibitors

Article abstract of DOI:10.1016/j.cclet.2013.01.005

A group of 3-amino-2-pyrones were synthesized and their biological activities were evaluated for inhibiting cyclooxygenase (COX) activity. This study has led to the identification of COX-1-selective inhibitors. Among the tested compounds, the compound 5j exhibited the most potent COX-1 inhibitory activity (IC₅₀ = 19.32 μg/mL) and COX-1 selectivity index (SI = 41.98).

Full text of DOI:10.1016/j.cclet.2013.01.005

Chinese Chemical Letters 24 (2013) 120–122
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis and biological evaluation of 3-amino-2-pyrones as selective
cyclooxygenase-1 (COX-1) inhibitors
*
*
Xue-Ping Chu, Qing-Fa Zhou , Shen Zhao, Fei-Fei Ge, Mian Fu, Jia-Peng Chen, Tao Lu
Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A group of 3-amino-2-pyrones were synthesized and their biological activities were evaluated for
inhibiting cyclooxygenase (COX) activity. This study has led to the identification of COX-1-selective
inhibitors. Among the tested compounds, the compound 5j exhibited the most potent COX-1 inhibitory
Received 2 December 2012
Received in revised form 21 December 2012
Accepted 27 December 2012
Available online 4 February 2013
activity (IC50 = 19.32
mg/mL) and COX-1 selectivity index (SI = 41.98).
ß 2013 Qing-Fa Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
3-Amino-2-pyrone
Biological activity
COX-1-selective inhibitor
Synthesis
1. Introduction
cardiotonic [13], pheromonal [14], androgen-like [15] and
phytotoxic [16] properties. Simple changes in the substitution
Prostaglandin and thromboxane biosynthesis involves the
transformation of arachidonic acid to prostaglandin H2 (PGH2), a
reaction catalyzed by the sequential actions of COX and
prostaglandin endoperoxidase synthase (PGHS) [1]. Two isoforms
of COX (COX-1, COX-2) have been isolated [2]. COX-2 is reported to
be inducible with various stimuli, while COX-1 is constitutively
expressed in many organs or tissues. However, recent studies have
shown many exceptions for this paradigm. For example, recent
research implied that COX-1 can play an important role in early
pathogenesis of Alzheimer disease, even as a potential target for
early intervention of Alzheimer disease [3]. Moreover some
experimental results have indicated possible involvement of
COX-1 in pain and cancer development [4], thus providing the
rationale for the development of selective COX-1 inhibitors.
Although many selective COX-2 inhibitors [5] have been found,
research on COX-1 selective inhibitors is less-advanced [6] due to
the dogma that COX-1 inhibitors inevitably cause gastrointestinal
toxicity [7]. So, the development of COX-1 selective inhibitors is
important for the development of novel drugs to treat COX-
associated diseases, such as inflammatory diseases and cancer.
2-Pyrones are found in numerous natural products [8] and
exhibit a wide range of biological activities, such as anti-HIV [9],
telomerase inhibition [10], antimicrobial [11], antifungal [12],
pattern on the 2-pyrone ring often lead incredible diverse
biological activity. For example, the 2-pyrone PD 107067 (1)
(Fig. 1) has been shown to be an effective inhibitor of HIV protease
[17], and Fairlamb et al. found that 4-substituted-6-methyl-2-
pyrone (2) demonstrated remarkable antimicrobial activity,
human ovarium carcinoma (A2780) and human chronic myeloge-
nous leukemia (K562) inhibitory properties [18]. Recent studies
have shown that 3,4,6-triphenylpyran-2-one (3) and 3,4-diphe-
nylpyran-2-one (4) were selective COX-2 inhibitors with good
anti-inflammatory and analgesic activity profiles [19]. Herein we
want to report on synthetic details and novel selective COX-1
inhibitors of 3-amino-2-pyrones (5).
2. Experimental
The synthetic methods used to prepare the target 3-amino-2-
pyrones are outlined in Scheme 1 [20]. The initial strategy was to
synthesis the prop-2-yn-1-ols (9), which was achieved by the
condensation of phenylacetylene or pent-1-yne with a substituted
benzaldehyde in the presence of ethylmagnesium bromide.
Subsequent oxidation of 9 using Jones reagent afforded the
corresponding prop-2-yn-1-one (10). The 3-amino-2-pyrones 5
were obtained by hydrolysis of 3-amino-2-pyrone derivatives 11,
which are obtained by condensation of ethyl 2-(diphenyl-
methyleneamino)acetate
7 with prop-2-yn-1-one 10 in the
* Corresponding authors.
presence of NaOH at 25 8C as shown in Scheme 1.
E-mail addresses: zhouqingfa@cpu.edu.cn (Q.-F. Zhou), lutao@163.com (T. Lu).
1001-8417/$ – see front matter ß 2013 Qing-Fa Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.005

X.-P. Chu et al. / Chinese Chemical Letters 24 (2013) 120–122
121
Table 1
OH
COX-inhibitory activity of the target compounds .
SO2Me
S
O
H2N
R1
O
O
O
O
O
O
O
R2
1
2
MeO
R1
3
SO2Me
NH
2
Compound
R1
R2
IC50
(
m
g/mL)
COX-2
SI
R2
O
O
S
O
O
COX-1
4
5
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Pr
Ph
23.94
26.33
28.72
43.79
80.2
631.2
105.7
219.6
75.70
148.72
581.37
26.37
4.01
7.65
1.73
1.85
11.90
–
4-F-Ph
Fig. 1. The structures of compounds 1–5.
4-Cl-Ph
4-MeO-Ph
3,4-MeO-Ph
3,4,5-MeO-Ph
4-MeSO2-Ph
4-F-Ph
O
Ph
Ph
O
a
b
48.84
89.65
37.17
24.48
19.32
H2N
N
HCl
H2N
R1
OEt
5g
5h
5i
<50%
COOEt
OH
6
97.93
262.03
811.04
2.63
10.70
41.98
7
Pr
3-CF3-Ph
4-Br-Ph
5j
Pr
O
OH
R2
R1
e
1) c
2) d
R1
R2
10
8
9
condensation of 14 with ethyl 2-(diphenyl-methyleneamino)ace-
tate with prop-2-yn-1-one in the presence of NaOH as shown in
Scheme 2.
R1
R1
Ph
Ph
NH2
O
N
O
g
f
R2
O
R2
7
O
3. Results and discussion
11
5
A group of 3-amino-2-pyrones were prepared to investigate the
effect of different substituents on COX-1 selectivity and potency.
The ability of the 3-amino-2-pyrones to inhibit the COX-1 and
COX-2 isozymes was determined according to the reported
method [21]. In vitro COX-1/COX-2 inhibition studies showed
that all compounds 5 were selective inhibitors of the COX-1
Scheme 1. Reagents and conditions: (a) EtOH, SOCl2, reflux, 2.5 h; (b) CH2Cl2, Et3N,
diphenylmethanimine, 12 h; (c) THF, ethylmagnesium bromide, 0 8C, 4 h; (d)
aldehyde, 0 8C ꢀr.t., 12 h; (e) propan-2-one, Jones reagent, 2–4 h; (f) CH2Cl2, NaOH,
4–12 h; (g) propan-2-one, 10% HCl, 2 h.
The 3-amino-2-pyrone with a C-4 4-methanesulfonylphenyl
substituent 5g was prepared using the reaction sequence shown in
Scheme 2. Thus, the prop-2-yn-1-one derivative 13 was synthe-
sized by condensation of 4-methylthiobenzaldehyde with ethy-
nylbenzene in the presence of ethylmagnesium bromide to afford
the prop-2-yn-1-ol 12 which was subsequently oxidized to the
corresponding ketone 13 using MnO2. Subsequent oxidation of 13
using aqueous oxone afforded the methanesulfonyl derivative 14
in good yield. The final cyclization reaction was carried out by
isozyme with IC50 values with potency of 19.32–89.65
mg/mL
range, and COX-1 selectivity indexes (SI) in the 3–40 g/mL range
m
(Table 1). These data also showed that the nature of the substituent
attached to C-4 of 3-amino-2-pyrone ring influenced both
selectivity and potency for COX-1 inhibitory activity. Our results
indicated that the introduction of suitable substituents such as -F
(5b) and -OMe (5d) at the para-position of C-4 phenyl ring
increased potency for COX-2 inhibitory activity. According to these
results,
3-fluorophenyl-2-(4-methylsulfonyl
phenyl)-1,3-
g/
benzthiazinan-4-one 5j was the most potent (IC50 = 19.32
m
mL) and selective (SI = 41.98) COX-1 inhibitor among the synthe-
sized compounds.
O
OH
Ph
Ph
1) a
2) b
c
Ph
4. Conclusion
SMe
Ph
In summary, we have found that 3-amino-2-pyrones possess
COX-1/2-inhibiting activity and show potent COX inhibiting
activity preferentially to COX-1 subtype. Further structural
development aimed at improvement of the COX-1/COX-2 selec-
tivity and pharmacological application studies are in progress in
our lab.
13
SMe
12
O
Ph
Ph
N
O
e
d
f
Ph
O
SO2Me
MeO S
2
14
15
Acknowledgments
Ph
NH2
O
We thank the National Natural Science Foundation of China (No.
21102179) and Fundamental Research Funds for the Central
Universities (No. JKZ2011011) for the financial support.
O
MeO S
2
5g
References
Scheme 2. Reagents and conditions: (a) THF, ethylmagnesium bromide, 0 8C, 4 h;
(b) 4-(methylthio)benzaldehyde, 0 8C ꢀr.t., 12 h; (c) propan-2-one, MnO2, 2 h; (d)
propan-2-one, aqueous oxone, 2 h; (e) ethyl 2-(diphenylmethylene-amino)acetate,
CH2Cl2, NaOH, 4 h; (f) propan-2-one, 10% HCl, 2 h.
[1] C.J. Hawkey, COX-2 inhibitors, Lancet 353 (1999) 307–314.
[2] W.L. Xie, J.G. Chipman, D.L. Robertson, R.L. Erikson, D.L. Simmons, Expression of a
mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA
splicing, Proc. Natl. Acad. Sci. U.S.A. 88 (1991) 2692–2696.

122
X.-P. Chu et al. / Chinese Chemical Letters 24 (2013) 120–122
[3] S.A. Frautschy, Thinking outside the box about COX-1 in Alzheimer’s disease,
[11] (a) A.F. Barrero, J.E. Oltra, M.M. Herrador, et al., Gibepyrones: a-pyrones from
Gibberella fujikuroi, Tetrahedron 49 (1993) 141–150;
Neurobiol. Dis. 38 (2010) 492–494.
[4] J.L. Teeling, C. Cunningham, T.A. Newman, V.H. Perry, The effect of non-steroidal
anti-inflammatory agents on behavioural changes and cytokine production fol-
lowing systemic inflammation: implications for a role of COX-1, Brain Behav.
Immun. 24 (2010) 409–419.
[5] (a) F. Wuest, X. Tang, T. Kniess, J. Pietzsch, M. Suresh, Synthesis and cyclooxy-
genase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl
derivatives, Bioorg. Med. Chem. 17 (2009) 1146–1151;
(b) W.R. Abraham, H. Arfmann, Fusalanipyrone, a monoterpenoid from Fusarium
solani, Phytochemistry 27 (1988) 3310–3311.
[12] (a) A. Evidente, A. Cabras, L. Maddau, et al., Viridepyronone, a new antifungal 6-
substituted 2H-pyran-2-one produced by Trichoderma viride, J. Agric. Food Chem.
51 (2003) 6957–6960;
(b) A. Simon, R.W. Dunlop, E.L. Ghisalberti, K. Sivasithamparam, Trichoderma
koningii produces
a pyrone compound with antibiotic properties, Soil Biol.
(b) M. Scholz, H.K. Ulbrich, O. Soehnlein, et al., Diaryl-dithiolanes and -isothia-
zoles: COX-1/COX-2 and 5-LOX-inhibitory, ꢁOH scavenging and anti-adhesive
activities, Bioorg. Med. Chem. 17 (2009) 558–568;
(c) F. Wuest, T. Kniess, R. Bergmann, J. Pietzsch, Synthesis and evaluation in vitro
and in vivo of a 11C-labeled cyclooxygenase-2 (COX-2) inhibitor, Bioorg. Med.
Chem. 16 (2008) 7660–7662;
Biochem. 20 (1988) 263–264;
(c) N. Claydon, M. Asllan, J.R. Hanson, A.G. Avent, Antifungal alkyl pyrones of
Trichoderma harzianum, Trans. Br. Mycol. Soc. 88 (1987) 503–513;
(d) H.G. Cutler, R.H. Cox, F.G. Crumley, P.O. Cole, 6-Pentyl-a-pyrone from Tricho-
derma harzianum: its plant growth inhibitory and antimicrobial properties, Agric.
Biol. Chem. 50 (1986) 2943–2945.
(d) A.S. Kalgutkar, Selective cyclooxygenase-2 inhibitors as non-ulcerogenic anti-
inflammatory agents, Exp. Opin. Ther. Patents 8 (1999) 831–849;
(e) T.D. Penning, J.J. Talley, S.R. Bertenshaw, et al., Synthesis and biological
evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identi-
fication of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide (SC-58635, Celecoxib), J. Med. Chem. 40 (1997) 1347–1365.
[6] (a) H. Kakuta, R. Fukai, X. Zheng, et al., Identification of urine metabolites of TFAP,
a cyclooxygenase-1 inhibitor, Bioorg. Med. Chem. Lett. 20 (2010) 1840–1843;
(b) H. Sano, T. Noguchi, A. Miyajma, Y. Hashimoto, H. Miyachi, Anti-angiogenic
activity of basic-type, selective cyclooxygenase (COX)-1 inhibitors, Bioorg. Med.
Chem. Lett. 16 (2006) 3068–3072;
[13] K.K. Chen, A.J. Kovarikova, Pharmacology and toxicology of toad venom, J. Pharm.
Sci. 56 (1967) 1535–1541.
[14] X. Shi, W.S. Leal, Z. Liu, E. Schrader, J. Meinwald, A new synthesis of alkylated 2H-
pyran-2-ones and its application to the determination of the relative and absolute
configuration of supellapyrone, sex pheromone of the brownbanded cockroach,
Supella longipalpa, Tetrahedron Lett. 36 (1995) 71–74.
[15] G. Schlingmann, L. Milne, G.T. Carter, New a-pyrones produced by fungal culture
LL-11G219 function as androgen receptor ligands, Tetrahedron 54 (1998) 13013–
13022.
[16] H. Sato, K. Konoma, S. Sakamura, Three new phytotoxins produced by Pyreno-
chaeta terrestris: pyrenochaetic acids A, B and C, Agric. Biol. Chem. 45 (1981)
1675–1679.
(c) H. Sano, T. Noguchi, A. Tanatni, Y. Hashimoto, H. Miyachi, Design and synthesis
of subtype-selective cyclooxygenase (COX) inhibitors derived from thalidomide,
Bioorg. Med. Chem. 13 (2005) 3079–3091;
[17] S. Hagen, J.V.N. Vara Prasa, B.D. Tait, Nonpeptide inhibitors of HIV protease, Adv.
Med. Chem. 5 (2000) 159–195.
(d) T. Noguchi, R. Shimazawa, K. Nagasawa, Y. Hashimoto, Thalidomide and its
analogues as cyclooxygenase inhibitors, Bioorg. Med. Chem. Lett. 12 (2002) 1043–
1046.
[18] (a) L.R. Marrison, J.M. Dickinson, I.J.S. Fairlamb, Bioactive 4-substituted-6-meth-
yl-2-pyrones with promising cytotoxicity against A2780 and K562 cell lines,
Bioorg. Med. Chem. Lett. 12 (2002) 3509–3513;
[7] (a) M.C. Allison, A.G. Howatson, C.J. Torrance, F.D. Lee, R.I. Russell, Gastrointesti-
nal damage associated with the use of nonsteroidal antiinflammatory drugs, N.
Engl. J. Med. 327 (1992) 749–754;
(b) J.R. Vane, Y.S. Bakhle, R.M. Botting, Cyclooxygenase 1 and 2, Annu. Rev.
Pharmacol. Toxicol. 38 (1998) 97–120.
[8] (a) J.M. Dickinson, Microbial pyran-2-ones and dihydropyran-2-ones, Nat. Prod.
Rep. 10 (1993) 71–98;
(b) L.R. Marrison, J.M. Dickinson, I.J.S. Fairlamb, Suzuki cross-coupling
approaches to the synthesis of bioactive 3-substituted and 5-substituted-4-
methoxy-6-methyl-2-pyrones, Bioorg. Med. Chem. Lett. 13 (2003) 2667–2671.
[19] (a) P.N. Praveen Rao, M. Amini, H. Li, A.G. Habeeb, E.E. Knaus, Design, synthesis,
and biological evaluation of 6-substituted-3-(4-methanesulfonylphenyl)-4-phe-
nylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2
inhibitors, J. Med. Chem. 46 (2003) 4872–4882;
(b) G.P. McGlacken, I.J.S Fairlamb, 2-Pyrone natural products and mimetics:
isolation, characterization and biological activity, Nat. Prod. Rep. 22 (2005)
369–385.
(b) P.N. Praveen Rao, M.J. Uddin, E.E. Knaus, Design, synthesis, and structure–
activity relationship studies of 3,4,6-triphenylpyran-2-ones as selective cyclooxy-
genase-2 inhibitors, J. Med. Chem. 47 (2004) 3972–3990.
[9] J.V.N. Vara Prasad, K.S. Para, E.A. Lunney, et al., Novel series of achiral, low
molecular weight, and potent HIV-1 protease inhibitors, J. Am. Chem. Soc. 116
(1994) 6989–6990.
[10] A. Kanai, T. Kamino, K. Kuramochi, S. Kobayashi, Synthetic studies directed toward
the assembly of the C-glycoside fragment of the telomerase inhibitor D8646-2-6,
Org. Lett. 5 (2003) 2837–2839.
[20] (a) Q.F. Zhou, Y. Zhu, W.F. Tang, T. Lu, Michael addition-lactonization reaction of
electron-deficient alkynes with N-(diphenylmethylene)glycinates: an efficient
synthesis of 3-amino-2-pyrone derivatives, Synthesis (2010) 211–216;
(b) Q.F. Zhou, S. Zhao, X. Wang, T. Lu, Research progress in the synthesis of 2-
pyrone derivatives, Chin. J. Org. Chem. 30 (2010) 1652–1663.
[21] W. Duan, L. Zhang, Cyclooxygenase inhibitors not inhibit resting lung cancer A549
cell proliferation, Prostaglandins Leukot Essent Fatty Acids 74 (2006) 317–321.