cyclic enaminone as new chemotype for selective ......cyclic enaminone as new chemotype for...

SUPPLEMENTARY DATA

Cyclic enaminone as new chemotype for selective

cyclooxygenase-2 inhibitory, anti-inflammatory, and

analgesic activities

Raj Kumar, †,£

Nirjhar Saha, † Priyank Purohit,

†Sanjeev K. Garg,

†Kapileswar Seth,

†Vachan S.

Meena, § Sachin Dubey,

§ Khyati Dave,

‡ Rohit Goyal,

$ Shyam S. Sharma,

‡ Uttam C. Banerjee

and Asit K. Chakraborti*†

†Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and

Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India.

§Department of Pharmaceutical Technology (Biotechnology), National Institute of

Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab,

India.

‡Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education

and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.

$Indo-Soviet Friendship (ISF) College of Pharmacy, Moga, 142 001, Punjab, India (present

address: School of Pharmaceutical Sciences, Shoolini University, Solan, HP, 173212, India).

£Present Address: Department of Pharmaceutical Sciences and Natural Products, Central

University of Punjab, Mansa Road, Bathinda-151001, India.

*Corresponding Author: Tel: 91-(0)-172 229 2027; Fax: 91-(0)-172-2214692. E-mail:

akchakraborti@niper.ac.in; akchakraborti@rediffmail.com.

Table of Content

I. Necessity for the Development of Catalyst-free Synthetic Methodology for Cyclic

Enaminones- Disadvantages of the Reported Procedures S4

II. Spectral data for known compounds S5-7

III. Scanned spectra: S8-54

1H NMR spectrum of compound 7a (Entry 1, Table 2)

13C NMR spectrum of compound 7a (Entry 1, Table 2)

HPLC chromatogram of compound 7a

1H NMR spectrum of compound 7b (Entry 2, Table 2)

HPLC chromatogram of compound 7b

1H NMR spectrum of compound 7c (Entry 3, Table 2)

HPLC chromatogram of compound 7c

1H NMR spectrum of compound 7d (Entry 4, Table 2)

HPLC chromatogram of compound 7d

1H NMR spectrum of compound 7e (Entry 5, Table 2)

HPLC chromatogram of compound 7e

1H NMR spectrum of compound 7f (Entry 6, Table 2)

HPLC chromatogram of compound 7f

1H NMR spectrum of compound 7g (Entry 7, Table 2)

HPLC chromatogram of compound 7g

1H NMR spectrum of compound 7h (Entry 8, Table 2)

13C NMR spectrum of compound 7h (Entry 8, Table 2)

HPLC chromatogram of compound 7h

1H NMR spectrum of compound 7i (Entry 9, Table 2)

13C NMR spectrum of compound 7i (Entry 9, Table 2)

HPLC chromatogram of compound 7i

1H NMR spectrum of compound 7j (Entry 10, Table 2)

13C NMR spectrum of compound 7j (Entry 10, Table 2)

HPLC chromatogram of compound 7j

1H and NMR spectrum of compound 7k (Entry 11, Table 2)

13C NMR spectrum of compound 7k (Entry 11, Table 2)

HPLC chromatogram of compound 7k

1H NMR spectrum of compound 7l (Entry 12, Table 2)

HPLC chromatogram of compound 7l

1H NMR spectrum of compound 7m (Entry 13, Table 2)

13C NMR spectrum of compound 7m (Entry 13, Table 2)

HPLC chromatogram of compound 7m

1H NMR spectrum of compound 7n (Entry 14, Table 2)

HPLC chromatogram of compound 7n

1H NMR spectrum of compound 7o (Entry 15, Table 2)

HPLC chromatogram of compound 7o

1H NMR spectrum of compound 7p (Entry 16, Table 2)

HPLC chromatogram of compound 7p

1H NMR spectrum of compound 7q (Entry 17, Table 2)

HPLC chromatogram of compound 7q

1H NMR spectrum of compound 7r (Entry 18, Table 2)

13C NMR spectrum of compound 7r (Entry 18, Table 2)

HPLC chromatogram of compound 7r

1H NMR spectrum of compound 7s (Entry 19, Table 2)

HPLC chromatogram of compound 7s

1H NMR spectrum of compound 7t (Entry 20, Table 2)

HPLC chromatogram of compound 7t

1H NMR spectrum of compound 7u (Entry 21, Table 2)

13C NMR spectrum of compound 7u (Entry 21, Table 2)

HPLC chromatogram of compound 7u

1H NMR spectrum of compound 8

13C NMR spectrum of compound 8

HPLC chromatogram of compound 8

IV. Determination of Interaction of 7d, 8, and 9 with the COX-2 active site S55-61

V. References S62-63

I. Necessity for the Development of Catalyst-free Synthetic Methodology for

Cyclic Enaminones- Disadvantages of the Reported Procedures:

A convenient route for the synthesis of cyclic enaminones involves the condensation of an

amine with cyclic 1,3-diones (Scheme S1).[1] The reported procedures involve performing the

reaction in boiling solvents[2-4] (EtOH-EtOAc or EtOH-benzene or EtOAc-benzene) with

azeotropic removal of water using Dean-Stark water separator, the use of special equipment

(microwave oven) in the presence[5] or absence of a catalyst,[6] and the use of corrosive and

costly catalyst.[7-9] Heterogeneous catalyst systems such as HClO4-SiO2[10] invented by

Chakraborti et al[11] and silica chloride (as well as ionic liquid)[12] have also been used for the

purpose. Apart from the inherent disadvantages (e.g., special efforts for catalyst preparation, use

of moisture sensitive, corrosive and costly catalysts and requirement of special apparatus) most

of the reported synthetic procedures require heating and chromatographic purification. These

made us to realize the necessity to develop an efficient and catalyst-free methodology for a

convenient synthesis of cyclic β-enaminones.

Scheme S1. Generalized synthetic strategy for the preparation of cyclic β-enaminones.

II. Spectral data for known compounds:

3-(4-Methylphenylamino)cyclohex-2-enone[13] (7b, Entry 2, Table 1)

Pale yellow solid (0.407 g, 81%). mp: 122-124 °C; IR (KBr): 3214, 3030, 2936, 1536, 1243,

1184 cm-1

H NMR (400 MHz, CDCl3): δ 1.98-2.04 (m, 2H, CH2), 2.32 (s, 3H, CH3), 2.34 (t, J

= 6.2 Hz, 2H, CH2), 2.48 (t, J = 6.2 Hz, 2H, CH2), 5.50 (s, 1H, C=C-H), 6.50 (brs, 1H, NH),

7.01-7.04 (m, 2H, Ar-H), 7.12 (d, J = 8.0 Hz, 2H, Ar-H); 13

C NMR (100 MHz, CDCl3): δ 20.95,

21.88, 29.73, 36.48, 99.55, 124.11, 129.88, 135.36, 135.51, 162.54, 198.15; MS (APCI) m/z:

202.1 (MH+).

3-(4-Methoxyphenylamino)cyclohex-2-enone[12] (7c, Entry 3, Table 1)

Yellow solid (0.397 g, 82%). mp: 164-166 °C; 1H NMR (400 MHz, CDCl3): δ 1.97-2.02 (m, 2H,

CH2), 2.31-2.34 (m, 2H, CH2), 2.48 (t, J = 6.2 Hz, 2H, CH2), 3.80 (s, 3H, OCH3), 5.36 (s, 1H,

C=C-H), 6.31 (brs, 1H, NH), 6.85 (d, J = 8.8 Hz, 2H, Ar-H), 7.07 (d, J = 8.8 Hz, 2H, Ar-H); 13

NMR (100 MHz, CDCl3): δ 21.90, 29.58, 36.46, 55.51, 99.20, 114.52, 126.32, 130.62, 157.71,

163.29, 197.99; MS (APCI) m/z: 218.2 (MH+).

3-(4-Chlorophenylamino)cyclohex-2-enone[12] (7d, Entry 4, Table 1)

Yellow solid (0.419 g, 76%). mp: 189-191 °C; IR (KBr): 3250, 2949, 1601, 1574, 1519, 1244,

1181, 1138, 1085, 816 cm-1

; 1H NMR (400 MHz, CDCl3): δ 1.97-2.03 (m, 2H, CH2), 2.33 (t, J =

6.4 Hz, 2H, CH2), 2.49 (t, J = 6.4 Hz, 2H, CH2), 5.47 (s, 1H, C=C-H), 7.05-7.08 (m, 2H, Ar-H),

7.25-7.28 (m, 2H, Ar-H); 13

C NMR (100 MHz, CDCl3): δ 21.78, 29.58, 36.44, 99.73, 125.15,

129.41, 130.76, 136.73, 162.51, 198.54; MS (APCI) m/z: 222.1 (MH+).

3-(4-Fluorophenylamino)cyclohex-2-enone[13] (7e, Entry 5, Table 1)

1409, 1244, 1178, 1142, 819 cm-1

; 1H NMR (400 MHz, CDCl3): δ 1.97-2.03 (m, 2H, CH2), 2.32

(t, J = 6.4 Hz, 2H, CH2), 2.49 (t, J = 6.4 Hz, 2H, CH2), 5.36 (s, 1H, C=C-H), 6.96 (brs, 1H, NH),

6.97-7.03 (m, 2H, Ar-H), 7.07-7.12 (m, 2H, Ar-H); 13

C NMR (100 MHz, CDCl3): δ 21.82, 29.49,

36.45, 99.20, 116.01, 116.24, 126.28, 126.36, 133.95, 133.98, 159.14, 161.58, 163.26, 198.30.

3-(4-Nitrophenylamino)cyclohex-2-enone[13] (7f, Entry 6, Table 1)

Yellow solid (0.406 g, 70%). mp: 165-167 °C; 1H NMR (400 MHz, CD3OD): δ 2.01-2.07 (m,

2H, CH2), 2.38 (t, J = 6.4 Hz, 2H, CH2), 2.63 (t, J = 6.4 Hz, 2H, CH2), 5.76 (s, 1H, C=C-H), 7.39

(d, J = 8.4 Hz, 2H, Ar-H), 8.24 (d, J = 8.4 Hz, 2H, Ar-H); 13

C NMR (100 MHz, CD3OD): δ

21.37, 28.66, 35.72, 100.50, 121.59, 124.75, 143.44, 145.24, 163.30, 200.61.

3-(4-Cyanophenylamino)cyclohex-2-enone[13] (7g, Entry 7, Table 1)

Off-white solid (0.429 g, 81%). mp: 199-201 °C; 1H NMR (400 MHz, CDCl3): δ 2.02-2.10 (m,

2H, CH2), 2.40 (t, J = 6.2 Hz, 2H, CH2), 2.54 (t, J = 6.2 Hz, 2H, CH2), 5.77 (s, 1H, C=C-H), 6.79

(brs, 1H, NH), 7.23-7.26 (m, 2H, Ar-H), 7.59-7.62 (m, 2H, Ar-H); 13

C NMR (100 MHz, CDCl3):

δ 21.64, 29.89, 36.52, 102.62, 107.30, 118.57, 122.08, 133.52, 142.85, 159.56, 198.69; MS

(APCI) m/z: 213.3 (MH+).

3-(4-Chlorophenylamino)-5,5-dimethylcyclohex-2-enone[14] (7l, Entry 12, Table 1)

1255, 1181, 803 cm-1

; 1H NMR (400 MHz, CD3OD): δ 1.10 (s, 6H, 2CH3), 2.21 (s, 2H, CH2),

2.45 (s, 2H, CH2), 5.45 (s, 1H, C=C-H), 7.20 (d, J = 8.0 Hz, 2H, Ar-H), 7.39 (d, J = 8.0 Hz, 2H,

Ar-H); 13

C NMR (100 MHz, CD3OD): δ 28.37, 33.70, 43.53, 43.56, 50.67, 97.64, 126.54,

126.58, 130.51, 131.98, 138.64, 165.59, 165.68, 200.75; MS (EI) m/z: 249 (M+), 251 (M+2)

3-(4-Chlorophenylamino)cyclopent-2-enone[15] (7n, Entry 14, Table 1)

Yellow solid (0.414 g, 80%). mp: 217-219 °C; IR (KBr): 3390, 3130, 1610, 1408 cm-1

; 1H NMR

(400 MHz, CD3OD): δ 2.44 (t, J = 4.6 Hz, 2H, CH2), 2.83 (t, J = 4.6 Hz, 2H, CH2), 5.49 (s, 1H,

C=C-H), 7.21 (d, J = 8.4 Hz, 2H, Ar-H), 7.38 (d, J = 8.4 Hz, 2H, Ar-H); 13

C NMR (100 MHz,

CD3OD): δ 29.77, 34.11, 69.01, 101.93, 123.87, 130.51, 131.09, 140.05, 177.08, 209.53; MS

(EI) m/z: 207 (M+).

3-Benzylaminocyclohex-2-enone[12] (7o, Entry 15, Table 1)

1368, 1236, 1187, 1144 cm-1

; 1H NMR (300 MHz, CDCl3): δ 1.94-1.97 (m, 2H, CH2), 2.26-2.29

(m, 2H, CH2), 2.36-2.40 (m, 2H, CH2), 4.20-4.21 (m, 2H, NHCH2), 5.15 (s, 1H, C=C-H), 5.41

(brs, 1H, NH), 7.25-7.36 (m, 5H, Ar-H); 13

C NMR (75 MHz, CDCl3): δ 21.97, 29.60, 36.49,

47.13, 97.39, 127.73, 127.85, 128.84, 136.77, 164.40, 197.40. MS (APCI) m/z: 202.1 (MH+).

3-[(Furan-2-ylmethyl)amino]cyclohex-2-enone[16] (7p, Entry 16, Table 1)

Off-white solid (0.429 g, 90%). mp: 108-110 °C; IR (KBr): 3195, 3012, 2929, 1543, 1262, 1188,

749 cm-1

; 1H NMR (400 MHz, CDCl3): δ 1.94-2.01 (m, 2H, CH2), 2.30-2.37 (m, 4H, CH2), 4.23

(d, J = 5.2 Hz, 2H, NHCH2), 4.85 (brs, 1H, NH), 5.22 (s, 1H, C=C-H), 6.27 (d, J = 3.2 Hz, 1H,

Het-H), 6.33-6.35 (m, 1H, Het-H), 7.37-7.38 (m, 1H, Het-H); 13

C NMR (100 MHz, CDCl3): δ

21.92, 29.60, 36.43, 40.06, 97.70, 108.39, 110.58, 142.60, 149.79, 163.50, 197.52; MS (APCI)

m/z: 191.9 (MH+).

3-Pyrrolidin-1-yl-cyclohex-2-enone[17] (7q, Entry 17, Table 1)

Yellow solid (0.363 g, 88%). mp: 84-86 °C; 1H NMR (300 MHz, CDCl3): δ 1.98-2.03 (m, 6H,

3CH2), 2.24-2.28 (m, 2H, CH2) 2.47-2.51 (m, 2H, CH2), 3.23 (m, 2H, CH2), 3.48 (m, 2H, CH2)

5.04 (s, 1H, C=C-H); 13

C NMR (75 MHz, CDCl3): δ 21.34, 23.99, 24.60, 27.19, 34.92, 47.34,

97.27, 163.44, 195.34; MS (APCI) m/z: 166.6 (MH+).

3-[(Furan-2-ylmethyl)-amino]-5,5-dimethylcyclohex-2-enone[12] (7t, Entry 20, Table 1)

Yellow solid (0.479 g, 86%). mp: 143-145 °C; IR (KBr): 3234, 3067, 1600, 1543, 1450, 1251,

1154 cm-1

; 1H NMR (400 MHz, CD3OD): δ 1.07 (s, 6H, 2CH3), 2.18 (s, 2H, CH2), 2.32 (s, 2H,

CH2), 4.33 (s, 2H, NHCH2), 5.24 (s, 1H, C=C-H), 6.33 (s, 1H, Het-H), 6.38 (s, 1H, Het-H), 7.47

(s, 1H, Het-H); 13

C NMR (100 MHz, CD3OD): δ 28.32, 33.71, 40.64, 43.54, 50.53, 95.03,

109.06, 111.46, 143.74, 151.70, 167.98, 199.46; MS (APCI) m/z: 220.1 (MH+).

III. Scanned spectra

1H NMR spectrum of compound 7a (Entry 1, Table 2)

13C NMR spectrum of compound 7a (Entry 1, Table 2)

HPLC chromatogram of compound 7a

Water: Acetonitrile = 80:20

Flow Rate = 1 mL/min

Column= C18

UV Wavelength = 305 nm

1H NMR spectrum of compound 7b (Entry 2, Table 2)

HPLC chromatogram of compound 7b

Column= C18

1H NMR spectrum of compound 7c (Entry 3, Table 2)

HPLC chromatogram of compound 7c

Column= C18

1H NMR spectrum of compound 7d (Entry 4, Table 2)

HPLC chromatogram of compound 7d

Column= C18

1H NMR spectrum of compound 7e (Entry 5, Table 2)

HPLC chromatogram of compound 7e

Column= C18

1H NMR spectrum of compound 7f (Entry 6, Table 2)

HPLC chromatogram of compound 7f

Column= C18

1H NMR spectrum of compound 7g (Entry 7, Table 2)

HPLC chromatogram of compound 7g

Column= C18

1H NMR spectrum of compound 7h (Entry 8, Table 2)

13C NMR spectrum of compound 7h (Entry 8, Table 1)

HPLC chromatogram of compound 7h

Column= C18

1H NMR spectrum of compound 7i (Entry 9, Table 2)

13C NMR spectrum of compound 7i (Entry 9, Table 1)

HPLC chromatogram of compound 7i

Column= C18

1H NMR spectrum of compound 7j (Entry 10, Table 2)

13C NMR spectrum of compound 7j (Entry 10, Table 1)

HPLC chromatogram of compound 7j

Column= C18

1H NMR spectrum of compound 7k (Entry 11, Table 2)

13C NMR spectrum of compound 7k (Entry 11, Table 1)

HPLC chromatogram of compound 7k

Column= C18

1H NMR spectrum of compound 7l (Entry 12, Table 2)

HPLC chromatogram of compound 7l

Column= C18

1H NMR spectrum of compound 7m (Entry 13, Table 2)

13C NMR spectrum of compound 6m (Entry 13, Table 2)

HPLC chromatogram of compound 7m

Column= C18

1H NMR spectrum of compound 7n (Entry 14, Table 2)

HPLC chromatogram of compound 7n

Column= C18

1H NMR spectrum of compound 7o (Entry 15, Table 2)

HPLC chromatogram of compound 7o

Column= C18

1H NMR spectrum of compound 7p (Entry 16, Table 2)

HPLC chromatogram of compound 7p

Column= C18

1H NMR spectrum of compound 7q (Entry 17, Table 2)

HPLC chromatogram of compound 7q

Column= C18

1H NMR spectrum of compound 7r (Entry 18, Table 2)

13C NMR spectrum of compound 7r (Entry 18, Table 1)

HPLC chromatogram of compound 7r

Column= C18

1H NMR spectrum of compound 7s (Entry 19, Table 2)

HPLC chromatogram of compound 7s

Column= C18

1H NMR spectrum of compound 7t (Entry 20, Table 2)

HPLC chromatogram of compound 7t

Column= C18

HPLC chromatogram of compound 7u

Column= C18

13C NMR spectrum of compound 8

Column= C18

IV. Determination of Interaction of the Compounds 7d, 8, and 9 Belonging

to the Newly Designed Scaffold I in the COX-2 Active Site:

The X-ray crystal structures of COX-1 (3KK6.pdb),[18] COX-2(6COX.pdb)[19] with compound SC-

558 were used. ‘PyMOL 1.3’ was used to optimize the enzyme by removing water molecules, residues

and fragments of enzyme. The file was saved in pdb file format. After protein optimization a standard

mode of ‘GOLD 4.1.2’ software was used for the docking purpose. ‘GOLD’ gives the best poses by a

Genetic algorithm search strategy. In ‘GOLD’ software ‘hermes 1.3.1’ was used as the visualizer.

Validation of process was done by calculating root-mean-square deviation (RMSD), which was 0.49. For

docking of the molecules, optimized protein was loaded in the ‘GOLD’ software, followed by addition of

hydrogen and deletion of ligand. The atom and residue were selected in 10 Å range. Then celecoxib (1),

lumiracoxib (4) and compounds 7d, 8, 9 were separately added to the active site of enzyme. The analysis

of the interactions was done in ‘PyMOL’ software. Results are summarized in Table S1 and S2 with

interaction and comparison of docking pose/score are summarized in Figure S1.

Table S1. Compounds with their docking score and interaction.

COMPOUND DOCKING POSE INTERACTION GOLD

Celecoxib (1)

1- Gln192 (N-H….O=C-

Gln192, 2.5 Å)

2- Leu352 (N-H…O=C-

Leu352, 1.9 Å)

3- Ser353 (NH…

O=C-Ser353, 2.8 Å).

4- His90 (S=O…H-N-

His90, 2.8 Å).

Lumiracoxib (4)

1- Tyr 385 (C=O…..O-H -

Tyr 385 2.62 Å)

2- Ser 530 (C=O …. O-H –

Ser 530 2.5 Å)

3- Leu 385 ( CH3- Leu 385

Hydrophobic

interaction)

No strong interaction. 41.82

1- Val 523 ( N-H….O=C-

Val 523, 2.9 Å)

2- Ser 530 ( C=O….H –O-

Ser 530 3.0 Å)

3- Tyr 385 (C=O…H-

O-Tyr 385

3.1 Å).

1- Cyclohexanone C=O,

Ser 530 ( C=O….H –O-Ser

530 2.85 Å)

Tyr 385 (C=O…H-O-

Tyr 385

2.73 Å).

Ser 530 ( C=O….H –O-Ser

530 2.88 Å)

Tyr 385 (C=O…H-O-

Tyr 385

2.28 Å).

Table S2. Compounds with their docking score and interaction in COX-1.

COMPOUND DOCKING POSE INTERACTION

Cyclohexanone C=O, Ser

530 ( C=O….H –O-Ser 530

3.2 Å)

t-butyl C=O, Tyr 355

(C=O…H-O-Tyr 355

2.3 Å).

Cyclohexanone C=O, Tyr

385 (C=O…H-O-Tyr 385

3.0 Å).

Figure S1: Comparison of the docking poses of celecoxib (1), lumiracoxib (4) with that of the

compounds 7d, 8, and 9 inside the active site of COX-2.

Celecoxibi (1) in green color, 7d in yellow color. Lumiracoxib (4) is in red color, 7d in yellow color.

Lumiracoxib (4) is in red color, 7d is in cyano Lumiracoxib (4) is in red color, 7d is in cyano.

8 is in orange, 9 is in gray white.

Lumiracoxib (4) is in red color, compound 8 is in orange Lumiracoxib (4) is in red color, compound 9 is in

gray white

V. References

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[18] G. Rimon, R.S. Sidhu, D.A. Lauver, J.Y. Lee, N.P. Sharma, C. Yuan, R.A. Frieler, R.C. Trievel, B.R. Lucchesi, W.L. Smith, Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1, Proc. Natl. Acad. Sci. 107 (2010) 28-33. [19] R.G. Kurumbail, A.M. Stevens, J.K. Gierse, J.J. McDonald, R.A. Stegeman, J.Y. Pak, D. Gildehaus, T.D. Penning, K. Seibert, P.C. Isakson, Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents, Nature 384 (1996) 644-648.

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