Synthesis and characterization of some chalcones and ... - Springer Link

Cent. Eur. J. Chem. • 8(1) • 2010 • 174–181 DOI: 10.2478/s11532-009-0124-x

Central European Journal of Chemistry

Synthesis and characterization of some chalcones and their cyclohexenone derivatives Research Article

Thekke V. Sreevidya1, Badiadka Narayana1*, Hemmige S. Yathirajan2 1

Department of Post-Graduate Studies and Research in Chemistry, Mangalore University, Mangalagangotri 574 199, INDIA 2 Department of Studies in Chemistry, University of Mysore, Mysore 570 006, INDIA

Received 27 February 2009; Accepted 18 August 2009

Abstract: A series of chalcones and their derivatives have been synthesized. Chalcones, 1-(1,3-benzodioxol-5-yl)-3-(aryl)-prop-2-en-1-ones were prepared by the aldol condensation of 1-(1,3-benzodioxol-5-yl)ethanones and aryl aldehydes. Based-catalyzed condensation of 1-(1,3-benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones with ethyl acetoacetate yields corresponding ethyl 4-(1,3-benzodioxol-5-yl)-6(aryl)-2-oxocyclohex-3-ene-1-carboxylates. Some of the synthesized chalcones were reported in the literature; the newly synthesized compounds were characterized by single crystal X-ray studies, IR, 1H-NMR and LCMS mass spectral analysis. Keywords: Chalcones • Michael addition • Single crystal XRD • Cyclohexenones

© Versita Warsaw and Springer-Verlag Berlin Heidelberg.

1. Introduction Chalcones, one of the major classes of natural products with widespread occurrence in fruits, vegetables, spices, tea and soy-based foodstuff, have been recently the subject of extensive investigations due to their interesting pharmacological activities. Chemically they consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon α,βunsaturated carbonyl system. It is a unique template molecule that is associated with several biological activities. The radical quenching properties of the phenolic groups present in many chalcones have raised interest in the use of the compounds or chalcone-rich plant extracts as either drugs or food preservatives [1]. Chalcones have been reported to possess many useful properties, including anti-inflammatory [2], antifungal [3-5], antioxidant [6], cytotoxic [7] and anticancer [8-11] activities. Certain chalcone derivatives are reported to inhibit the polymerization of tubulin to form microtubules and can be used as antimitotic agents [12-15]. Chalcone derivatives are also known to inhibit the destruction of myelin sheath in the central nervous system of multiple

sclerosis patients and are thus useful in controlling the progressive nature of the disease [16]. Apart from being biologically important compounds, chalcone derivatives show non-linear optical (NLO) properties with excellent blue light transmittance and good crystallizability. Not only photonics deals with the synergy between optics and electronics, it also provides the ties between optical materials, devices and systems. The inventions of lasers and nonlinear optical phenomena (NLO) have opened up many new areas of devices and systems, like frequency conversion and optical switching, that are of practical interest to mankind [17]. The NLO effect in the organic molecules originates from a strong donoracceptor intermolecular interaction, a delocalized π-electron system, and is also due to the ability to crystallize in non-centrosymmetric manner. Organic NLO materials are attracting a great deal of interest as they have greater optical susceptibilities, and higher optical thresholds for laser power compared to inorganic materials, as well as inherent ultrafast response times [18]. It is widely accepted that the NLO response is greatly increased upon lengthening of the chain of the conjugated π-bridge and chalcone derivatives have * E-mail: [email protected]

174

T.V. Sreevidya, B. Narayana, H. S. Yathirajan

such a configuration, with two planar rings connected by a conjugated double bond and hence, show significant nonlinearity [19]. Many chalcones have been reported as having high antimalarial activity, probably as a result of Michael addition of nucleophilic species to the double bond of the enone [20,21]. Licochalcone A, isolated from Chinese liquorice roots, has been reported as highly effective in chloroquine resistant Plasmodium falciparum strains in a [3H] hypoxanthine uptake assay [22,23]. Michael addition reactions of chalcones and azachalcones with ethyl acetoacetate have been successfully performed in the presence of catalytic amount of K2CO3 and under high speed vibration milling conditions [24]. The reactions took place at ambient temperature, without any solvent, and were completed within a very short time. In most cases, conventional side reactions were avoided and thus high chemoselectivity and quantitative yields were achieved. The desired Michael adducts obtained consisted exclusively of two diastereomers, ‘anti’ and ‘syn’, which were determined and assigned by 1H-NMR spectroscopy. Herein, we discuss the synthesis and characterization of two series of organic compounds, viz., chalcones and their cyclohexenone derivatives. Some of the chalcones were already reported in literature [25-28]. The newly synthesized compounds were characterized by elemental, IR, 1H-NMR and LCMS mass spectral analysis; a few chalcones were characterized using single crystal XRD.

2. Experimental procedure Melting points were taken in open capillary tubes and are uncorrected. The purity of the compounds was confirmed by thin layer chromatography using Merck silica gel 60 F254 coated aluminium plates in petroleum ether/ethyl acetate medium. IR spectra were recorded on Shimadzu- FTIR Infrared spectrometer in KBr (νmax in cm-1). 1H NMR spectra were recorded in CDCl3 on a Bruker (300 MHz) spectrometer using TMS as internal standard and mass spectra were recorded in LC/MSD Trap XCT spectrometer.

2.1. General procedure for the synthesis of chalcones (3a-n)

3’,4’-Methylenedioxyacetophenone (0.01 mol) and substituted aryl aldehydes (0.01 mol) were dissolved in methanol (25 mL) and 5 mL of 10% KOH solution was slowly added to it under stirring at 15-20°C. Stirring continued for 2 h at the same temperature. Progress of the reaction was monitored by TLC. The precipitate 175

was filtered off and washed with cold methanol. Recrystallization from methanol yielded the pure compounds with 62-89% yields. Synthesis of chalcones can also be carried out using LiOH as a dual activation catalyst [25].

2.2. General procedure for the synthesis of ethyl 4-(1, 3-benzodioxol-5-yl)-2-oxo- 6-(aryl) cyclohex-3-ene-1-carboxylate (5a-i)

Chalcones and ethyl acetoacetate in the 1:1 ratio were refluxed in 15 mL of ethanol for 2 h in the presence of 0.5 mL 10% KOH. The reaction mixture was kept overnight at room temperature. The precipitate was filtered off and recrystallized from ethanol to yield the required material, as an isomeric mixture, with 58-78% yield.

2.3. Spectral data

2.3.1. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(4-lorophenyl)2-oxocyclohex-3-ene-1-carboxylate (5a)

IR (KBr, cm-1): 1664 cm-1 (νc=o ketone), 1735 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.06 (t, 3H, CH3), 2.562.70 (m, 2H, -CH-CH-Ar), 3.23-3.41(m, 2H, CH2-CHAr), 4.07- 4.14 (q, 2H, -OCH2), 6.05 (s, 2H, -OCH2O), 6.32 (s,1H, =CH), 6.89 (m, 3H, ArH), 7.31 (m, 4H, ArH); LCMS: 399 (M+1), 400 (M+2).

2.3.2. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(3, 4dimethoxyphenyl)-2-oxocyclohex-3-ene-1-carboxylate (5b)

IR (KBr, cm-1): 1656 cm-1 (νc=o ketone), 1735 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.14 (t, 3H, CH3), 2.82-3.12 (m, 2H, -CH-CH-Ar), 3.56-3.68 (m, 2H, CH2-CH-Ar), 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.10- 4.16 (q, 2H, -OCH2), 6.08 (s, 2H, -OCH2O), 6.42 (s,1H, =CH), 6.74(d, 1H, ArH), 6.82 (m, 2H, ArH), 7.12 (m, 3H, ArH); LCMS: 425 (M+1), 426 (M+2).

2.3.3. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(3bromophenyl)-2-oxocyclohex-3-ene-1-carboxylate (5c)

IR (KBr, cm-1): 1663 cm-1 (νc=o ketone), 1733 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.10 (t, 3H, CH3), 2.863.10 (m, 2H, -CH-CH-Ar ), 3.71-3.82 (m, 2H, CH2-CHAr), 4.07- 4.14 (q, 2H, -OCH2), 6.04 (s, 2H, -OCH2O), 6.49 (d,1H, ArH), 6.86 (d, 1H, ArH), 7.05 (d, 1H, ArH), 7.12 (m,1H, ArH), 7.26 (m, 2H, ArH), 7.44 (m, 1H, ArH), 7.49 (s,1H, =CH); LCMS: 445 (M+1), 446 (M+2).

2.3.4. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(2methoxynaphthalen-6-yl)-2-oxocyclohex-3-ene-1carboxylate (5d) 175

Synthesis and characterization of some chalcones and their cyclohexenone derivatives

IR (KBr, cm-1): 1658 cm-1 (νc=o ketone), 1737 cm-1 (νc=o ester); H-NMR (300 MHz): δ 1.06 (t, 3H, CH3), 2.82-3.11 (m, 2H, -CH-CH-Ar ), 3.75-3.80 (m, 2H, CH2-CH-Ar), 3.86(s, 3H, OCH3), 4.03- 4.10 (q, 2H, -OCH2), 6.08 (s, 2H, -OCH2O), 6.39 (s,1H, =CH), 6.82 (dd, 2H, ArH), 6.86 (d, 1H, ArH), 7.44 (m, 6H, ArH); LCMS: 445 (M+1), 446 (M+2). 1

2.3.5. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(3-nitrophenyl)2-oxocyclohex-3-ene-1- carboxylate (5e)

IR (KBr, cm-1): 1660 cm-1 (νc=o ketone), 1733 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.12 (t, 3H, CH3), 2.923.15 (m, 2H, -CH-CH-Ar ), 3.73-3.81 (m, 2H, CH2-CHAr), 4.07- 4.16 (q, 2H, -OCH2), 6.08 (s, 2H, -OCH2O), 6.51 (s,1H, =CH), 6.86 (m, 3H, ArH),7.25 (m, 2H, ArH), 7.62 (m, 2H, ArH); LCMS: 406 (M+1), 407 (M+2).

2.3.6. Ethyl 4,6-bis(1,3-benzodioxol-5-yl)-2oxocyclohex-3-ene-1-carboxylate (5f)

IR (KBr, cm-1): 1658 cm-1 (νc=o ketone), 1729 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.05 (t, 3H, CH3), 2.823.07 (m, 2H, -CH-CH-Ar), 3.66-3.77 (m, 2H, CH2-CHAr), 4.03- 4.10 (q, 2H, -OCH2), 6.04 (s, 2H, -OCH2O), 5.97 (s, 2H, -OCH2O), 6.48 (d,1H, ArH), 6.79 (d, 1H, ArH), 6.83 (d,1H, ArH), 6.86 (s, 1H, =CH ), 7.05 (d, 1H, ArH), 7.09 (d, 1H, ArH), 7.12 (d, 1H, ArH); LCMS: 409 (M+1), 410 (M+2).

2.3.7. Ethyl 4-(1,3-benzodioxol-5-yl)-6-(2bromophenyl)-2-oxocyclohex-3-ene-1-carboxylate (5g)

IR (KBr, cm-1): 1664 cm-1 (νc=o ketone), 1737 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.10 (t, 3H, CH3), 2.863.12 (m, 2H, -CH-CH-Ar ), 3.73-3.81 (m, 2H, CH2-CHAr), 4.07- 4.14 (q, 2H, -OCH2), 6.06 (s, 2H, -OCH2O), 6.49 (d, 1H, ArH), 6.79 (d, 1H, ArH), 7.08 (d, 1H, ArH), 7.16 (m, 1H, ArH), 7.41 (m, 3H, ArH), 7.48 (s,1H, =CH); LCMS: 445 (M+1), 446 (M+2).

2.3.8. Ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6phenylcyclohex-3-ene-1-carboxylate (5i)

IR (KBr, cm-1): 1663 cm-1 (νc=o ketone), 1737 cm-1 (νc=o ester); 1H-NMR (300 MHz): δ 1.05 (t, 3H, CH3), 2.763.11(m, 2H, -CH-CH-Ar), 3.76-3.81(m, 2H, CH2-CH-Ar), 4.03- 4.10 (q, 2H, -OCH2), 6.04 (s, 2H, -OCH2O), 6.50 (d, 1H, ArH), 6.86 (d,1H, ArH), 7.12 (dd, 2H, ArH), 7.32 (m,5H, ArH), 7.37 (s,1H, =CH); LCMS: 365 (M+1), 366 (M+2).

3. Results and Discussion Chalcones were synthesized by a basecatalyzed Claisen–Schmidt condensation of 3’,4’-methylenedioxyacetophenone and substituted

176

aryl aldehydes. The reaction of chalcones with ethyl acetoacetate is known to lead to three structurally diverse types of compounds, depending on the experimental conditions. The catalyst plays a major role in directing the reaction towards different end products. A strong Lewis acid such as BF3.etherate generates pyrylium cations during the reaction of chalcones and acetoacetic esters, but basic catalyst would turn the intermediate Michael addition product into cyclohexenones through the intramolecular cyclocondensation of the methyl group, originating from acetoacetic acid ester, and the ketone function of the chalcone. Thus in the presence of a base, chalcones containing 1,3-benzodioxolyl (3a-n) react with ethyl acetoacetate (4) to produce cyclohexenones (5a-i) by means of an intermediate Michael adduct, as given in Scheme 1. 1-(1,3-Benzodioxol-5-yl)-3-(aryl) prop-2-en-1-ones (3a-n) were prepared by the reaction of 1-(1,3-benzodioxol-5-yl)ethanones (1) with aromatic aldehydes (2) in presence of KOH in ethanol as given in Scheme 1. The newly synthesized chalcones were characterized by elemental and X-ray analysis. Some of the synthesized chalcones were already reported in literature as being synthesized in the presence of LiOH in methanol. In both, the reported and proposed method, the yields were higher than 70%; it seemed that the presence of LiOH increased the rate of the reaction. A much shorter reaction time and lack of an extraction step are the advantages of our procedure over the one reported in literature [25]. Thus 1-(1,3-benzodioxol-5-yl)-3-(aryl)prop-2-en-1ones formed on treatment with ethyl acetoacetate in presence of KOH in ethanol yield Michael addition product. The intermediate formed on cyclization gave ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-(aryl)cyclohex-3ene-1-carboxylate. This cyclization proceeds through the intramolecular condensation of a methyl group and a carbonyl group. The cyclocondensation of ethyl acetoacetate with chalcones leads to the generation of two chirality centers in the structure of cyclohexenones and both, R and S, configurations of the chiral carbon atoms are expected a mixture of diastereomers will result. No attempt has been undertaken to separate the diastereomeric cyclohexenones and they have been characterized as a mixture. The newly synthesized compounds have been characterized by elemental, IR, 1 H-NMR and mass spectral analysis. The spectral data are reported in the experimental section and elemental analysis data are given in Tables 1 and 2. The structures of some chalcones viz., (2E)-1-(1,3-benzodioxol-5-yl)3-(4-chlorophenyl)prop-2-en-1-one (I), ( 2E)-1-(1,3benzodioxol-5-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1one (II) and (2E)-1-(1,3-benzodioxol-5-yl)-3-(3-


Table 1.

Characterization Data of 1-(1,3-Benzodioxol-5-yl)-3-(aryl)prop-2-en-1-ones O O

Ar

O

Compound No.

Melting Point ºC

Molecular Formula

68

162-166

C16H11ClO3

70

132-134

66

Yield* (%)

Ar

Nature of Products

Elemental Analysis, % Found (Calculated) C

H

N

Cream powder

67.14 (67.03)

3.60 (3.87)

-

C18H16O5

White powder

69.20 (69.22)

5.00 (5.16)

-

147-149

C17H14O4

White powder

72.20 (72.33)

4.98 (5.00)

-

82

161-163

C17H12O5

Cream crystals

68.78 (68.92)

3.99 (4.08)

-

3e

62

122-124

C24H16O3

Yellow powder

81.89 (81.80)

5.00 (4.58)

-

3f

78

139-141

C16H12O3

Cream crystals

76.04 (76.18)

4.52 (4.79)

-

75

92-94

C18H17NO3

Yellow powder

73.12 (73.20)

5.68 (5.80)

4.81 (4.74)

56

131-133

C16H11NO5

Yellow crystals

64.61 (64.65)

3.52 (3.73)

4.68 (4.71)

62

144-146

C16H11NO5

Yellow crystals

64.56 (64.65)

370 (3.73)

4.66 (4.71)

74

101-103

C17H14O5

Off-white powder

68.38 (68.45)

4.70 (4.73)

-

77

120-122

C16H11BrO3

Brownish powder

57.96 (58.03)

3.42 (3.35)

-

69

117-119

C16H11BrO3

Brownish powder

58.12 (58.03)

3.47 (3.35)

-

65

124-126

C21H16O4

Cream powder

75.68 (75.89)

4.66 (4.85)

-

78

118-120

C16H11FO3

Off -white powder

71.04 (71.11)

4.16 (4.10)

-

3a Cl

3b

H3C O OCH3

3c H3C O O

3d

3g

O

H3C

N CH3

3h

NO 2

3i NO 2

3j

HO OCH3

3k Br

3l

Br

3m H3C O

3n F

177

177


Table 2.

Characterization Data of (Ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-(aryl)cyclohex-3-ene-1-carboxylate) O COOC2H5 O

Ar

O

Compound No.

Yield* (%)

Ar

5a

Melting Point ºC

Molecular Formula

Nature of Products

H3C O

H

N

135-137

C22H19ClO5

Cream powder

66.12 (66.25)

4.72 (4.80)

-

62

132-134

C24H24O7

Yellow powder

67.60 (67.91)

5.62 (5.70)

-

80

126-128

C22H19BrO5

Cream powder

59.45 (59.61)

4.90 (4.32)

-

76

116-118

C27H24O6

Cream powder

73.00 (72.96)

5.14 (5.44)

-

64

151-153

C22H19NO7

Yellow powder

64.17 (64.54)

4.85 (4.68)

3.91 (3.42)

85

170-172

C23H20O7

Off white powder

67.70 (67.64)

5.00 (4.94)

-

77

121-123

C22H19BrO5

Cream powder

59.48 (59.61)

4.55 (4.32)

-

65

86-88

C24H25NO5

Yellowish powder

70.52 (70.74)

6.04 (6.18)

3.40 (3.44)

79

155-157

C22H20O5

Off-white powder

72.23 (72.51)

5.25 (5.53)

-

OCH3

5c

C 78 Cl

5b

Elemental Analysis, % Found (Calculated)

Br

5d H3C O

5e NO 2

O

5f O

5g

Br

5h

H3C

N CH3

5i

bromophenyl)prop-2-en-1-one (III) were confirmed by single crystal X-ray study [29,30] and are given in Figs. 1, 2 and 3. The compound, (2E)-1-(1,3-benzodioxol-5yl)-3-(4-chlorophenyl)prop-2-en-1-one (I), crystallizes in the monoclinic P21/c space group with cell parameters, a=2.7231(15), b = 4.9239(4), c = 11.9995(7)Å, β= 99.953(6)˚. The compound, (2E)-1-(1,3-benzodioxol-5-yl)-3-(3,4dimethoxyphenyl)prop-2-en-1-one (II), crystallizes in the triclinic crystal system, space group P1 with a = 8.2961(2) Å, b = 13.8829(6) Å, c = 14.6713(7)Å, α = 64.185(4), β = 83.560(3)˚, γ = 84.966(3)˚ and in 178

(2E)-1-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)prop2-en-1-one (III), the molecule adopts an E configuration with respect to the C=C double bond of the propenone unit and crystallizes in monoclinic, P21/c, a = 14.237(3) Å, b = 8.1811 (17) Å, c=11.717(2) Å, β= 100.658(3)°. The 13 non-H atoms of the benzodioxol and propenone units in III are approximately coplanar and the bromobenzene ring plane forms a dihedral angle of 10.8(1)° to this plane. The structure is layered, with the molecules forming a herring-bone arrangement within each layer.


(a)

(b)

Figure 1. Ortep drawings (a) and molecular packing (b) for (2E)-1-(1,3-benzodioxol-5-yl)-3-(4- chlorophenyl)prop-2-en-1-one

(c)

(d)

Figure 2. Ortep drawings (c) and molecular packing (d) for (2E)-1-(1,3-benzodioxol-5-yl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one

(e)

(f)

Figure 3. Ortep drawings (e) and molecular packing (f) for (2E)-1-(1,3-benzodioxol-5-yl)-3-(3- bromophenyl)prop-2-en-1-one

179

179


O O

O O

CH3

Ar

+

O

H

O

Base EtOH

O

2

1

Ar (3a-n)

COOC2H5 Base H3C O

O

O

*

COOC2H5

*

Ar

O

H3C

4

O

O O

COOC2H5 Ar

O (5a-i)

Scheme 1.

Claisen–Schmidt condensation of 3’,4’-methylenedioxyacetophenone and substituted aryl aldehydes

Hydrogen bonding and crystal packing effects influence the twist angle between the mean planes of the 1,3-benzodioxol-5yl and benzene groups in both I and II, while π-π stacking interactions between the adjacent 5-membered dioxol rings and the 9-membered benzodioxol group, as well as the benzyl ring, stabilize the crystal packing. In I there is an intermolecular C–H·O hydrogen bond between the C15 and O1 atoms. The dihedral angle between the mean planes of the 1,3-benzodioxol-5-yl group and the benzene ring is 18.26°. In II the compound crystallizes with two independent molecules in the asymmetric unit. Intermolecular C–H-O hydrogen bond interactions occur in both molecules that help to stabilize the crystal packing in the unit cell. The dihedral angle between the mean planes of the 1,3-benzodioxol-5-yl group and the benzene ring in the two independent molecules in II is 7.8(9)° (A) and 37.9(7)° (B), respectively. The molecular packing in I and II is stabilized by hydrogen bonding and also by π-π stacking interactions. 180

4. Conclusions Some chalcones, such as 1-(1,3-benzodioxol-5yl)-3-(aryl)prop-2-en-1-ones, and their cyclized products with ethyl acetoacetate, such ethyl 4-(1,3-benzodioxol-5-yl)-2-oxo-6-(aryl)cyclohex-3ene-1-carboxylate derivatives, were synthesized and characterized by spectral analysis.

Acknowledgements One of the author (TVS) thanks Mangalore University for the use of the research facilities and DST & UGC, Govt. of India, for financial support through FIST & SAP programmes.


References [1] D.N. Dhar, The Chemistry and Related Compounds (John Wiley, New York,1981) [2] Z. Nowakowska, Eur. J. Med. Chem. 42, 125 (2007) [3] S. Lopez et al., Bioorg. Med. Chem. 9, 1999 (2001) [4] P. Boeck et al., Arch Pharmacy 338, 87 (2005) [5] H.N. Elsohly, A.S. Joshi, A.C. Nimrod, L.A. Walker, A.M. Clark, Planta Medica 67, 87 (2001) [6] N. Yayli et al., J. Photochem.Photobiol. A 169, 229 (2005) [7] M.V.B. Reddy et al., Bioorg. Med. Chem. 16, 7358 (2008) [8] G. Saydam et al., Lukemia Research 27, 57 (2003) [9] M. Cabrera et al., Bioorg. Med. Chem. 15, 356(2007) [10] C. Nakamura et al., Bioorg. Med. Chem. 10, 699 (2002) [11] A. Modzelewska, C. Pettit, G. Achanta, N.E. Davidson, P. Huang, S.R. Khan, Bioorg. Med. Chem. 14, 3491 (2006) [12] D.J. Kerr, E. Hamel, M.K. Jung, B.L. Flynn, Bioorg. Med. Chem. 15, 3290 (2007) [13] D.Y. Kim et al., J.Med. Chem. 49, 5664 (2006) [14] N.J. Lawrence, R.P. Patterson, L.-L. Ooi, D. Cook, S. Ducki, Bioorg. Med. Chem. Lett. 16, 5844 (2006) [15] J.A. Hadfield, S. Ducki, N. Hirst, A.T. McGown, Progress in Cell Cycle Research 5, 309 (2003) [16] M.L. Edwards, S.P. Sunkara, D.M. Stemerick, US Patent No. 4863968, 1989.09.05. [17] M.D. Aggarwal, W.S. Wang, K. Bhat, B.G. Penn, D.O. Frazeir, In: H.S. Nalwa (Ed.), Handbook of Advanced Electronic and Photonic Materials and Devices (Academic Press, USA, 2001) Vol. 9, 193

181

[18] M. Samoc, A. Samoc, B. Luther-Davies, J. Opt. Soc. Am. B 15, 817 (1998) [19] J. Indira, P.P. Karat, B.K. Sarojini, J. Cryst. Growth 242, 209 (2002) [20] L. Troeberg et al., Mol. Med. 6, 660 (2000) [21] V.J. Ram, A.X. Saxena, S. Srivastava, S. Chandra, Bioorg. Med. Chem. Lett. 10, 2159 (2000) [22] M. Chen, T.G. Theander, S.B. Christensen, L. Hviid, L. Zhai, A. Kharazmi, Antimicrobial Agents and Chemotherapy 38, 1470 (1994) [23] A. Kharazmi, M. Chen, T. Theander, S.B. Christensen, Annals Trop. Med. Parasite. 91, S91 (1997) [24] Z. Zhang, Y.W. Dong, G.W. Wang, Chem. Lett. 33, 168 (2004) [25] J-C. Jung et al., J. Med. Chem. 51, 4054 (2008) [26] M.K. Ruby, R. Venkataramanan, Chem. Heterocycl. Comp. 40, 631(2004) [27] B. Insuasty, F. Orozco, J. Quiroga, R. Abonia, M. Nogueras, J. Cobo, Eur. J. Med. Chem. 43, 1955 (2008) [28] B. Lygo, S.D. Gardiner, M.C. McLeod, D.C.M. To, Org. Biomol. Chem. 5, 2283 (2007) [29] J.P. Jasinski, R.J. Butcher, T.V. Sreevidya, H.S. Yathirajan, B. Narayana, Analytical Sciences, 24, x245 (2008) [30] H. Li, T.V. Sreevidya, B. Narayana, B.K. Sarojini, H.S. Yathirajan, Acta Crystallographica, E64, o2387 (2008)

181