International Journal of Organic Chemistry, 2011, 1, 167-175 doi:10.4236/ijoc.2011.14025 Published Online December 2011 (http://www.SciRP.org/journal/ijoc) Copyright © 2011 SciRes. IJOC 167 Synthesis and Antibacterial Activity of Urea and Thiourea Derivatives at C-8 Alkyl Chain of Anacardic Acid Mixture Isolated from a Natural Product Cashew Nut Shell Liquid (CNSL) N. Subhakara Reddy1,2, A. Srinivas Rao1*, M. Adharvana Chari3,4*, V. Ravi Kumar1, V. Jyothi3, V. Himabindu2 1Medicinal Chemistry Laboratory, GVK Biosciences Pvt. Ltd., Hyderabad, India 2Centre for Environment, Institute of Science and Technology, JNT University, Hyderabad, India 3Dr. MACS Bio-Pharma Pvt. Ltd., Hyderabad, India 4Department of Complexity Science and Engineering, School of Frontier Sciences, University of Tokyo, Chib a, Japan E-mail: drmac_s@yahoo.com Received August 12, 2011; revised September 23, 2011; accepted October 5, 2011 Abstract Synthesis and antibacterial activity of some novel urea and thiourea derivatives (7a-7k, 8a-8f) of anacardic acid prepared from commercially available anacardic acid which is obtained from natural product Cashew Nut Shell Liquid (CNSL). Compounds (7a-7k, 8a-8f) were tested for Gram positive and Gram negative bac- terial cultures. Most of the compounds were showed active compared with standard drug ampicilline. Keywords: Synthesis, Urea and Thiourea Derivatives, Anacardic Acid, Anti-Bacterial Activity 1. Introduction Among the different families of plants, Anacardiaceae- shrub family is very important since this plant consist of Non-isoprenoid phenolic lipids. The cashew tree, Ana- cardium occidentale L., is a botanical species native of eastern Brazil and was introduced into other tropical countries such as India, Africa, Indonesia and South East Asia in the 16th century [1-2]. Approximately 2 - 3 cm in length kidney shaped structure is true fruit of cashew is the nut, which is attached to the end of a fleshy bulb, generally called the cashew apple. The shell consist of the raw nut (50% of the weight), the kernel (25%) and the remaining 25% consists of the natural cashew nut shell liquid (CNSL), a viscous reddish brown liquid. The CN- SL is traditionally obtained as a by-product during the iso- lation of the kernel by roasting the raw nuts. Crude CN- SL represents one of the major and cheapest sources of naturally occurring non-isoprenoid phenolic lipids such as anacardic acids (1), cardols (2), cardanols (3), methy- lcardols (4) (Figure 1) and polymeric materials. CNSL has found important commercial usage as the phenolic raw material for the manufacture of certain resins and plastics having unusual electric and frictional properties [3-6]. An- acardic acid mixture (1a-d) isolated from a natural prod- uct Cashew Nut Shell Liquid (CNSL) which is a by-pro- duct of cashew nut industry and these are salicylic acid derivatives with a nonisoprenoid alk(en)yl side chain [7]. Anacardic acid (pentadecyl salicylic acid) is a phenolic constituent present in Cashew Nut Shell Liquid (CNSL); (Anacardium occidentale L.) and exhibits antimicrobial properties [8-14], which have led to the preparation of various analogues [15-20] and soybean lipoxygenase-1 inhibitory activity [21-22] Kubo et al. [23] reported the separation of anacardic acid into monoene (15:1), diene (15:2) and triene (15:3) by preparative HPLC and tested against cancer cells, and found to show moderate cyto- toxic activity on BT-20 breast and HeLa epithelioid cer- vix carcinoma cells. The emergence of drug resistant strains in clinical applications [24-26] especially to Gram positive bacteria[27-28] has created a problem of global proportions [29-30] G. C. Reddy et al. reported the syn- thesis of benzamide derivatives of anacardic acid [31], sildenafil analogues [32], dihydropyridine analogues [33] as calcium channel blockers, isonicotinoylhydrazones for antimycobacterial activity [34] starting from anacardic
N. S. REDDY ET AL. 168 OH C15H31-n a b d n=0 n=2 n=4 n=6 1 OH C15H31-n 2 OH C15H31-n 3 OH C15H31-n 4 HO HO H3C 14 8 11 8 11 8 c OH O Figure 1. Naturally occurring non-isoprenoid phenolic lip- ids such as anacardic acids (1), cardols (2), cardanols (3) and methylcardols (4). acid. Recently, a few anacardic acid derivatives exhibited various activities like affect the structure of the enzyme [35], anacardic acid is a specific activator of kinase ac- tivity of Aurora Kinase A [36], suppresses expression of nuclear factor-kB regulated gene products leading to potentiation of apoptosis [37] inhibitor of the HAT ac- tiveity of recombinant Plasmodium falciparum GCN5 [38] and as modulators of histone acetyltransferases [29]. Synthesis of lasiodiplodin from the non-isoprenoid phe- nolic lipids of CNSL as well as the salicylate macrolac- tone and other derivatives were reported by santos et al. [40-43]. In the present work we wish to report to synthesize novel cell permeable urea and thiourea compounds from cheaply available anacardic acid which was a major con- stituent of Cashew Nut Shell Liquid (CNSL) natural sour- ce to evaluate their biological activity by various anti- bacterial strains. This report describes the synthesis, spec- troscopic identification and antibacterial activity of some novel urea and thiourea derivatives at C-8 alkyl chain of anacardic acids against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes bacterial strains. 2. Results and Discussion Here we described the synthesis of various biologically active novel urea and thiourea derivatives using anacar- dic acid mixture as starting material and various reagents in the given below conditions (Scheme 1). The anacardic acid mixture (1a-d) was isolated from commercially available CNSL by a reported method [44, 45]. Accordingly CNSL was treated with calcium hy- droxide, during which anacardic acid present in CNSL becomes calcium anacardate, which was isolated and hy- drolyzed with dil. hydrochloric acid to generate anacar- dic acid ene mixture, which was a mixture of monoene, diene and triene located at (8’), (8’,11’) and (8’,11’,14’) of the C15 alkyl chain respectively. Anacardic acid ene mixture was methylated using dimethyl sulphate in presence of potassium carbonate in acetonitrile to afford 2. Ozonolysis of Compound 2 resulted in the formation of 3, C8-OH. The compound 3 was converted to 4 using carbon tetra bromide in Dichloromethane. The com- pound 4 was reacted with sodium azide followed by re- duction with Pd/C under H2 pressure to obtaine amine 6 coupled with various isocynate or isothiocynate in chlo- roform to obtain compounds (7a-7k, 8a-8f, Scheme 1) of O O O O O O OH b,c e f 6 2 3 4 5 g 7(a-k) R d O O O Br O O O N3 O O O NH2 OO O N H CR1 O OH OH O C15H31-n a b c d n=0 n=2 n=4 n=6 1 8(a-f) OO O N H CR2 S h Scheme 1. Synthesis of various biologically active urea and thiourea (at C8 alky l chain) derivatives from anacardic acid mix- ture. Reagents: (a) Di methyl sulfate, K2CO3, Acetonitrile, 90˚C, 24 h; (b) Ozonalasis, MeOH, CH2Cl2, –78˚C, 6 h; (c) MeOH, NaBH4, 18 h, 0˚C, R.T; (d) CBr4, Pyridine, TPP, CH2Cl2, 0˚C, R.T, 8 h; (e) NaN3, DMF, 100˚C, 4 h; (f) 10% Pd/C, 50 psi, 2 h; (g) different isocyanate, CHCl3; (h) different isothiocyanate, CHCl3. Copyright © 2011 SciRes. IJOC
169 N. S. REDDY ET AL. urea and thiourea derivatives were purified by column chromatography to yield title compounds. The structure of urea and thiourea derivatives (7a-7k, 8a-8f) was de- termined by using different spectroscopic techniques 1H NMR, IR, Mass. The resulting compounds are screened for their antibacterial activity. Biological Activity The urea and thiourea derivatives (7a-7k, 8a-8f) were screened for their antibacterial activity [27] against some of the pathogenic bacteria viz. E. coli (MTCC443), P. aeruginosa (MTCC424), S. aureus, (MTCC96) and S. pyogenes (MTCC443) using agar well diffusion method according to the literature protocol [46]. The anti-bacte- rial activity of the analogues was compared with stan- dard drug ampicilline and the results of investigation have been presented in Table 1 and observed that some of the compounds are showed high biological activity. Table 1. Antibacterial activity of urea and thiourea derivatives at C-8 alkyl chain of anacardic acid mixture. Name of the Bacteria (Conc. 250 µg/ml) & Inhibition Zone in mm Compound No. R E. coli MTCC443 P. aeruginosa MTCC424 S. aureus MTCC96 S.pygenes MTCC442 S* ampicilline SD* amplicilline 20 20 18 19 7a 17 16 17 16 7b 19 19 15 19 7c 21 18 17 17 7d Cl 19 16 18 15 7e Cl Cl 17 16 18 19 7f F 19 18 17 15 7g NC 20 17 17 17 7h CN 17 17 17 19 7i CF 3 17 16 16 17 7j O 18 17 17 15 7k O 16 16 16 16 8a 16 21 17 17 8b Cl 19 17 17 18 8c Cl Cl 17 16 16 18 8d F 16 20 15 17 8e CN 22 20 16 17 8f CF 3 15 16 17 19 Copyright © 2011 SciRes. IJOC
N. S. REDDY ET AL. 170 Based on the test results it is evident that several of syn- thesized anacardic acid analogues possess moderate to good activity against the Gram +ve and Gram –ve bacte- ria. Of all the compounds prepared entities 7a, 7b, 7c, 7d, 7f, 7g, 8b and 8e activity against E. coli, MTCC443, 7a, 7b, 8a, 8d and 8e activity against P. aeruginosa, MT- CC424; display good to excellent activity while the re- maining compounds showed moderate activity. The most active antibacterial agent against Escherichia coli found to be compound 7c, 7f, 7g, and 8e having -CN,F groups and other compounds in the series exhibited moderate to good activity. The compounds 7d, 7e, 8b and 8f showed good activity against S. aureus MTCC96 and 7a, 7b, 7e, 7h, 8b, 8c and 8f showed good activity against S. pyo- genes MTCC442. This indicates chloro, dichloro, flouro, cyano and methoxy substituted compounds showed bet- ter activity when compared to other substituted groups. Here seems to be, thiourea substituted novel compounds are exhibiting better activity than urea substituted com- pounds. The activity depends to some extent on the R substituent, however all the compounds showed antibac- terial activity. It may be suggested that the anacardic acid derivative with a suitable R may lead to a good antibac- terial agent against all the Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes bacterial strains. 3. Conclusions In summary, the present study describes a convenient and efficient protocol for the synthesis of sulfonamide derivatives by using anacardic acid mixture using various reagents and different conditions. We believe that this procedure is convenient, economic and a user-friendly process for the synthesis of these various novel urea and thiourea compounds from anacardic acid mixture. All compounds structures are supported by physico chemical and IR, NMR, Mass spectral data. Urea and thiourea de- rivatives were screened for their antibacterial activity ag- ainst few bacterial strains and observed that some of the compounds are showed more biological activity than stan- dards used. 4. Experimental Section 4.1. General Reagents and Equipment All chemicals and solvents were obtained from Aldrich and Spectrochem., India and used without further purifi- cation. Column chromatographic separations were carri- ed out on silica gel 60 - 120 mesh size and eluting with a gradient of hexane: ethyl acetate. Analytical thin layer chromatography was performed on precoated Merck si- lica gel (60F254/0.2 mm) plates using UV light, 5% eth- anolic phosphomolybdic acid or iodine vapours to visu- alize the spots. Melting points were determined in open glass capillaries on a Mel-temp apparatus and are uncorr- ected. The IR spectra were recorded on a Thermo Ni- colet IR 200 FT-IR spectrometer as KBr pellets and the wave numbers were given in cm−1. The 1H and 13C NMR spectra of samples were recorded on a Varian EM-360, NMR spectrometer using TMS as an internal standard in CDCl3.The mass spectra were recorded on Jeol JMS-D 300 and Finnigan Mat b at 70 eV with an emission current of 100 µA. The oxidative cleavages were performed with a Welsbach T-408 ozonizator and the catalytic hydroge- nations in a Parr apparatus. 4.2. General Procedure: Isolation of Anacardic Acids (1) The shells (500 g) of cashew nuts from Anacardiumoc- cidentale were extracted in a Soxhletextractor with com- mercial 95% ethanol (2.0 L) during 6 h, yielding a crude extract (CNSL, 157 g, 31% by weight). Anacardic acids (1) were removed in 61% from CNSL (15.25 g) either by precipitation with lead nitrate or calcium hydroxide ac- cording to protocols described in the literature [44,45]. The spectral properties were identical to those reported in the literature [44,45]. Preparation of Methyl anacardate methyl ethers ene mixture (2): To a solution of Compound 1 (65 g, 186.78 mmol) in acetone was added K2CO3 (103.1 g, 747.12 mmol), Di methyl sulfate (44.3 mL, 466.95 mmol). The contents were heated at 65˚C for 5 h. Reac- tion mixture was cooled to room temperature, filtered and washed with ethyl acetate. Filtrate was distilled off, crude compound was re dissolved in ethyl acetate (300 mL). Organic layer was washed with water, brine solu- tion and dried over anhydrous sodium sulphate and dis- tilled off ethyl acetate. Crude compound was purified by 60 - 120 silica pet ether pack column compound was eluted with 5% ethyl acetate: pet ether to get compound 2, Yield: 58 g, light yellow liquid. Synthesis of 2-(8-Hydroxy-octyl)-6-methoxybenzo- ic acid methyl ester (3): A solution of compound 2 (15 g, 40.540 mmol) in dichloro methane: methanol (1:1, 500 mL) was added a pinch of Sudan red catalyst and cooled to –78˚C. Ozone gas purged through reaction mixture until starting material was completed (8 h). Nitrogen gas was purged through reaction mixture for 30 min (to re- move excess O3 gas), dimethyl sulfide was added few drops and stirred for 20 min at –15˚C. Sodium boro- hydride (9.970 g, 263.51 mmol) was added portion wise over a period of 45 min. Reaction mixture was slowly bring it to room temperature and stirred at this tempera- Copyright © 2011 SciRes. IJOC
171 N. S. REDDY ET AL. ture for 18 h. Reaction mixture was quenched with cold water (400 mL), dichloro methane and methanol distilled off and crude compound was diluted with water and ex- tracted with ethyl acetate (2 × 200 mL). The combined organic layer was washed with brine solution (150 mL) dried over anhydrous sodium sulphate, filtered and eva- porated under vacuum, to obtaine crude compound was purified by neutral alumina pet ether packed column, compound was eluted with 20% ethyl acetate: pet ether to obtain compound (3) as yellow liquid (7.1 g, 59.5%); IR (DCM film): 3401, 2930, 1728, 1586, 1467, 1268, 1110, 1071, 954, 749 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.31 (bs, 8H), 1.53 - 1.59 (m, 4H), 2.53 (t, 2H, J = 8.0 Hz), 3.63 (t, 2H, J = 6.8 Hz), 3.81 (s, 3H), 3.90 (s, 3H), 6.75 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.26 - 7.28 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3), δ: 25.58, 29.16, 29.23, 29.63, 31.00, 32.62, 33.35, 52.10, 55.73, 62.81, 108.23, 121.37, 123.26, 130.18, 141.17, 156.10, 168.93 ppm; ESIMS (m/z): 295 (M + H)+. Synthesis of 2-(8-bromo-octyl)-6-methoxy-benzoic acid methyl ester (4): A solution of compound 2 (15 g, 51.02 mmol) in Dichloro methane (150 mL) was added dry pyridine (42 mL, 510.2 mmol) tri phenyl phosphene (22.73 g, 86.734 mmol) at 0˚C. Carbon tetra bromide (25.4 g, 76.53 mmol) was added portion wise over a pe- riod of 15 min. The contain were slowly bring it to rt and stirred at rt for 6 h. Reaction mixture was diluted with DCM (100 mL) washed with 2N HCl (2 × 150 mL), wa- ter (200 mL), brine solution (175 mL), dried over anhy- drous Na2SO4, filtered and evaporated under vacuum, Cru- de compound was purified by 100 - 200 silica pet ether column compound was eluted with 10% ethyl acetate: pet ether and distilled off solvent to obtain compound 4 (16.5 g, 90.8%) as yellow liquid; IR (DCM film): 3071, 3002, 2931, 2854, 1732, 1588, 1464, 1437, 1268, 1109, 1072, 960, 749 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.29 - 1.42 (m, 8H), 1.52 - 1.59 (m, 4H), 1.80 - 1.87 (m, 2H), 2.53 (t, 2H, J = 8.0 Hz), 3.40 (t, 2H, J = 7.2 Hz), 3.82 (s, 3H), 3.90 (s, 3H), 6.76 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 7.6 Hz), 7.24 - 7.28 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3), δ: 28.05, 28.56, 29.12, 29.26, 31.02, 32.72, 33.36, 34.02, 52.13, 55.78, 108.27, 121.39, 123.32, 130.20, 141.14, 156.14, 168.90 ppm; ESIMS(m/z): 357 (M + H)+, 359 (bromo). Synthesis of 2- (8-aza-octyl)-6 -methoxy-b enzoic acid methyl ester (5): A solution of compound 3 (2.0 g, 5.617 mmol) in DMF (10 mL) was added Sodium azide (548 mg, 8.426). The contain were heated at 100˚C for 3 h, reaction mixture was poured into cool water (70 mL) and extracted with diethyl ether (2 × 40 mL), the organic layer was washed with water (50 mL), brine solution (30 mL), dried over anhydrous Na2SO4, filtered and evapo- rated under vacuum to obtain compound 5 as yellow liq- uid (1.5 g, 83.7%); IR (DCM film): 3087, 3002, 2932, 2856, 2095, 1731, 1588, 1464, 1266, 1109, 1071, 753 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.30 (bs, 8H), 1.59 (bs, 4H), 2.53 (t, 2H, J = 7.6 Hz), 3.25 (t, 2H, J= 7.2 Hz), 3.82 (s, 3H), 3.91 (s, 3H), 6.76 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 8.0 Hz), 7.25 - 7.29 (m, 1H) ppm; ESIMS (m/z): 320 (M + H)+. Synthesis of 2-(8-Amino-octyl)-6-methoxy-benzoic acid methyl ester (6): A solution of compound 4 (2.0 g, mmol) in ethanol (30 mL) was taken into a 500 mL Parr- hydrogenation vessel and added a suspension of 10% Pd/C (220 mg, 10%) in 20 mL of ethanol under argon atmos- phere and applied H2-pressure (60 psi) for 2 h. Reaction mixture was filtered through celite bed and concentrated the filtrate under reduced pressure to obtain 2-(8-Ami- no-octyl)-6-methoxy-benzoic acid methyl ester (6) (1.7 g, 92.5%) as a yellow liquid. IR (neat): 3436, 2931, 2857, 1729, 1587, 1467, 1438, 1268, 1111, 1073, 829, 753 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.273 (bs, 8H), 1.54 (bs, 2H), 1.65 - 1.79 (m,2H), 2.51 (t, 2H, J = 7.6 Hz), 2.94 (t, 2H, J = 8.0 Hz), 3.79 (s, 3H), 3.89 (s, 3H), 6.74 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 8.0 Hz), 7.23 - 7.27 (m, 1H) ppm ; ESIMS (m/z): 294 (M + H)+. Synthesis of urea and thio urea compounds: A so- lution of amine (300 mg, 1.023 mmol) in dry CHCl3 was taken in seal tube was added isocynate or iso thiocynate (1.22 mmol) at rt and stirred at rt for 3 h to 8 h and dis- tilled off solvent and crude compound was purified by column. Synthesis of methyl 2-(8-(3-ethylureido)octyl)-6-me- thoxybenzoate (7a): Using 6 and ethyl isocyanate as starting materials, the title compound 7a was obtained as a off white solid (Yield = 44.4%); m.p. 71˚C - 72˚C; IR (KBr): 3338, 2929, 2854, 1729, 1625, 1579, 1466, 1269, 1108, 1072, 738 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.11 - 1.15 (m, 3H), 1.28 (bs, 8H), 1.45 - 1.59 (m, 4H), 2.53 (t, 2H, J = 8.0 Hz), 3.12 - 3.24 (m, 4H), 3.82 (s, 3H), 3.91 (s, 3H), 4.23 (s, 2H), 6.76 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J =7.2 Hz), 7.25 - 7.29 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3), δ: 15.46, 26.73, 29.07, 29.18, 29.21, 30.14, 30.94, 33.35, 35.01, 40.25, 52.10, 55.78, 108.33, 121.43, 123.30, 130.24, 141.17, 156.15, 158.65, 169.05 ppm; ESIMS (m/z): 365 (M + H)+. Synthesis of methyl 2-(8-(3-cyclopentylureido)octyl) -6-methoxybenzoate (7b): Using 6 and cyclopentyl iso- cyanate as starting materials, the title compound 7b was obtained as a white solid (Yield = 60.4%); m.p. 80˚C - 81˚C; IR (DCM film): 3339, 2932, 2858, 1731, 1630, 1574, 1466, 1267, 1110, 1073, 749 cm–1; 1H NMR (CD- Cl3, 400 MHz): δ 1.28 - 1.65 (m, 18H), 1.92 - 2.00 (m, 2H), 2.53 (t, 2H, J = 7.6 Hz), 3.12 - 3.16 (q, 2H), 3.81 (s, 3H), 3.90 (s, 3H), 3.91 - 3.95 (m, 1H), 4.31 (s, 1H), 6.75 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.25 - 7.29 Copyright © 2011 SciRes. IJOC
N. S. REDDY ET AL. 172 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3), δ: 23.51, 26.78, 29.09, 29.19, 29.23, 30.21, 30.96, 33.35, 33.51, 40.24, 51.86, 52.09, 55.77, 108.31, 121.42, 123.30, 130.23, 141.16, 156.15, 158.34, 169.01 ppm; ESIMS (m/z): 405 (M + H)+. Synthesis of methyl 2-methoxy-6-(8-(3-phenylur- eido)octyl) benzoate (7c): Using 6 and phenyl isocy- anate as starting materials, the title compound 7c was ob- tained as a cream color semi solid (Yield = 66.2%); IR (DCM film): 3345, 3298, 3085, 3008, 2929, 2853, 1729, 1637, 1589, 1552, 1467, 1270, 1111, 1071, 735 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.26 (bs, 8H), 1.43 - 1.55 (m, 4H), 2.53 (t, 2H, J = 8.0 Hz), 3.17 - 3.22 (q, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 5.07 (bs, 1H), 6.76 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.01 - 7.05 (m, 1H), 7.24 - 7.31 (m, 5H) ppm; ESIMS (m/z): 413 (M + H)+. Synthesis of methy l 2-(8-(3-(3-chlorophenyl)ureido) octyl)-6-methoxybenzoate (7d): Using 6 and 3-chlor- ophenyl isocyanate as starting materials, the title com- pound 7d was obtained as a white color solid (Yield = 35%); m.p. 102˚C - 103˚C; IR (DCM film): 3347, 3080, 3004, 2930, 2855, 1729, 1659, 1590, 1549, 1473, 1429, 1268, 1110, 1073, 766 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.27 (bs, 8H), 1.40 - 1.60 (m, 4H), 2.54 (t, 2H, J = 7.6 Hz), 3.19 - 3.24 (q, 2H), 3.80 (s, 3H), 3.92 (s, 3H), 5.04 (s, 1H), 6.76 - 6.85 (m, 3H), 6.97 (d, 1H, 7.2 Hz), 7.14 - 7.37 (m, 4H) ppm ; ESIMS (m/z): 447 (M + H)+. Synthesis of methyl 2-(8-(3-(3,4-dichlorophenyl)ur- eido)octyl)-6-methoxybenzoate (7e): Using 6 and 3, 4 dichlorophenyl isocyanate as starting materials, the title compound 7e was obtained as a light brown solid (Yield = 65%); m.p. 80˚C - 82˚C; IR (DCM film): 3351, 3099, 2930, 2855, 1729, 1661, 1587, 1542, 1470, 1381, 1270, 1115, 1072, 1028, 820, 746 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.25 (bs, 8H), 1.41 - 1.58 (m, 4H), 2.55 (t, 2H, J = 8.0 Hz), 3.17 - 3.22 (q, 2H), 3.80 (s, 3H), 3.93 (s, 3H), 5.15 (s, 1H), 6.77 (d, 1H, J = 8.0 Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.08 - 7.19 (m, 2H), 7.20 - 7.31 (m, 2H), 7.48 (s, 1H) ppm; ESIMS (m/z): 481 (M + H)+. 483 (chloro). Synthesis of methyl 2-(8-(3-(2-fluorophenyl)ureido) octyl)-6-methoxybenzoate (7f): Using 6 and 2-fluoro- phenyl isocyanate as starting materials, the title com- pound 7f was obtained as a light brown solid (Yield = 68.2%); m.p. 92˚C - 93˚C; IR (DCM film): 3348, 3073, 3006, 2930, 2855, 1730, 1658, 1551, 1457, 1265, 1188, 1109, 1073, 810 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.28 (bs, 8H), 1.42 - 1.60 (m, 4H), 2.54 (t, 2H, J = 7.6 Hz), 3.21 - 3.25 (q, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 5.04 (s, 1H), 6.67 (s, 1H), 6.75 (d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 6.92 - 6.98 (m, 1H), 7.01 - 7.10 (m, 2H), 7.24 - 7.29 (m, 1H), 8.01 - 8.10 (m, 1H) ppm; ESIMS (m/z): 431 (M + H)+. Synthesis of methyl 2-(8-(3-(2-cyanophenyl)ureido) octyl)-6-methoxybenzoate (7g): Using 6 and 2-cyano- phenyl isocyanate as starting materials, the title com- pound 7g was obtained as a light green semi solid (Yield = 26.7%); IR (DCM film): 3346, 3078, 3000, 2930, 2855, 2221, 1728, 1662, 1581, 1546, 1452, 1268, 1110, 1072, 758 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.30 (bs, 8H), 1.51 - 1.57 (m, 4H), 2.54 (t, 2H, J = 7.6 Hz), 3.23 - 3.28 (q, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 5.33 (s, 1H), 6.75 (d, 1H, J = 8 Hz), 6.81 (d, 1H, J = 7.6 Hz), 7.02 (t, 1H, J = 7.6 Hz), 7.11 (s, 1H), 7.24 - 7.28 (m, 1H), 7.49 - 7.54 (m, 2H), 8.31 (d, 1H, J = 8.0 Hz) ppm; ESIMS (m/z): 436 (M + H)+. Synthesis of methyl 2-(8-(3-(3-cyanophenyl)ureido) octyl)-6-methoxybenzoate (7h): Using 6 and 3-cyano phenyl isocyanate as starting materials, the title compound 7h was obtained as a pale yellow solid (Yield = 33.5%); m.p. 75˚C - 76˚C; IR (DCM film): 3355, 3083, 3006, 2930, 2855, 2230, 1728, 1664, 1587, 1552, 1470, 1431, 1271, 1111, 1072, 791, 747 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.26 (bs, 8H), 1.41 - 1.58 (m, 4H), 2.55 (t, 2H, J = 8.0 Hz), 3.19 - 3.24 (q, 2H), 3.80 (s, 3H), 3.93 (s, 3H), 5.2 (s, 1H), 6.78 - 6.84 (m, 2H), 7.22 - 7.33 (m, 3H), 7.57(s, 1H), 7.63 - 7.65 (m, 1H) ppm; ESIMS (m/z): 438 (M + H)+. Synthesis of methyl 2-methoxy-6-(8-(3-(3-(trifluo- romethyl)phenyl)ureido)octyl)benzoate (7i): Using 6 and 3-trifluromethyl phenyl isocyanate as starting mate- rials, the title compound 7i was obtained as a white solid (Yield = 42.6%); m.p. 99˚C - 101˚C; IR (DCM film): 3349, 3096, 3005, 2932, 2856, 1730, 1660, 1564, 1442, 1335, 1266, 1120, 1072 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.26 (bs, 8H), 1.41 - 1.58 (m, 4H), 2.55 (t, 2H, J = 7.6 Hz), 3.19 - 3.24 (q, 2H), 3.79 (s, 3H), 3.93 (s, 3H), 5.12 (s, 1H), 6.77 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 8.0 Hz), 7.075 (s, 1H), 7.22 - 7.36 (m, 3H), 7.55 - 7.59 (m, 2H) ppm; ESIMS (m/z): 481 (M + H)+. Synthesis of methyl 2-methoxy-6-(8-(3-(3-methoxy phenyl)ureido)octyl)benzoate (7j): Using 6 and 3-me- thoxy phenyl isocyanate as starting materials, the title compound 7j was obtained as a off white solid (Yield = 88.4%); m.p. 82˚C - 83˚C; IR (DCM film): 3343, 2935, 2861, 1726, 1567, 1466, 1266, 1109, 1072, 772 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.26 (bs, 8H), 1.40 - 1.58 (m, 4H), 2.53 (t, 2H, J = 8.0 Hz), 3.19 - 3.22 (q, 2H), 3.77 (s, 3H), 3.80 (s, 3H), 3.91 (s, 3H), 5.08 (s, 1H), 6.59 - 6.60 (m, 1H), 6.75 - 6.82 (m, 3H), 7.05 (s, 1H), 7.12 - 7.18 (m, 1H), 7.25 - 7.30 (m, 1H) ppm; ESIMS (m/z): 443 (M + H)+. Synthesis of methyl 2-(8-(3-(2,2-dimethyl-2,3-dihy- dro benzofuran-7-yl)ureido)octyl)-6-methoxybenzoate (7k): Using 6 and 7-isocyanato-2, 2-dimethyl-2, 3-dihy- dro benzofuran as starting materials, the title com- pound 7k was obtained as a light brown color solid (Yield: Copyright © 2011 SciRes. IJOC
173 N. S. REDDY ET AL. 44.4%); m.p. 96˚C - 97˚C; IR (DCM film): 3347, 3050, 2929, 2855, 1730, 1658, 1565, 1441, 1374, 1300, 1267, 1111, 1070, 877, 765, 738 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.28 (bs, 8H), 1.46 (s,6H), 1.46 - 1.60 (m, 4H), 2.53 (t, 2H, J = 7.6 Hz), 3.03 (s, 2H), 3.21 - 3.26 (q, 2H), 3.81 (s, 3H), 3.90 (s, 3H), 4.85 (s, 1H), 6.21 (s, 1H), 6.74 - 6.85 (m, 4H), 7.24 - 7.28 (m, 1H), 7.54 (d, 1H, J = 8.0 Hz) ppm; 13C NMR (100 MHz, CDCl3), δ: 26.78, 28.20, 29.09, 29.20, 29.26, 30.01, 30.98, 33.39, 40.30, 43.32, 52.13, 55.80, 87.56, 108.33, 119.50, 119.69, 120.59, 121.46, 122.97, 123.36, 126.89, 130.22, 141.24, 148.55, 155.82, 156.20, 168.97 ppm; ESIMS (m/z): 483 (M + H)+. Synthesis of methyl 2-methoxy-6-(8-(3-phenyl thi- oure ido)octyl) benzoate (8a): Using 6 and phenyl thio- isocyanate as starting materials, the title compound 8a was obtained as a light brown liquid (Yield = 50.2%); IR (DCM film): 3280, 3054, 3005, 2930, 2854, 1728, 1590, 1536, 1502, 1465, 1304, 1267, 1110, 1072, 753 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.29 (bs, 8H), 1.57 (bs, 4H), 2.54 (t, 2H, J = 8.0 Hz), 3.60 - 3.64 (m, 2H), 3.82 (s, 3H), 3.91 (s, 3H), 6.02 (s, 1H), 6.77 (d, 1H, J = 8 Hz), 6.82 (d, 1H, J = 8.0 Hz), 7.22 - 7.34 (m, 4H), 7.43 - 7.47 (m, 2H), 7.59 (s, 1H) ppm; ESIMS (m/z): 429 (M + H)+. Synthesis of methyl 2-(8-(3-(3-chlorophenyl) thioure ido)octyl)-6-methoxybenzoate (8b): Using 6 and 3- chloro phenyl thioisocyanate as starting materials, the title compound 8b was obtained as a off white solid (Yield = 80.3%); m.p. 103˚C - 104˚C; IR (DCM film): 3349, 3083, 3004, 2930, 2855, 1730, 1660, 1592, 1544, 1473, 1429, 1269, 1110, 1073, 773, 741 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.25 (bs, 8H), 1.44 - 1.60 (m, 4H), 2.54 (t, 2H, J = 7.6 Hz), 3.18 - 3.20 (m, 2H), 3.8 (s, 3H), 3.92 (s, 3H), 5.2 (s, 1H), 6.77 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 7.6 Hz), 6.95 (d, 1H, J = 8.0 Hz), 7.12 - 7.21 (m, 2H), 7.28 - 7.35 (m, 2H) ppm; ESIMS (m/z): 463 (M + H)+. Synthesis of methyl 2-(8-(3-(3,4-dichlorphenyl)thi- oureido)octyl)-6-methoxybenzoate (8c): Using 6 and phenyl thioisocyanate as starting materials, the title com- pound 8c was obtained as a pale brown color liquid (Yield = 98.4%); IR (DCM film): 3298, 3055, 3008, 2930, 2855, 1725, 1588, 1533, 1470, 1269, 1115, 1072, 1030, 822, 736 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.37 (bs, 8H), 1.58 (s, 4H), 2.55 (t, 2H, J = 7.2 Hz), 3.60 (bs, 2H), 3.81 (s, 3H), 3.91 (s, 3H), 6.06 (s, 1H), 6.77 (d, 1H, J = 8.0 Hz), 6.82 (d, 1H, J = 7.2 Hz), 7.13 (d, 1H, J = 8.4 Hz), 7.26 - 7.30 (m, 1H), 7.38 (s, 1H), 7.48 (d, 1H, J = 8.8 Hz), 7.67 (s, 1H) ppm; ESIMS (m/z): 497 (M + H)+. 499 (chloro). Synthesis of methyl 2-(8-(3-(2-fluorophenyl)thiour- eido)octyl)-6-methoxybenzoate (8d): Using 6 and 2- fluorophenyl thioisocyanate as starting materials, the title compound 8d was obtained as a pale brown liquid (Yield = 74.3%); IR (DCM film): 3259, 3050, 3006, 2931, 2855, 1728, 1587, 1541, 1505, 1465, 1268, 1110, 1072, 956, 752 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.30 (bs, 8H), 1.58 (bs, 4H), 2.54 (t, 2H, J = 8.0 Hz), 3.63 (bs, 2H), 3.82 (s, 3H), 3.92 (s, 3H), 6.04 (s, 1H), 6.77 (d, 1H, J = 8.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 7.19 - 7.41 (m, 5H) ppm; ESIMS (m/z): 447 (M + H)+. Synthesis of methyl 2-(8-(3-(3-cyanophenyl)thiour- eido)octyl)-6-methoxybenzoate (8e): Using 6 and 3- cyanophenyl thioisocyanate as starting materials, the title compound 8e was obtained as a yellow solid (Yield = 36.6%); m.p. 114˚C - 115˚C; IR (DCM film): 3334, 2939, 2862, 2223, 1725, 1639, 1549, 1466, 1265, 1109, 1071 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.33 (bs, 8H), 1.58 (bs, 4H), 1.80 - 1.82 (m, 2H), 2.53 (t, 2H, J = 8.0 Hz), 3.81 (s, 3H), 3.91 (s, 3H), 4.6 (s, 1H), 6.75 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 8.0 Hz), 6.95 (d, 1H, J = 8.0 Hz), 7.23 - 7.28 (m, 3H), 7.47 - 7.51 (m, 1H) ppm; ESIMS (m/z): 454 (M + H)+. Synnthesis of methyl 2-methoxy-6-(8-(3-(3-(trifluoro methyl)phenyl)thioureido)octyl) benzoate (8f): Using 6 and 3-trifluromethylphenyl thioisocyanate as star- ting materials, the title compound 8f was obtained as a light yellow liquid (Yield = 46.7%); IR (DCM film): 3325, 3070, 3013, 2931, 2856, 1725, 1666, 1582, 1459, 1331, 1269, 1119, 1073, 894 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.288 (bs, 8H), 1.58 (bs, 4H), 2.53 (t, 2H, J = 8.0 Hz), 3.61 (bs, 2H), 3.79 (s, 3H), 3.90 (s, 3H), 6.06 (s, 1H), 6.75 (d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.25 - 7.29 (m, 1H), 7.46 - 7.55 (m, 4H), 7.74 (s, 1H) ppm; ESIMS (m/z): 495(M – H)+. Antibacterial Bioassay [27]: Urea and thiourea deriva- tives of Anacardic acid (7a-7k, 8a-8f) were dissolved in dimethyl sulphoxide at 250 μg/mL concentration. The composition of nutrient agar medium was Bactotryptone (10 g), yeast extract (5 g), NaCl (10 g), final pH 7.4. Af- ter 18 h the exponentially growing cultures of the six bacteria in nutrient broth at 37˚C were diluted in sterile broth. From each of these diluted cultures, 1mL was added to 100 mL sterilized and cooled nutrient agar me- dia to give a final bacterial count of 1 × 106 cell/ml. The plates were set at room temperature and later dried at 37˚C for 20 h. Paper discs (6 mm, punched from What- mann no. 41 paper) were ultraviolet sterilized and used for the assays. Discs were soaked in different concentra- tion of the test solution and placed on the inoculated agar media at regular intervals of 6 - 7 cm, care was taken to ensure that excess solution was not on the discs. All the samples were taken in triplicates. The plates were incu- bated at 37˚C in an inverted fashion. Activity was deter- mined by zones showing complete inhibition (mm). Gr- owth inhibition was calculated with reference to positive Copyright © 2011 SciRes. IJOC
N. S. REDDY ET AL. 174 control. 5. Acknowledgements We thank GVK Biosciences Private Limited for the fi- nancial support and encouragement. We also thankful to the analytical department for their analytical data and to Dr. Balaram Patro for his helpful suggestions. 6. References [1] J. D. Mitchell and S. A. Mori, “The Cashew and Its Rela- tives (Anacardium:Anacardiaceae),” New York Botanical Garden, New York, 1987. [2] D. V. Johnson, “O Caju do Nordeste do Brasil—Um Estudo Geográfico,” ETENE/BNB, 1974. [3] J. S. Aggarwal, “Cashewnut Shell Liquid: Part I—Ch- emistry, Chemicals and Other Useful Products from It,” Journal of the Colour Society, Vol. 14, No. 3, 1975, pp. 1-9. [4] M. S. Ramaiah, “Progress of Research in Cashew Indus- try,” Fette, Seifen, Anstrichmittel, Vol. 78, 1976, pp. 472- 477. doi:10.1002/lipi.19760781204 [5] O. Attanasi, F. Serra-Zanetti, F. Perdomi and A. Scag- liarini, La Chimica & L’Industria, Vol. 61, 1979, pp. 718-725. [6] J. H. P. Tyman, Chemistry & Industry, Vol. 2, 1980, pp. 59. [7] J. H. P. Tyman, “Non-Isoprenoid Long Chain Phenols,” Chemical Society Reviews, Vol. 8, No. 4, 1979, pp. 499- 537. doi:10.1039/cs9790800499 [8] I. Kubo, H. Muroi, M. Himejima and Y. Yamigiwa, “Structure-Antibacterial Activity Relationships of Ana- cardic Acids,” Journal of Agricultural and Food Chemis- try, Vol. 41, No. 6, 1993, pp. 1016-1019. doi:10.1021/jf00030a036 [9] J. L. Gillerman, N. J. Walsh, N. K. Werner and H. Schlenk, “Antimicrobial Effects of Anacardic Acids,” Canadian Journal of Microbiology, Vol. 15, 1969, pp. 1219-1213. [10] M. Toyomizu, K. Okamoto, T. Ishibashi, Z. Chen and T. Nakatsu, “Uncoupling Effect of Anacardic Acids from Cashew Nut Shell Oil on Oxidative Phosphorylation of Rat Liver Mitochondria,” Life Sciences, Vol. 66, No. 3, 2000, pp. 229-234. doi:10.1016/S0024-3205(99)00585-8 [11] B. Prithiviraj, M. Manickam, V. P. Singh and A. B. Ray, “Antifungal Activity of Anacardic Acid, a Naturally Oc- curring Derivative of Salicylic Acid,” Canadian Journal of Botany, Vol. 75, No. 1, 1997, pp. 207-211. doi:10.1139/b97-021 [12] H. Muroi and I. Kubo, “Antibacterial Activity of Ana- cardic Acid and Totarol, alone and in Combination with Methicillin, against Methicillinresistant Staphylococcus Aureus,” Journal of Applied Microbiology, Vol. 80, No. 4, 1996, pp. 387-394. doi:10.1111/j.1365-2672.1996.tb03233.x [13] J. Kubo, J. R. Lee and I. Kubo, “Anti-Helicobacter Pylori Agents from the Cashew Apple,” Journal of Agricultural and Food Chemistry, Vol. 47, No. 2, 1999, pp. 533-537. doi:10.1021/jf9808980 [14] I. Kubo, H. Muroi and M. Himejima, “Structure-Anti Bacterial Activity Relationships of Anacardic Acids,” Journal of Agricultural and Food Chemistry, Vol. 41, 1993, p. 1016. [15] A. S. Gulati and B. C. Subba Rao, Indian Journal of Chemistry, Vol. 2, 1964, p. 337. [16] M. A. EIShol, P. D. Adawadkar, D. A. Benign, E. S. Watson and T. L. Little Jr., “6-(Alkylamino)-9-benzyl- 9H-purines. A New Class of Anticonvulsant Agents,” Journal of Medicinal Chemistry, Vol. 29, 1986, pp. 606- 612. [17] R. Paramashivappa, P. P. Kumar, P. V. S. Rao and S. A. Rao, “Design, Synthesis and Biological Evaluation of Benzimidazole/Benzothiazole and Benzoxazole Deriva- tives as Cyclooxygenase Inhibitors,” Bioorganic & Me- dicinal Chemistry Letters, Vol. 13, No. 4, 2003, pp. 657-660. doi:10.1016/S0960-894X(02)01006-5 [18] M. A. Elsholy, P. D. Adawadkar, D. A. Beniggni, E. S. Watson and T. L. Little Jr., “Analogs of Poison Ivy Urushiol. Synthesis and Biological Activity of Disubsti- tuted N-Alkylbenzenes,” Journal of Medicinal Chemistry, Vol. 29, No. 5, 1986, pp. 606-611. doi:10.1021/jm00155a003 [19] L. S. Kiong and J. H. P. Tyman, “Long-Chain Phenols. Part 18. Conversion of Anacardic Acid into Urushiol,” Journal of the Chemical Society, Perkin Transactions 1, 1981, pp. 1942-1952. doi:10.1039/p19810001942 [20] A. S. Gulati and B. C. S. Subba Rao, Indian Journal of Chemistry, Vol. 2, 1964, p. 339. [21] S. V. Shoba, C. S. Ramadoss and B. Ravindranath, “Inhi- bition of Soybean Lipoxygenase-1 by Anacardic Acids, Cardols, and Cardanols,” Journal of Natural Products, Vol. 57, No. 12, 1994, pp.1755-1757. doi:10.1021/np50114a025 [22] T. J. Ha and I. Kubo, “Lipoxygenase Inhibitory Activity of Anacardic Acids,” Journal of Agricultural and Food Chemistry, Vol. 53, No. 11, 2005, pp. 4350-4354. doi:10.1021/jf048184e [23] I. Kubo, M. Ochi, P. C. Viera and S. Komatsu, Journal of Agricultural and Food Chemistry, Vol. 41, 1993, pp. 1012-1015. [24] M. J. Rybak and R. L. Akins, “Emergence of Methicil- lin-Resistant Staphylococcus Aureus with Intermediate Glycopeptide Resistance: Clinical Significance and Treat- ment Options,” Drugs, Vol. 61, No. 1, 2001, pp. 1-7. doi:10.2165/00003495-200161010-00001 [25] M. Lipsitch, “The Rise and Fall of Antimicrobial Resis- tance,” Trends in Microbiology, Vol. 9, No. 9, 2001, pp. 438-444. doi:10.1016/S0966-842X(01)02130-8 [26] B. A. Cunha, Drugs Today, Vol. 34, 1998, pp. 691-698. [27] A. Marchese, G. C. Schito and E. A. Debbia, Journal of Copyright © 2011 SciRes. IJOC
N. S. REDDY ET AL. Copyright © 2011 SciRes. IJOC 175 Chemotherapy, Vol. 12, 2000, pp. 459-462. [28] Y. Cetinkaya, P. Falk and C. G. Mayhall, “Vancomycin- Resistant Enterococci,” Clinical Microbiology Reviews, Vol. 13, No. 4, 2000, pp. 686-707. doi:10.1128/CMR.13.4.686-707.2000 [29] G. H. Cassell and J. Mekalanos, “Development of An- timicrobial Agents in the Era of New and Reemerging Infectious Diseases and Increasing Antibiotic Resis- tance,” Journal of the American Medica l Associa tion, Vol. 285, No. 5, 2001, pp. 601-605. doi:10.1001/jama.285.5.601 [30] D. T. W. Chu, J. J. Plattner and L. Katz, “New Directions in Antibacterial Research,” Journal of Medicinal Chem- istry, Vol. 39, No. 20, 1996, pp. 3853-3874. doi:10.1021/jm960294s [31] V. Chandregowda, A. Kush and G. C. Reddy, “Synthesis of Benzamide Derivatives of Anacardic Acid and Their Cytotoxic Activity,” European Journal of Medicinal Che- mistr y , Vol. 44, No. 6, 2009, pp. 2711-2719. doi:10.1016/j.ejmech.2009.01.033 [32] R. Paramashivappa, P. Phanikumar, P. V. Subba Rao and A. Srinivasa Rao, “Synthesis of Sildenafil Analogues from Anacardic Acid and Their Phosphodiesterase-5 Inhibition,” Journal of Agricultural and Food Chemistry, Vol. 50, No. 26, 2002, pp. 7709-7713. doi:10.1021/jf0258050 [33] P. Phanikumar, S. C. Stotz, R. Paramashivappa, M. Beedle, G. W. Zamponi and A. Srinivasa Rao, “Synthesis and Evaluation of a New Class of Nifedipine Analogs with T-Type Calcium Channel Blocking Activity,” Mole- cular Pharmacology, Vol. 61, No. 3, 2002, pp. 649- 658. doi:10.1124/mol.61.3.649 [34] B. Narayana Swamy, T. K. Suma, G. Venkateswara Rao and G. Chandrasekara Reddy, European Journal of Me- dicinal Chemistry, Vol. 42, 2007, pp. 422424. [35] K. Mantelingu, A. H. Kishore, K. Balasubramanyam, G. V. Kumar, M. Altaf, S. N. Swamy, R. Selvi, C. Das, C. Narayana, K. S. Rangappa and T. K. Kundu, “Activation of p300 Histone Acetyltransferase by Small Molecules Altering Enzyme Structure: Probed by Surface-Enhan- ced Raman Spectroscopy,” Journal of Physical Chemistry B, Vol. 111, No. 17, 2007, pp.4527-4534. doi:10.1021/jp067655s [36] A. Hari Kishore, B. M. Vedamurth, K. Mantelingu, S. Agrawal, B. A. Ashok Redd, S. Roy, K. S. Rangappa and T. K. Kundu, “Specific Small-Molecule Activator of Aurora Kinase A Induces Autophosphorylation in a Cell- Free System,” Journal of Medicinal Chemistry, Vol. 51, No. 4, 2008, pp. 792-797. doi:10.1021/jm700954w [37] B. Sung, M. K. Pande, K. S. Ahn, T. Yi, M. M. Cha- turved, M. Liu and B. B. Aggarwal, “Anacardic Acid (6-Nonadecyl Salicylic Acid), an Inhibitor of Histone Acetyltransferase, Suppresses Expression of Nuclear Fa- ctor-κB-Regulated Gene Products Involved in Cell Sur- vival, Proliferation, Invasion, and Inflammation through Inhibition of the Inhibitory Subunit of Nuclear Factor-κBα Kinase, Leading to Potentiation of Apoptosis,” Blood, Vol. 111, No. 10, 2008, pp. 4880-4891. doi:10.1182/blood-2007-10-117994 [38] L. Cui, J. Miao, T. Furuya, Q. Fan, X. Li, P. K. Rathod, X. Z. Su and L. Cui, “Histone Acetyltransferase Inhibitor Anacardic Acid Causes Changes in Global Gene Expres- sion during in Vitro Plasmodium Falciparum Develop- ment,” Eukaryotic Cell, Vol. 7, No. 7, 2008, pp. 1200- 1210. doi:10.1128/EC.00063-08 [39] G. Sbardella, S. Castellano, C. Vicidomini, D. Rotili, A. Nebbioso, M. Miceli, L. Altucci and A. Mai, “Iden- tification of Long Chain Alkylidenemalonates as Novel Small Molecule Modulators of Histone Acetyltransfe- rases,” Bioorganic & Medicinal Chemistry Letters, Vol. 18, No. 9, 2008, pp. 2788-2792. doi:10.1016/j.bmcl.2008.04.017 [40] M. L. Dos Santos and G. C. de Magalhães, Química Nova, Vol. 16, 1993, p. 534. [41] M. G. Carvalho, R. Braz-Filho, M. L. Dos Santos and G. C. de Magalhães, Journal of the Brazilian Chemical So- ciety, Vol. 4, 1993, pp. 158-164. [42] M. L. Dos Santos and G. C. de Magalhães, “Utilisation of Cashew Nut Shell Liquid from Anacardium Occidentale as Starting Material for Organic Synthesis: A Novel Route to Lasiodiplodin from Cardols,” Journal of the Brazilian Chemical Society, Vol. 10, No. 1, 1999, pp. 13-18. doi:10.1590/S0103-50531999000100003 [43] Lúcio P. L. Logrado, Dâmaris Silveira, Luiz A. S. Romeiro, Manoel O. de Moraes, Bruno C. Cavalcanti, Letícia V. Costa-Lotufo, Cláudia do Ó Pessoa and Maria Lucilia dos Santos, Journal of the Brazilian Chemical Society, Vol. 16, 2005, pp. 1217-1225. [44] L. S. Kiong and J. H. P. Tyman, “Long-Chain Phenols. Part 18. Conversion of Anacardic Acid into Urushiol,” Journal of the Chemical Society, Perkin Transactions 1, Vol. 1, 1981, p. 1942. doi:10.1039/p19810001942 [45] R. Paramashivappa, P. Phanikumar, P. J. Vithayathil and A. Srinivasa Rao, “Novel Method for Isolation of Major Phenolic Constituents from Cashew (Anacardium occi- dentale L.) Nut Shell Liquid,” Journal of Agricultural and Food Chemistry, Vol. 49, No. 5, 2001, pp. 2548-2551. doi:10.1021/jf001222j [46] A. Rahman, M. L. Choudhary and W. J. Thomsen, “Bio- assay Techniques for Drug Development,” Harwood Aca- demic Publishers, The Netherlands, 2001.
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