Synthesis and anticancer evaluation of imidazolinone and benzoxazole derivatives

Heba A. El-Hady; Samar A. Abubshait

doi:10.1016/j.arabjc.2014.05.006

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Original article

10 (

2_suppl

); S3725-S3731

doi:

10.1016/j.arabjc.2014.05.006

Synthesis and anticancer evaluation of imidazolinone and benzoxazole derivatives

Heba A. El-Hady^{^a,^b,⁎}, Samar A. Abubshait^{^c}

a Chemistry Department, Faculty of Science (for Girls), Al-Azhar University, Nasr City, Egypt

b Chemistry Department, Faculty of Applied Science, Umm al Qura University, Saudi Arabia

c Chemistry Department, Girls College of Science, University of Dammam, Dammam, Saudi Arabia

⁎Corresponding author at: Chemistry Department, Faculty of Applied Science, Umm al Qura University, PO Box 715, Saudi Arabia. Tel.: +966 546195348; fax: +966 25580159. Hebaa_elhady@yahoo.com (Heba A. El-Hady)

Received: 2013-2-24, Accepted: 2014-5-20, Published: 2014-05-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Graphical abstract

Abstract

A series of imidazolinone and benzoxazole derivatives (3 and 5) have been synthesized by the condensation of oxazolinone derivatives (2a–c) with aniline and 2-hydroxyaniline. Acetyl derivatives (4, 6 and 7) were prepared via acetylation of compounds 3 and 5 with acetic anhydride and chloroacetyl chloride. The results revealed that imidazolinone and benzoxazole derivatives are potent against the cancer cell lines MCF-7 and HePG2. In particular, benzoxazole derivatives are more potent than imidazolinone derivatives.

Keywords

Imidazolinone

Benzoxazole

Anticancer evaluation against MCF-7 and HePG2 cell lines

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1 Introduction

Imidazolinone (Wilson et al., 1998; Behai, 2003) and benzoxazole derivatives (Isomura et al., 1983; Unidine et al., 2003; Sham et al., 2006 ) have been reported to possess anti-inflammatory, analgesic and kinase inhibition activities in some literature. The antimicrobial activities of imidazolinones and benzoxazoles have long been established. Derivatives of these compounds are known for their antibacterial (Nakamura, 1955), trichomonacidal (Cavaileri et al., 1978), anthelmintic (Cunkier and Mezey, 1966), fungicidal (Maxwell, 1971) and antiviral (Hollinahead and Smith, 1958) activities. Some of these compounds exhibited anticancer activity (Shu-Ting et al., 2006). In a review on the chemistry of imidazolinones and benzoxazoles, a pit of commercially available compounds and their therapeutic uses was included. The objective of the present work was to investigate the anticancer activities of the synthesized imidazolinone and benzoxazole derivatives.

2 Materials and methods

Melting points were taken in open capillaries with a Thomas uni-melt apparatus and they are uncorrected. ¹H NMR spectra were recorded on a general electric QE300 instrument and chemical shifts are given with respect to TMS. The ¹³C NMR (500 MHz) spectra were run in dimethyl sulfoxide (DMSO-d₆). Chemical shifts were related to that of the solvent. IR spectra were recorded on a Perkin-Elmer 1420 spectrometer and a Bio-Rad FTS7 (KBr). Mass spectra were obtained on a Joel JMS D-300 spectrometer operating at 70 Ev. Microanalyses were conducted using an elemental analyzer 1106.

(Z)-4-(arylidene)-2-aryloxazol-5(4H)-ones (2a–c). A mixture of N-aroylglycine (0.01 mol), aromatic aldehydes (such as 4 hydroxybenzaldehyde and 3-bromo-4-hydroxybenzaldehyde) (0.01 mol) and fused sodium acetate (0.03 mol) was fused in the presence of acetic anhydride (5 ml) on a hot plate for 3–5 min. The reaction mixture was heated on a water-bath for 2 h, then cooled and poured into water. The resulting solid was filtered off, washed with water, dried and purified by suitable solvent to give 2.

(Z)-4-(4-hydroxybenzylidene)-2-phenyloxazol-5(4H)-one (2a) as yellow crystals, yield 63%, m.p. 165 °C. IR (KBr): 3430–2895 (br. OH), 1758 (C⚌O), 1628 (C⚌N), 1615, 1589 (C⚌C), 1215, 1178, 1095 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 7.12–7.81 (m, 10H, Ar-H and H-olefinic), 11.23 (s, 1H, OH) ppm. Anal. Calcd. For C₁₆H₁₁NO_3: C, 72.45; H, 4.15; N, 5.28. Found: C, 72.22; H. 4.03; N, 5.17.

(Z)-4-(3-bromo-4-hydroxybenzylidene)-2-phenyloxazol-5(4H)-one (2b) as yellow crystals, yield 71%, m.p.187 °C. IR (KBr): 3421–2981 (br. OH). 1751 (C⚌O), 1629 (C⚌N), 1612, 1592 (C⚌C), 1178, 1085 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆): δ: 7.12–7.81(m, 9H, Ar-H and H-olefinic), 11.3 (s, 1H, OH) ppm. Anal. Calcd. For C₁₆H₁₀NBrO₃: C, 55.98; H, 2.91; N, 4.08. Found: C, 55.68; H, 2.71; N, 3.98.

(Z)-4-(3-bromo-4-hydroxybenzylidene)-2-(4-chlorophenyl)-oxazol-5(4H)-one (2c) as yellow crystals, yield 73%, m.p. 186 °C. IR (KBr): 3395–2820 (br. OH), 1756 (C⚌O), 1627 (C⚌N), 1613, 1583 (C⚌C), 1215, 1125, 1095 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 7.12–7.88 (m, 8H, Ar-H and H-olefinic), 1 1.37 (s, 1H, OH) ppm. Anal. Calcd. For C₁₆H₉NClBrO₃: C, 50.86; H, 2.38; N, 3.71; Found: C, 50.68; H, 2.19; N, 3.53.

4-(3-bromo-4-hydroxybenzylidene)-2-aryl-1H-1-phenyl-imidazol-5(4H)-ones (3a, b).

(Z)-N-(1-(benzo[d]oxazol-2-yl)-2-(4-hydroxyphenyl) vinyl)benzamide (5a, b). A mixture of 2 (0.01 mol) and aromatic amines (namely, aniline and 2-hydroxy aniline) in acetic acid (30 ml) was heated under reflux for 4 h. The reaction mixture was cooled and poured into ice-water. The solid obtained was filtered off, washed with water, dried and purified by suitable solvent to give 3 and 5.

4-(3-bromo-4-hydroxybenzylidene)-1, 2-diphenyl-1H-imidazol-5(4H)-one (3a) as yellow crystals, yield 67%, m.p. 212 °C. IR (KBr): 3381–2851 (br. OH), 1695 (C⚌O), 1628 (C⚌N), 1616, 1595 (C⚌C), 1175, 1043 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 6.98–7.83 (m, 14H, Ar-H and H-olefinic), 11.21 (s, 1H, OH) ppm. ¹³C NMR (DMSO-d₆) δ: 173.2(C⚌O), 150 (N⚌C—N), 131.9, 134.1 (HC⚌C), 110.0, 118.2, 121.9, 124.1, 125.4, 126.2, 128.2, 128.3, 129.4, 129.9, 130.5, 132.6, 138.0, 159.6 (C_aromatic). MS: m/z (%) = 420 (M⁺², 5.30), 418 (M⁺, 5.60), 181 (3.90), 480 (17.80), 179 (6.10), 125 (2.80), 119 (5.60), 118 (3.30), 114 (3.30), 106 (14.40), 105 (100), 104 (23.90), 103 (4.40), 101 (5.00), 94 (4.40), 93 (24.40), 92 (27.80), 88 (3.90), 87 (4.40), 81 (6.70), 80 (5.60), 79 (4.40), 77 (55.00), 76 (48.30), 75 (7.80), 66 (11.10), 65 (12.20), 64 (6.70), 51 (20.00), 50 (15.60), Anal. Calcd. For C₂₂H₁₅N₂BrO₂: C, 63.16; H, 3.59; N, 6.69. Found: C, 63.01; H, 3.37; N, 6.51.

4-(3-bromo-4-hydroxybenzylidene)-2-(4-chlorophenyl)-1H-1-phenyl-imidazol-5(4H)-one (3b) as yellow crystals, yield 73%, m.p. 217 °C. IR (KBr): 3392–2912 (br. OH), 1699 (C⚌O), 1625 (C⚌N), 1613, 1581 (C⚌C), 1185, 1078 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 6.89–7.81 (m, 13H, Ar-H and H-olefinic), 11.31 (s, 1H, OH) ppm. ¹³C NMR (DMSO-d₆) δ: 173.0 (C⚌O), 150.6 (N⚌C-N), 131.6, 133.9 (HC⚌C), 109.8, 117.6, 120.1, 124.0, 126.2, 126.8, 128.1, 129.0, 129.2, 130.7, 132.0, 134.7, 137.9, 159.5 (C_aromatic). MS: m/z (%) = 456 (M⁺⁴, 2.40), 454 (M⁺², 4.30), 452 (M⁺, 3.70), 266 (1.80), 217 (2.40), 216 (13.70), 215 (7.60), 214 (34.80), 213 (25.00), 209 (2.70), 186 (1.50), 185 (2.70), 180 (4.60), 179 (3.40), 178 (3.40), 169 (3.70), 168 (4.30), 156 (3.00), 154 (3.00), 151 (2.70), 142 (4.00), 141 (34.50), 140 (24.40), 139 (100), 138 (69.80), 113 (8.50), 112 (6.40), 111 (23.50), 110 (20.10), 105 (14.30), 104 (10.70), 103 (4.60), 102 (5.80), 101 (6.70), 94 (7.00), 93 (42.70), 92 (27.10), 91 (3.70), 87 (6.70), 82 (4.30), 81 (3.00), 80 (1.50), 78 (9.50), 77 (95.70), 76 (38.70), 75 (19.50), 66 (6.10), 65 (7.30), 64 (5.20), 51 (47.00), 50 (21.60), Anal. Calcd. For C₂₂H₁₄N₂ClBrO₂: C, 58.41; H, 3.10; N, 6.19. Found: C, 58.17; H, 2.93; N, 6.01.

(Z) 2-[β- (4-Hydroxyphenyl)-α-(benzoylamino) vinyl]-benzoxazole (5a) as yellow crystals, yield 64%, m.p. 135 °C. IR (KBr): 3225 (NH), 3351–2815 (br. OH), 1689 (CO), 1628 (C⚌N), 1615, 1589 (C⚌C), 1195, 1081 (C-O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 6.93–7.89 (m, 14H, Ar-H and H-olefinic), 9.83 (br. s, 1H, NH), 11.23 (s, 1H, OH) ppm. MS: m/z (%) = 357 (M⁺², 7.10), 356 (M⁺, 26.40), 355 (M⁻¹, 16.00), 328 (1.20), 327 (1.70), 265 (2.60), 264 (1.50), 263 (1.60), 253 (1.70), 251 (3.30), 250 (2.10), 236 (1.50), 235 (2.40), 224 (1.80), 197 (6.00), 196 (22.60), 195 (12.00), 180 (1.20), 178 (2.90), 167 (3.30), 166 (3.20), 145 (1.60), 141 (1.20), 133 (1.60), 132 (6.00), 131 (2.70), 121 (1.80), 120 (1.50), 119 (2.40), 118 (3.40), 117 (2.00), 106 (10.00), 105 (100), 104 (84.90), 103 (12.20), 93 (3.90), 92 (2.90), 91 (2.20), 89 (4.40), 88 (2.80), 78 (5.40), 77 (36.60), 76 (27.00), 75 (4.20), 65 (17.60), 64 (16.60), 63 (8.10), 51 (13.20), 50 (7.60) .Anal. Calcd. For C₂₂H₁₆N₂O₃: C, 74.16; H, 4.49; N, 7.86. Found: C, 74.03; H, 4.23; N, 7.61.

(Z) 2-[β-(3-bromo-4-Hydroxyphenyl)-α-(benzoyl amino) vinyl]-benzoxazole (5b) as orange crystals, yield 67%, m.p. 125 °C, IR (KBr): 3395–2950 (br. OH), 3223 (NH), 1687 (C⚌O), 1628 (C⚌N), 1612, 1588 (C⚌C), 1215, 1089 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 6.98–7.87 (m, 13H, Ar-H and H-olefinic), 9.81 (s, 1H, NH), 11.26 (s, IH, OH) ppm. ¹³C NMR (DMSO-d₆) δ: 164.0 (C⚌O), 152.1 (N⚌C—O—), 132.6, 105.3 (HC⚌C), 11O.2, 117.3, 120.2, 124.0, 124.9, 126.4, 126.9, 128.2, 129.5, 130.6, 131.6, 133.2, 140.0, 149.0, 159.4, 163.9 (C_aromatic) MS: m/z (%) = 436 (M⁺², 1.30), 434 (M⁺,1.60), 423 (7.40), 421 (10.60), 417 (7.40), 377 (6.40), 280 (6.40), 279 (0.60), 278 (7.40), 265 (8.50), 264 (6.40), 197 (4.30), 196 (12.80), 195 (45.70), 194 (19.10), 180 (16.00), 179 (12.80), 168 (4.30), 167 (21.30), 166 (11.70), 156 (6.40), 155 (8.50), 151 (9.60), 150 (10.60), 149 (22.30), 148 (14.90), 141 (18.10), 139 (23.40), 138 (22.30), 133 (18.10), 132 (12.80), 122 (7.40), 121 (12.80), 120 (19.10), 119 (19.10), 112 (11.70), 111 (13.80), 110 (10.80), 109 (19.10), 106 (14.90), 105 (100), 104 (83.00), 93 (18.10), 92 (19.10), 91 (17.00), 85 (10.60), 84 (12.80), 82 (10.50), 80 (13.80), 79 (7.40), 78 (20.20), 77 (55.30), 76 (47.90), 75 (22.30), 73 (11.70), 71 (16.00), 70 (12.80), 66 (12.80), 65 (18.10), 64 (30.90), 63 (29.80), 62 (25.50), 60 (20.20), 51 (38.30), 50 (21.30), Anal. Calcd. For C₂₂H₁₅N₂BrO₃: C, 60.83; H, 3.45; N, 6.45. Found: C, 60.61; H, 3.22; N, 6.31.

(E)-2-bromo-4-[(2-(4-chlorophenyl)-5-oxo-1-phenyl-1H-imidazol-4(5-ylidene) methyl] phenyl acetate (4a, b).

(Z)-4-(2-benzamido-2-(benzo[d]oxazol-2-yl) vinyl)-2-bromophenyl acetate (6). A solution of 3 and 5b (0.01 mol) in acetic anhydride (20 ml) was heated under reflux for 2hr, then cooled and poured into ice-water. The solid formed was filtered off, washed with water, dried and purified by recrystallization from benzene to give 4 and 6.

(E)-2-bromo-4-[(5-oxo-1, 2-diphenyl-1H-imidazol-4(5H)-ylidene) methyl] phenyl acetate (4a) as yellow crystals, yield 63%, m.p.110 °C. IR (KBr): 1748, 1693 (C⚌O), 1625 (C⚌N), 1605, 1598 (C⚌C), 1215, 1093 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 2.33 (s, 3H, COCH3), 6.98–7.81 (m, 14H, Ar-H and H-olefinic) ppm. ¹³C NMR (DMSO-d₆) δ: 172.9, 167.5 (2C⚌O), 149.9 (N⚌C—N), 132.0, 134.1 (HC⚌C), 16.2 (CH_3aliph.), 114.9, 120.0, 122.9, 123.9, 125.0, 125.3, 128.3, 128.4, 129.6, 132.5, 133.4, 128.4, 129.6, 132.5, 133.4, 137.9, 155.2 (C_aromatic). MS: m/z (%) = 462 (M⁺², 0.20), 460 (M⁺, 0.30), 425 (72.4), 424 (74.20), 423 (84.70), 422 (94.50), 420 (13.20), 345 (43.60), 344 (41.20), 343 (41.50), 291 (1.03), 290 (1.30), 289 (0.30), 181 (6.30), 180 (8.30), 171 (7.80), 149 (0.30), 148 (0.40), 141 (0.30), 139 (4.20), 136 (3.60), 135 (0.70), 134 (0.30), 106 (9.10), 105 (100), 103 (1.20), 102 (0.70), 101 (1.20), 100 (1.70), 88 (0.60), 87 (1.60), 78 (3.70), 77 (50.90), 75 (2.70), 65 (0.50), 64 (0.40), 63 (1.10), 62 (1.30), 52 (1.20), 51 (17.10), 50.20 (9.00) Anal. Calcd. For C₂₄H₁₇N₂BrO₃: C, 62.61; H, 3.69; N, 6.09. Found: C, 62.43; H, 3.39; N, 5.97.

(E)-2-bromo-4-[(2-(4-chlorophenyl)-5-oxo-1-phenyl-1H-imidazol-4(5H)-ylidene)methyl]phenyl acetate (4b) as yellow crystals, yield 66%, m.p. 100 °C. IR (KBr): 1746, 1693 (C⚌O), 1623 (C⚌N), 1607, 1588 (C⚌C), 1195, 1093 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 2.34 (s, 3H, COCH3), 6.89–7.83 (m, 13H, Ar-H and H-olefinic) ppm. ¹³C NMR (DMSO-d₆) δ: 173.4, 167.2 (2C⚌O), 149.4 (N⚌C—N), 133.9, 132.0 (HC⚌C), 16.5 (C_aliph.), 115.2, 119.6, 122.4, 123.1, 126.8, 128.7, 129.0, 129.7, 130.9, 133.3, 134.5, 138.0, 155.6. MS: m/z (%) = 496 (M⁺², 2.30), 494 (M⁺, 3.30), 459 (4.10), 458 (4.10), 457 (7.60), 456 (7.40), 455 (3.30), 454 (3.60), 423 (2.80), 215 (1.80), 214 (5.60), 180 (3.80), 169 (1.30), 168 (4.80), 167 (2.30), 152 (1.50), 142 (2.80), 141 (29.30), 140 (23.20), 139 (100), 138 (84.00), 118 (2.30), 113 (7.60), 112 (6.40), 111 (25.40), 110 (27.50), 106 (4.10), 105 (23.40), 104 (30.00), 103 (4.10), 102 (1.20), 100 (3.80), 93 (7.10), 92 (10.40), 91 (2.00), 88 (2.50), 87 (3.30), 81 (2.80), 77 (26.50), 76 (15.30), 75 (21.10), 74 (12.50), 63 (3.30), 62 (2.50), 61 (2.30), 60 (3.80), 51 (9.90), 50 (10.70).Anal. Calcd. For C₂₄H₁₆N₂BrClO₃: C, 58.24; H, 3.23; N, 5.66. Found: C, 58.03; H, 3.17; N, 5.42.

Compound 6 as yellow crystals, yield 53%, m.p. 105 °C. IR (KBr): 1742, 1685 (C⚌O), 3228 (NH), 1631 (C⚌N), 1610, 1605, 1589 (C⚌C), 1223, 1178, 1075 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 2.35 (s, 3H, OCOCH3), 6.89–7.88 (m, 13H, Ar-H and H-olefinic), 9.83 (br. s, 1H, NH) ppm. ¹³C NMR (DMSO-d₆) δ: 164.0, 167.0 (2C⚌O), 152.2 (N⚌C—O—), 132.4, 105.0 (HC⚌C), 16.6 (CH_3aliph.), 110.1, 115.7, 120.0, 123.5, 123.9, 124.9, 125.2, 127.1, 128.4, 128.5, 131.2, 133.1, 133.5, 140.0, 150.0, 155.4 (C_aromatic). MS: m/z (%) = 478 (M⁺², 1.30), 477 (M⁺, 1.60), 459 (3.00), 458 (5.10), 457 (3.60), 456 (3.00), 425 (3.30), 429 (5.40), 423 (5.70), 422 (1.50), 361 (1.50), 347 (1.80), 346 (1.80), 345 (1.80), 264 (2.40), 263 (1.50), 183 (1.50), 180 (2.10), 167 (1.20), 158 (1.80), 157 (1.80), 152 (1.50), 140 (10.00), 139 (37.20), 138 (30.50), 133 (3.30), 132 (2.10), 118 (3.00), 117 (1.50), 113 (5.10), 112 (4.20), 111 (12.10), 110 (8.80), 109 (10.30), 108 (9.40), 106 (11.80), 105 (100), 104 (87.90), 103 (3.30), 93 (9.40), 92 (6.30), 87 (3.90), 85 (4.20), 79 (4.80), 78 (6.60), 77 (44.40), 76 (24.80), 75 (8.50), 65 (6.90), 62 (3.30), 60 (10.90), 51 (14.50), 50 (10.00). Anal. Calcd. For C₂₄H₁₇N₂BrO₄: C, 60.50; H, 3.57; N, 5.88. Found: C, 60.33; H, 3.33; N, 5.66.

(Z)-4-(2-benzamido-2-(benzo[d]oxazol-2-yl) vinyl)-2-bromophenyl 2-chloroacetate (7).

A mixture of 5b (0.01 mol) and chloroacetyl chloride (0.01 mol) in acetic acid (25 ml) was heated under reflux for 2 h, then cooled and poured into ice-water. The resulting solid was filtered off, washed with water, dried and purified by recrystallization from benzene to give 7 as yellow crystals, yield 67%, m.p. 118 °C. IR (KBr): 3230 (NH), 1748, 1687 (CO), 1626 (C⚌N), 1610, 1587 (C⚌C), 1195, 1078 (C—O) cm⁻¹. ¹H NMR (DMSO-d₆) δ: 4.35 (s, 2H, COCH2Cl), 6.89–7.89 (m, 13H, Ar-H and H-olefinic), 9.83 (s, 1H, NH) ppm. ¹³C NMR (DMSO-d₆) δ: 164.2, 163.1 (2C⚌O), 152.5 (N⚌C—O—), 132.6, 104.8 (HC⚌C), 47.5 (—CH₂—Cl), 110.3, 115.9, 120.1, 122.9, 123.8, 125.0, 125.2, 126.8, 127.9, 129.7, 131.3, 133.2, 133.5, 139.8, 150.0, 155.2 (C_aromatic). MS: m/z (%) = 512 (M⁺², 1.30), 510 (M⁺, 1.50), 500 (11.10), 498 (14.80), 497 (18.50), 496 (14.80), 280 (11.10), 279 (9.30), 278 (7.40), 180 (38.90), 179 (50.00), 159 (24.10), 141 (9.30), 127 (9.30), 106 (7.40), 105 (94.40), 104 (100), 99 (13.00), 98 (13.00), 94 (7.40), 91 (18.50), 78 (16.70), 77 (66.70), 76 (66.70), 75 (14.80), 74 (16.70), 68 (11.10), 67 (11.10), 61 (13.00), 60 (27.80), 58 (20.40), 51 (35.20), 50 (35.20). Anal. Calcd. For C₂₄H₁₆N₂BrClO₄: C, 56.47; H, 3.14; N, 5.49; Found: C, 56.27; H, 3.03; N, 5.23.

3 Results and discussion

3.1

3.1 Chemistry

(Z)-4-Arylidene-2-aryloxazol-5(4H)-one (2a–c) have been synthesized by the condensation of N-aroylglycine (1a, b) with 3-substituted-4-hydroxy benzaldehyde in the presence of fused sodium acetate and acetic anhydride under fusion (Kaushik et al., 2010). 4-(3-Bromo-4-hydroxybenzylidene)-2-aryl-1H-1-phenyl-imidazol-5(4H)-ones(3a, b) were prepared by the reaction of compounds (2b,c) with aniline by refluxing in acetic acid. Acetylation of 4-(3-bromo-4-hydroxybenzylidene)-2-aryl-1H-1-phenyl-imidazol-5(4H)-ones (3a, b) with acetic anhydride yielded the corresponding (E)-2-bromo-4-[(2-(4-chlorophenyl)-5-oxo-1-phenyl-1H-imidazol-4(5-ylidene)methyl] phenyl acetate (4a, b; Scheme 1). Treatment of oxazolinone derivatives (2a, b) with 2-aminophenol by refluxing in acetic acid afforded the corresponding (Z)-N-(1-(benzo[d]oxazol-2-yl)-2-(4-hydroxyphenyl) vinyl) benzamide (5a, b; Scheme 1). Acetylation of (Z)2-[β-(3-bromo-4-Hydroxyphenyl)-α-(benzoylamino)vinyl]-benzoxazole (5b) with acetic anhydride and chloroacetyl chloride gave the corresponding (Z)-4-(2-benzamido-2-(benzo[d]oxazol-2-yl)vinyl)-2-bromophenyl acetate 6 and (Z)-4-(2-benzamido-2-(benzo[d]oxazol-2-yl)vinyl)-2-bromophenyl 2-chloroacetate 7, respectively.

Preparation of oxazolone (2a–c), imidazolone (3a, b, 4a, b) and benzoxazolone derivatives (5a, b, 6, 7).

3.2

3.2 Cytotoxicity assays

Imidazolinone and benzoxazole derivatives were evaluated for their human tumor cell growth inhibitory activity against two cell lines: MCF-7 (breast carcinoma) and HePG2 (hepatocellular carcinoma). The measurements of cell growth and viability were determined as described in the Mossman (1983) and Vijayan et al. (2004) method (Mosmann, 1983; Vijayan et al., 2004). Inhibitory activity against breast carcinoma cells (MCF-7 cell line) and hepatocellular carcinoma cells (HePG2 cell line) was tested by using different concentrations of the imidazolinones, benzoxazoles and vinblastine drug as standard reference. The viability cells (%) were determined by the colorimetric method. Inhibitory concentration fifty (IC₅₀) of prepared compounds of MCF-7 cell line were calculated from Table 1 and Figs. 1 and 2.

Table 1 Evaluation of cytotoxicity of imidazolinones and benzoxazoles against MCF-7 cell line.

Sample conc. (μg)	Viability%
	Imidazolinones			Benzoxazoles
	3a	3b	4b	5a	5b	6	Vinblastine standard
50	34.84	25.28	24.16	19.58	21.74	26.47	7.82
25	48.96	39.74	40.48	35.24	38.33	39.74	15.18
12.50	67.39	57.96	57.12	48.32	54.85	59.96	29.60
6.25	80.94	73.18	79.87	69.26	72.47	73.18	48.75
3.125	91.12	89.22	90.54	84.51	88.19	89.22	60.35
1.56	97.98	96.15	97.31	93.24	96.54	95.46	76.24
0	100	100	100	100	100	100	100

Evaluation of cytotoxicity of compounds (3a, 3b, 4b, and standard vinblastine) against MCF-7 cell line.

Evaluation of cytotoxicity of compounds (5a, 5b, 6, and standard vinblastine) against MCF-7 cell line.

Inhibitory concentration fifty (IC₅₀) of synthesized compounds of HePG2 cell line were calculated from Table 2 and Figs. 3 and 4.

Table 2 Evaluation of cytotoxicity of imidazolinones and benzoxazoles of HePG2 cell line.

Sample conc. (μg)	Viability%
	Imidazolinones			Benzoxazoles
	3a	3b	4b	5a	5b	6	Vinblastine standard
50	18.63	14.59	19.66	13.80	15.07	15.86	14.38
25	27.56	23.75	28.26	24.74	22.42	26.37	16.13
12.50	58.12	40.62	49.32	33.32	51.08	37.84	24.25
6.25	72.29	76.88	75.56	51.16	74.86	51.58	45.13
3.125	81.41	89.55	88.84	65.14	90.52	68.61	55.00
1.56	90.93	97.63	93.77	81.71	98.34	82.15	72.13
0	100	100	100	100	100	100	100

Evaluation of cytotoxicity of compounds (3a, 3b, 4b, and standard vinblastine) against HePG2 cell line.

Evaluation of cytotoxicity of compounds (5a, 5b, 6, and standard vinblastine) against HePG2 cell line.

The results of inhibitory concentration fifty (IC₅₀) data are summarized in Table 3.

IC₅₀: is the concentration that induces 50% growth inhibition compared with untreated cells.
MCF-7 = human breast carcinoma cell line.
HePG2 = human hepatocellular carcinoma cell line.

Table 3 IC50 (μg) values of tumor cell lines after 72 h continuous exposure to test.

Compd.	Tumor type/cell line
	MCF-7	HePG2
3a	24.30	15.80
3b	18.0	10.90
4b	17.80	12.30
5a	12.0	6.70
5b	16.20	13.00
6	18.70	6.90
Vinblastine standard	6.10	4.60

In comparison with standard antitumor vinblastine, compound 5a is found to be less IC₅₀ value (12.0 μg) than other tested compounds against the human breast tumor cells (MCF-7). Compounds 5a and 6 are also found to be less IC₅₀ values (6.79 and 6.90 μg) than other tested compounds against the human hepatocellular carcinoma cells (HePG2). Benzoxazole derivatives are found to exhibit stronger anticancer activity cell lines than those of imidazolinone derivatives from the inhibitory concentration fifty (IC₅₀) results.

4 Conclusion

The biological results obtained for compounds 3–6 described in this paper confirm that they are most potent against the human breast tumor cells (MCF-7) and human hepatocellular cancer cells (HePG2). Compounds 5a and 6 have the most prominent activity against the human hepatocellular tumor cells (HePG2) IC₅₀ = (6.7 μg/ml) to (6.9 μg/ml).

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