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Synthesis, Reaction and Antiviral Activity of 2,4-Diaryl-1,3-selenazoles
Synthesis, Reaction and Antiviral Activity of 2,4-Diaryl-1,3-selenazoles
Journal of the Korean Chemical Society. 2008. Feb, 52(1): 36-46
Copyright © 2008, The Korean Chemical Society
1,3-Selenazoles, arylselenocarboxamides, α-bromoketones, X-ray, HIV-1
  • Received : August 21, 2007
  • Published : February 20, 2008
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About the Authors
Ali Z. Al-Rubaie
Wasfi A. Al-Masoudi
A part of a Ph.D Thesis, Department of Chemistry, College of Arts and Science in Tarhona, Al-Mergab University, Tarhona, Libya
Ali Jameel Hameed
Lina Z. Yousif
Mohsen Graia
Institut Préparatoire aux Etudes d’Ingénieurs de Sfax, B. P. 805, Sfax, Tunisia

Abstract
The cyclization of primary arylselenocarboxylic amides with α-bromoketones afforded a variety of new 2,4-diaryl-1,3-selenazoles. Halogenation of the 2,4-diaryl-1,3-selenazoles with chlorine, bromine and iodine gave the new 1,1-dihalo-2,4-diaryl-1,3-selenazoles in good yields. Antiviral activity of some 1,1-dihalo-2,4-diaryl-1,3-selenazoles has been tested against AIDS virus (HIV-1 and HIV-2). They showed some bioactivity against HIV-1. All compounds were characterized by their elemental analysis, 1 H NMR and mass spectroscopic data. The crystal structure of 2-(3,4-dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole displays the molecular configuration.
Keywords
INTRODUCTION
The synthesis of sulfur- and nitrogen containing heterocyclic compounds have been extensively studied, while the syntheses of selenium analogues have not been appreciably investigated. 1 , 2 This is mainly due to the difficultly in preparing primary selenocarboxamides. 3 Such compounds can be used to prepare the selenium-nitrogen heterocyclic compounds. 3b , 4 The reactions of primary selenoamides with α-haloketones have been already reported to prepare selenium-nitrogen heterocyclic compounds. 5
Recently, however, reports of selenium-containing heterocyclic compound synthesis have gradually increased because of their interesting reactivities and their pharmaceutical applications. The selenazole derivatives are of marked interest because of their anti-tumor, antibacterial and other notable activities. 6 - 9 For example, selenazofurin (2-β-Dribofuranosylselenazole-4-carboxamide) showed significant anti-tumor properties in animals and broad spectrum antiviral activity in cell culture experiments. 9 Thus, many synthetic routes of selenazole derivatives have been extensively investigated. 10
Recently, we used arylselenocarboxamides to prepare several new 3,5-diaryl-1,2,4-selenadiazoles using palladium(II) salt as a catalyst. 4a The present work describes the reaction of arylselenocarboxamides with α-bromoketones to prepare a variety of several unreported 2,4-diary-1,3-selenazoles. Furthermore, reactions of 2,4-diaryl-1,3-selenazoles with SO 2 Cl 2 , Br 2 and I 2 are reported and the biological significance of some of them was tested. The crystal structure of 2-(3,4-dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole has been determined by X-ray crystallography.
It is worth noting that Giesel et al 11 showed that the reaction of nitriles with P 2 Se 5 afforded primary selenocarboxylic amides. The cyclization of these compounds with α-haloketones afforded a variety of functionalized 1,3-selenazoles. 11
EXPERIMENTAL
- Physical measurements
1 H and 13 C NMR spectra were obtained with a Jeol-EX-90FT, a Bruker LA-250(250 MHz) and a Bruker 300 spectrometer instruments. They were recorded in DMSO-d 6 or CDCl 3 solutions containing TMS as internal standard. Chemical shifts for all 1 H and 13 C NMR spectra were reported in δ units downfield from internal reference Me 4 Si. Elemental analyses (C, H and N) were performed by Analytical Laboratories of Konstanz University, Germany. Mass spectra (EI) were determined on a Finnigan MAT-321 spectrometer at 70 eV and measurements were carried out on 80 Se isotope.
The structure of 2-(3,4-dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole( 13 ) was determined by single crystal X-ray diffraction. A colourless single crystal of 13 with dimensions 0.30×0.15×0.04 mm was mounted on a thin glass fiber. Data were collected on an Enraf Nonius CAD4 automated 40 circles diffractometer (Mo Kα radiation, λ= 0.71069Å) at 293 K in the range of 2.11<θ<22.10°. Data were corrected for Lorentz and polarization effects. The structure was solved by direct method using SHELXS-97 12 and subsequent difference Fourier syntheses and then refined by full-matrix leastsquares method on F 2 using SHELXL97. 12 All of the non-hydrogen atoms were refined anisotropically. Positions of the hydrogen atoms were fixed at their ideal positions. Refinement of F2 against all reflections. The weighted R-factor wR and goodness of fit S are based on F2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2sigma(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R- factors based on all data will be even larger.
- Synthesis
All reactions were carried out under dry nitrogen atmosphere. All solvents were dried and freshly distilled under nitrogen before use.
Phenylselenocarboxamide,4-bromophenylselenocarboxamide, 2-methoxyphenylselenocarboxamide, 4-methoxyphenylselenocarboxamide, 4-methylthiophenylselenocarboxamide, 4-ethoxyphenylselenocarboxamide, 2,3-dimethoxyphenylselenocarboxamide, 3,4-dimethoxyphenylselenocarboxamide, 3,5-dimethoxyphenylselenocarboxamide, 4-phenylphenylselenocarboxamide, 6-methoxynaphthyl-1-selenocarboxamide and 4-methoxynaphthyl-2-selenocarboxamide were prepared according to a literature method. 4a
2,4-Diary-1,3-selenazoles were prepared from the reaction of the corresponding arylselenocarboxamides with α-bromoketones (phenacyl bromide, 4-bromophenacyl bromide and 4-phenylphenyacyl bromide) by the following general procedure:
A solution of α-bromoketones (10 mmol) in 10 cm 3 of ethanol was added dropwise to a hot solution of arylselenocarboxamides (10 mmol) in 20 cm 3 ethanol. The reaction mixture was refluxed for 45-60 min (the end of the reaction was monitored by TLC). The mixture is then concentrated by a rotary evaporator and the residue neutralized with dilute aqueous ammonia (10%). The precipitate is deposited, collected by filtration and then washed several times with cold ethanol. Recrystallization from ethanol to give the corresponding 2,4-diary-1,3-selenazoles in fair to good yields.
- 2-Phenyl-4-(4-phenylphenyl)-1,3-selenazole (1)
Yield: 72%. M.p. 155-157 ℃. Anal. Calc. for C 21 H 15 NSe: C, 70.00; H, 4.19; N, 3.88. Found: C, 69.62; H, 3.97; N, 3.86%. 1 H NMR(DMSO-d 6 ): δ 7.55-7.21(m, 6H, Ar- H ), 7.81 (d, 4H, Ar- H , J =7.85 Hz), 8.38-7.92 (m, 4H, Ar- H ), 8.75 (s, 1H, Ar- H ).
MS: m/z: 361(M + ).
- 2,4-bis(4-Bromophenyl)-1,3-selenazole (2)
Yield: 63%. M.p. 161-163 ℃. Anal. Calc. for C 15 H 9 Br 2 NSe: C, 40.76; H, 2.05; N, 3.17. Found: C, 40.64; H, 1.98; N, 3.16%. 1 H NMR (DMSO-d 6 ): δ 7.85-7.48(m, 4H, Ar- H ), 8.10-7.90 (m, 4H, Ar- H ), 8.82 (s, 1H, Ar- H ).
- 2-(4-Bromophenyl)-4-(4-phenylphenyl)-1,3-selenazole (3)
Yield: 77%. M.p. 188-190 ℃. Anal. Calc. for C 21 H 14 BrNSe: C, 57.43; H, 3.21; N, 3.19. Found: C, 57.64; H, 3.18; N, 3.16%. 1 H NMR (DMSO-d 6 ): δ 7.52(d, 2H, Ar- H , J =8.25 Hz), 7.95-7.72(m, 7H, Ar- H ), 8.28-7.96 (m, 4H, Ar- H ), 8.80 (s, 1H, Ar- H ).
- 2-(4-Hydroxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (4)
Yield: 52%. M.p. 167-168 ℃. Anal. Calc. for C 15 H 10 BrNOSe: C, 47.52; H, 2.66; N, 3.69. Found: C, 47.33; H, 2.53; N, 3.60%. 1 H NMR (DMSO-d 6 ): δ 6.87(d, 2H, Ar- H , J =8.04 Hz), 7.64(d, 2H, Ar- H , J =6.89 Hz), 8.20-7.74 (m, 4H, Ar- H ), 8.60 (s, 1H, Ar- H ), 10.09 (s, 1H, OH ).
MS: m/z: 379/381(M + ).
- 2-(4-Methoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (5)
Yield: 61%. M.p. 174-176 ℃. Anal. Calc. for C 16 H 12 BrNOSe: C, 48.88; H, 3.08; N. Found: C, 48.63; H, 2.93; N, 3.62%. 1 H NMR (DMSO-d 6 ): δ 3.85(s, 3H, CH 3 ), 7.07(d, 2H, Ar- H , J =7.25 Hz), 7.72 (d, 2H, Ar- H , J =8.22 Hz), 8.10-7.87 (m, 4H, Ar- H ), 8.65 (s, 1H, Ar- H ).
- 2-(4-Methoxyphenyl)-4-(4-phenylphenyl)-1,3-selenazole (6)
Yield: 30%. M.p. 187-188 ℃. Anal. Calc. for C 22 H 17 NOSe: C, 67.69; H, 4.39; N, 3.59. Found: C, 67.63; H, 4.33; N, 3.60%. 1 H NMR (DMSO-d 6 ): δ 3.85 (s, 3H, OCH 3 ), 7.70-7.26 (m, 7H, Ar- H ), 8.20-7.92 (m, 4H, Ar- H ), 8.65 (s, 1H, Ar- H ).
- 2-(2-Methoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (7)
Yield: 69%. M.p. 165-167 ℃. Anal. Calc. for C 16 H 12 BrNOSe: C, 48.88; H, 3.08; N, 3.56. Found: C, 48.54; H, 2.60; N, 3.34%. 1 H NMR (DMSO-d 6 ): δ 4.10 (s, 3H, CH 3 ), 7.50-7.30 (m, 3H, Ar- H ),7.68 (d, 2H, Ar- H , J =7.68 Hz), 8.10 (d, 2H, Ar- H , J = 8.24 Hz), 8.47 (d, 1H, Ar- H , J =8.21 Hz), 8.79 (s, 1H, Ar- H ).
- 2-(2-Methoxyphenyl)-4-(4-phenylphenyl)-1,3-selenazole (8)
Yield: 55%. M.p. 175-177 ℃. Anal. Calc. for C 22 H 17 NOSe: C, 67.69; H, 4.39; N, 3.59. Found: C, 67.64; H, 4.35; N, 3.54%. 1 H NMR (DMSO-d 6 ): δ 4.10 (s, 3H, CH 3 ), 7.68-7.00 (m, 6H, Ar- H ),7.78 (d, 4H, Ar- H , J =7.35 Hz), 8.20 (d, 2H, Ar- H , J =8.04 Hz), 8.30 (d, 1H, Ar- H , J =7.45 Hz), 8.75 (s, 1H, Ar- H ).
- 2-(2-Ethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (9)
Yield: 60%. M.p. 158-160 ℃. Anal. Calc. for C 17 H 14 BrNOSe: C, 50.14; H, 3.46; N, 3.44. Found: C, 49.46; H, 3.45; N, 3.32%. 1 H NMR (DMSO-d 6 ): δ 1.38(t, 3H, CH 3 ), 4.11 (q, 2H, CH 2 ), 7.04 (d, 2H, Ar- H , J = 8.05 Hz),7.63 (d, 2H, Ar- H , J = 8.12 Hz), 7.97 (t, 4H, Ar- H ), 8.65 (s, 1H, Ar- H ).
- 2-(2,3-Dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (10)
Yield: 48%. M.p. 136-138 ℃. Anal. Calc. for C 17 H 14 BrNO 2 Se: C, 48.25; H, 3.33; N, 3.31. Found: C, 48.34; H, 3.45; N, 3.32%.
- 2-(2,3-Dimethoxyphenyl)-4-(4-phenylphenyl)-1,3-selenazole (11)
Yield: 73%. M.p. 155-157 ℃. Anal. Calc. for C 23 H 19 NO 2 Se: C, 65.72; H, 5.46; N, 3.30. Found: C, 65.50; H, 5.51; N, 3.28%.
MS: m/z: 421(M + ).
- 2-(3,5-Dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (12)
Yield: 43%. M.p. 98-100 ℃. Anal. Calc. for C 17 H 14 BrNO 2 Se: C, 48.25; H, 3.33; Br, N, 3.44. Found: C, 48.14; H, 3.31; N, 3.29%. 1 H NMR (DMSO-d 6 ): δ 3.85(s, 6H, OCH 3 ), 6.70 (s, 1H, Ar- H ), 7.15 (s, 2H, Ar- H ), 7.70 (d, 2H, Ar- H , J = 8.22 Hz), 8.08 (d, 2H, Ar- H , J =7.96 Hz), 8.65 (s, 1H Ar- H ).
- 2-(3,4-Dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (13)
Yield: 66%. M.p. 181-182 ℃. Anal. Calc. for C 17 H 14 BrNO 2 Se: C, 48.25; H, 3.33; Br, N, 3.44. Found: C, 48.34; H, 3.41; N, 3.31%. 1 H NMR (DMSO-d 6 ): δ 3.90(s, 6H, OCH 3 ), 7.13 (d 1H, Ar- H , J =8.20 Hz), 7.71 (d, 4H, Ar- H , J =7.22 Hz), 8.11 (d, 2H, Ar- H , J =7.80 Hz), 8.65 (s, 1H Ar- H ).
- 2-(3,4-Dimethoxyphenyl)-4-(4-phenylphenyl)-1,3-selenazole (14)
Yield: 73%. M.p. 160-161 ℃. Anal. Calc. for C 23 H 19 NO 2 Se: C, 65.72; H, 4.56; N, 3.30. Found: C, 65.24; H, 4.51; N, 3.30%. 1 H NMR (DMSO-d 6 ): δ 3.90(s, 6H, OCH 3 ), 7.12 (d, 1H, Ar- H , J = 8.24 Hz), 7.33-7.65 (m, 3H, Ar- H ), 7.67-8.45 (m, 8H, Ar- H ), 8.65 (s, 1H, Ar- H ).
- 2-(4-(Methylthio)phenyl)-4-(4-bromophenyl)-1,3-selenazole (15)
Yield: 61%. M.p. 172-173 ℃. Anal. Calc. for C 16 H 12 BrNSSe: C, 46.96; H, 2.96; N, 3.42. Found: C, 46.74; H, 2.86; N, 3.34%.
- 2-(4-(Methylthio)phenyl)-4-(4-phenylphenyl)-1,3-selenazole (16)
Yield: 53%. M.p. 194-196 ℃. Anal. Calc. for C 22 H 17 NSSe: C, 65.02; H, 4.22; N, 3.45. Found: C, 64.95; H, 3.88; N, 3.34%. 1 H NMR (DMSO-d 6 ): δ 2.52 (s, 3H, SCH 3 ), 7.60-7.25(m, 5H, Ar- H ), 7.77 (d, 4H, Ar- H , J =8.25 Hz), 8.18-7.84 (m, 4H, Ar- H ), 8.70 (s, 1H, Ar- H ).
- 2-(6-Methoxy-2-naphthyl)-4-(4-phenylphenyl)-1,3-selenazole (17)
Yield: 59%. M.p. 249-250 ℃. Anal. Calc. for C 26 H 19 NOSe: C, 70.91; H, 4.35; N, 3.18. Found: C, 71.23; H, 4.41; N, 3.34%. 1 H NMR (DMSO-d 6 ): δ 2.52 (s, 3H, OCH 3 ), 7.60-7.25 (m, 5H, Ar- H ), 7.80 (d, 4H, Ar- H , J =7.96 Hz), 8.22-7.88 (m, 4H, Ar- H ), 8.70 (s, 1H, Ar- H ).
MS: m/z: 441(M + ).
- 2-(6-Methoxy-2-naphthyl)-4-(4-bromophenyl)-1,3-selenazole (18)
Yield: 62%. M.p. 110 ℃. Anal. Calc. for C 20 H 14 BrNOSe: C, 54.20; H, 3.18; N, 3.16.
Found: C, 54.66; H, 3.34; N, 3.25%. 1H NMR (CDCl 3 ): 3.83 (s, 3H, OCH 3 ), 6.86 (dd, 1H, Ar- H , J =2.10, 8.42 Hz), 7.20 (d, 1H, Ar- H , J =7.9 Hz), 7.45 (d, 2H, Ar- H , J =8.41 Hz), 7.82-8.10 (m, 3H, Ar- H ), 8.11 (s, 1H, Ar- H ), 8.13-8.37 (m, 3H, Ar- H ).
- 2-(6-Methoxy-2-naphthyl)-4-phenyl-1,3-selenazole (19)
Yield: 70%. M.p. 189-190 ℃. Anal. Calc. for C 20 H 15 BrNOSe: C, 65.94; H, 4.15; N, 3.84. Found: C, 65.65; H, 4.06; N, 3.80%. 1 H NMR (CDCl 3 ): 3.95 (s, 3H, OCH 3 ), 7.17(dd, 1H, Ar- H , J =1.72, 8.50 Hz), 7.21(d, 1H, Ar- H , J =8.32 Hz), 7.38-7.32 (m, 1H, Ar- H ), 7.48-7.42(m, 2H, Ar- H ), 7.79(d, 1H, Ar- H , J =8.48Hz ), 7.89(d, 1H, Ar- H , J =8.80Hz), 8.06-8.01(m, 2H, Ar- H ), 8.09(s, 1H, Ar- H ), 8.08(dd, 1H, Ar- H , J =1.80, 8.14 Hz), 8.36(d, 1H, Ar- H , J =7.92 Hz). 13 C NMR(CDCl 3 ): 55.4, 105.9, 117.8, 119.7, 125.1, 126.5, 126.8, 127.4, 127.9, 128.7, 130.2, 131.9, 135.5, 135.7, 157.0, 158.7, 174.3.
- 2-(4-Methoxy-1-naphthyl)-4-phenyl-1,3-selenazole (20)
Yield: 40%. Yellow oil. Anal. Calc. for C 20 H 15 BrNOSe: C, 65.94; H, 4.15; N, 3.84. Found: C, 66.05; H, 4.23; N, 4.01%. 1 H NMR (CDCl 3 ): 3.96(s, 3H, OCH 3 ), 6.68(d, 1H, Ar- H , J =7.85 Hz), 7.23-7.61(m, 8H, Ar- H ), 7.75(d, 1H, Ar- H , J =7.83 Hz), 8.10(s, 1H, Ar- H ), 8.22(d, 1H, Ar- H , J =8.22 Hz).
- 2-(4-phenylphenyl)-4-(4-bromophenyl)-1,3-selenazole (21)
Yield: 21%. M.p. 203-205 ℃. Anal. Calc. for C 21 H 14 BrNSe: C, 57.43; H, 3.21; N, 3.19. Found: C, 57.22; H, 3.00, N, 3.12%. 1 H NMR (DMSO-d 6 ): 7.52 (d, 2H, Ar- H , J =7.45 Hz), 7.77-7.95 (m, 7H, Ar- H ), 7.95-6.25 (m, 4H, Ar- H ), 8,80 (s, 1H, Ar- H ).
- 2,4-Bis(4-phenylphenyl)-1,3-selenazole (22)
Yield: 42%. M.p. 255-257 ℃. Anal. Calc. for C 27 H 19 NSe: C, 74.31; H, 4.39; N, 3.21. Found: C, 73.73; H, 4.41; N, 3.30%. 1 H NMR (DMSO-d 6 ): 7.27-7.72(m, 14H, Ar- H ), 7.84(d, 2H, Ar- H , J = 8.07 Hz), 8.09(d, 2H, Ar- H , J =8.10 Hz), 8.58(s, 1H, Ar- H ).
- 2,4-Bis(4-(methylthio)phenyl)-1,3-selenazole (23)
Yield: 35%. M.p. 121-122 ℃. Anal. Calc. for C 17 H 15 NS 2 Se: C, 54.25; H, 4.02; N, 3.72. Found: C, 53.83; H, 4.01; N, 3.30%. 1 H NMR (DMSO-d 6 ): δ 1.68 (s, 3H, SCH 3 ), 2..52 (s, 3H, SCH 3 ) 7.90-.27 (m, 8H, Ar- H ), 8.00 (s, 1H, Ar- H ).
- 2-phenyl-4-(4-bromophenyl)-1,3-selenazole (24)
Yield: 75%. M.p. 129-131 ℃. Anal. Calc. for C 15 H 10 BrNSe: C, 49.62; H, 2.78; N, 3.86. Found: C, 49.83; H, 2.64; N, 3.70%. 1 H NMR (DMSO-d 6 ): δ 7.21 (d, 2H, Ar- H , J =8.40 Hz), 7.90-7.27 (m, 7H, Ar- H ), 8.00 (s, 1H Ar- H ).
MS: m/z: 363/365(M + ).
- Oxidative addition reactions of 2,4-diaryl-1,3-selenazoles
- Synthesis of 1,1-dichloro-2,4-diaryl-1,3-selenazoles
To a solution of 2,4-diaryl-1,3-selenazole (1.0 mmol) in dry diethyl ether (25 cm 3 ), sulfuryl chloride (0.70 ml) was added dropwise with stirring at 5 ℃. The reaction mixture was allowed to stand at room temperature for 4 h. Concentration under reduce pressure and addition of hexane afforded the colourless to pale yellow solid compounds.
Compounds 25 , 33 , 39 and 42 were prepared by the same above method, see 1 .
- Synthesis of 1,1-dibromo-2,4-diaryl-1,3-selenazoles
These compounds were prepared by the following method:
2-(3,4-Dimethoxy phenyl)-4-(4-phenylphenyl)-1.3-selenazole (0.70 g; 1.5 mmol) dissolved in diethyl ether (10 cm 3 ) and a solution of bromine (0.25 cm 3 , 1.5 mmol) in the same solvent was slowly added with stirring. A yellow precipitate was formed, which after 4 h was collected and recrystallized from ethanol/chloroform (4:1) to give 1,1-dibromo-2-(4,5-Dimethoxy phenyl)-4-(4-phenylphenyl)-1.3-selenazole( 26 ) as yellow crystal, m.p. 156-157 ℃.
Compounds 28 , 30 , 34 , 36 and 40 were prepared by the above method ( 1 ).
- Synthesis of 1,1-diiodo-2,4-diaryl-1,3-selenazoles
All diiodo derivatives were prepared according to the following method:
Iodine (0.39 g; 1.5 mmol) in dry diethyl ether (10 cm 3 ) was added dropwise to a solution of 2-(3,4-dimethoxy phenyl)-4-(4-phenylphenyl)-1,3-selenszole (0.70 g; 1.5 mmol) in dry diethyl ether (10 cm 3 ) with stirring at room temperature. A brown precipitate gradually formed which after 3 h, was collected by filtration and recrystallized from ethanol to give 1,1-diiodo-2-(3,4-dimethoxy phenyl)-4-(4-phenylphenyl)-1,3-selenszole ( 27 ) as yellow crystals, m.p. 136-139 ℃.
Compounds 29 , 31 , 32 , 35 , 37 , 41 and 43 were prepared by the same above method, 1 .
- Synthesis of 1-ethyl-1-diiodo-2,4-diaryl-1,3-selenazolium(35)
An excess of freshly distilled ethyl iodide (2.0 cm 3 ) was added slowly with stirring at room temperature to the solution of 9 (0.41 g; 1 mmol) in diethyl ether (20 cm 3 ). After stirring for 4 h at room temperature, a light yellow solid separated which was filtered, dried and recrystallized with DMF/water to give 35 in 81% yield. M.p. 144-146 ℃.
RESULTS AND DISCUSSION
- Synthesis
The reaction of several primary arylselenocarboxamides with 4-bromo- and 4-phenylphenacyl bromides gave the corresponding 2,4-diaryl-1,3-selenazoles in good yields (Experimental section). All selenazoles ( 1-24 ) are yellow to white crystalline solids with sharp melting point which are soluble in common organic solvents. The IR spectra of all compounds show an absorption band between 1580-1630 cm -1 due to ν(C=N) and an absorption band in range 595-560 cm -1 may assigned to ν(Se-C). 4a , 13 , 14 1 H NMR spectra of compounds 1-24 were recorded in DMSO-d 6 or CDCl 3 and gave a further support for the formation of these compounds. The 1 H NMR spectra consist of, in addition to SCH 3 /OCH 3 /OCH 2 CH 3 , low field signals of aryl protons at the range 6.18-8.82 ppm (Experimental section).
The 2,4-diaryl-1,3-selenazoles ( 1-24 ) are readily oxidized by SO 2 Cl 2 , Br 2 and I 2 to the corresponding Se(IV) dihalides ( i.e. 1,1-dihalo-2,4-diaryl-1,3-selenazoles ( 25-36 and 39-43 )), while the reaction of compound 9 with ethyl iodide gave the selenonium salt ( 38 ) in high yield ( 1 , Table 1 ). All these new compounds are stable toward moisture and air. They were characterized by IR, NMR, mass spectroscopic data and elemental analysis, ( 1 ). The IR spectra of the dihalo derivatives are quite similar to those of the 2,4-diaryl-1,3-selenazoles( 1-24 ) Thus, in the IR spectra of compounds 25-43 , a strong band appears in the region 1610-1580 cm -1 due to ν(C=N) 13 , 14 , while the (C-Se) stretching vibration appeared in the region 590-570 cm -1 . 13 , 14 Furthermore, the (C-H) vibrations for the selenazole ring in compounds 1-43 is observed in the region 3070-3011 cm -1 which is characteristic of heteroaromatic compounds. 15
Physical and Analytical data for 1,1-dihalo-2,4-diaryl-1,3-selenazoles*
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*Ar1 and Ar2 as illustrated below aCalculated values are in parentheses. # Contains one or two H2O molecules
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Preparative methods for compounds 1-43.
1 H NMR spectra of compounds 25-43 were recorded in CDCl 3 solution and show all the expected protons with proper intensity ratio, 1 .
The mass spectra of compounds 1 , 4 , 11 , 17 and 24 show the molecular ion with a correct isotope pattern for compounds containing selenium. The base peak of each spectrum was based on ArCN + which is corresponding to the loss of ArC=CHSe + ion. The dihalo derivatives ( i.e. compounds 27 , 28 , 29 , 31 , 35 , 36 and 38 ) show loss of halogens(X 2 ) in two steps from the parent ion. In general, the mass spectra of compounds 27 , 28 , 29 , 31 , 35 , 36 and 38 contain features characteristic of selenazole compounds, which show the exact fragmentation patterns.
- Biological activity
- In vitro-HIV assay
The cavity on glycoprotein 41 (gp41) of the HIV plays an important rule in the viral replication process, which could hold a small molecule inhibitor, and heterocyclic compounds namely non-reverse transcriptase inhibitors (NNRTI’s) that would fit this cavity have been identified and inhibit fusion.16 Accordingly, our synthetic strategy for synthesis of the new heterocyclic derivatives namely 2,4-diaryl-1,3-selenazoles depend on this hypothesis. Compounds 26 , 32 , 33 and 37 were tested for their anti HIV-1 and HIV-2 activity, in vitro , using III B and ROD strains, respectively, in human T-lymphocyte (MT-4) cells (T means the immune cells Thymus). The results are summarized in 2 , in which the data have been included for comparison purpose. Compounds-induced cytotoxicity was also measured in MT-4 cell in parallel with the antiviral activity. Non of the selenazole derivatives were found to inhibit HIV-1 replication, in vitro , at EC 50 lower than CC 50 in comparison to the antiviral NNRTI’s agents Efavirenz (EFV; 6-chloro-4-cyclopropyl-4-(trifluoromethyl)-1H-benzo[d][1,3]oxazin-2(4H)-one) 17 and Capravirin[(5-(3,5-dichlorophenylthio)-4-isopropyl-1-(pyridin-3-ylmethyl)-4,5-dihydro-1H-imidazol-2-yl)methyl carbamate], 18 except compound 32 which showed IC 50 > 11.8 μg/ml against HIV-1 (III B strain), and might lead to increase in activity on modification of the biofunctional group attached to the selenazole nucleous. The low Si<1 indicated no HIV selectivity.
In vitroanti-HIV-1aand HIV-2bof some selenazole compounds
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aAnti-HIV-1 activity measured with strain IIIB. bAnti-HIV-2 activity measured with ROD strain. cCompound concentration required to reduce the viability of mock-infected MT-4 cell by 50. dCompound concentration required to achieve 50% protection of MT-4 cell from the HIV-1 induced cytopathogenicity. eSI : Selectivity therapeutic index (IC50/CC50)
In conclusion, the structure-activity relationship suggested that the substitution of selenazole bearing another heterocycle moiety such as thiazole group might increase the activity against the HIV through the increasing of the binding between the gp41 of the virus and the suggested new selenazole derivatives.
- Crystal structure of 2-(3,4-dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole (13)
The absolute structure for 2-(3,4-dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole ( 13 ) was determined by using X-ray diffraction analysis ( 1 ). A summary of crystal data and structure refinement for compound 13 is provided in 3 . Selected bond lengths and angles are listed in 4 . The lengths of C8-N and C9-N in 13 are 1.384(11) Å and 1.268(11) Å ( 4 ) which are shorter than the usual single bond length of 1.47 Å. 19 , 20 This is indicating clearly their double bond character. The sum of the three angles around each of the C8 and C9 atom is 360.0, respectively. This means that the arrangements of N, C8, C7 and C4, and N, C9, Se and C10 atom is planar, 20 respectively, 4 .
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Molecular structure of 2-(3,4-dimethoxyphenyl)-4-(4-bromophenyl)-1,3-selenazole. Thermal elipoids are drawn at the 50% probability level.
Crystal and structure refinement for compound13.
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Crystal and structure refinement for compound 13.
Selected geometric parameters (Å,o) for compound 13.
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Symmetry codes: (i) x 1, y, z; (ii) 1 + x, y, z; (iii) 1/2 + x, 3/2 y, 1 z; (iv) x 1/2, 3/2 y, 1 z; (v) x, 3/2 y, 1/2 + z; (vi) x, 3/2 y, z 1/2; (vii) 1/2 + x, y, 1/2 z; (viii) x 1/2, y, 1/2 z; (ix) x, 2 y, 1 z.
- Supplementary Information
Crystallographic data for the structural analyses have been deposited with the Cambridge Crystallographic Data Centre CCDC no. CCDC 648453 for compounds 13 . Further details of the crystal structure investigations are available free of charge via www.ccdc.cam.ac.uk/deposit (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Facsimile: (44) 01223 336033; Telephone: (44) 01223 762910.
Acknowledgements
The authors are grateful to Professor Erick DeClereq (Rega Medical Institute), Katholiek University, Leuven, Belgium, for providing biological activity tests. Thanks are due to Professor N. A. Al-Masoudi (Konstanz University, Germany) for providing some elemental analysis, NMR and mass spectroscopic data and his help for providing biological activity tests. We are also grateful to college of arts and science in Tarhona, Al-Mergab University, Libya for providing the facilities.
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