Abstract
The importance of virus infections and the early successes with some antiviral drugs have prompted the search for new agents, and it has been focused on compounds that are active against herpesviruses, retroviruses, and rhinoviruses. In this paper, 3H-imidazo[4,5-a]acridones are introduced as new antiviral agents against a panel of DNA and RNA viruses, including herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, and herpes simplex virus-1 TK-KOS ACV r. Also, these compounds were cytostatic in the higher micromolar range. 3H-imidazo[4,5-a]acridones were synthesized by Tanasescu reaction of 3H-imidazo[4′,5′:3,4]benzo [c]isoxazoles in concentrated sulfuric acid containing nitrous acid in excellent yields. The advanced compounds were obtained from the reaction of N-alkyl-5-nitrobenzimidazoles with different aryl acetonitriles under basic conditions. Structures of all newly synthesized compounds were confirmed by IR, 1H NMR, and mass spectral data. The results indicated that the title compounds have mild-to-potent activities in comparison with their appropriate reference standards.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
An intensive search for drugs effective in chemotherapy of viral infections and/or various cancers has been underway for decades. Nitrogen-containing heterocycles have diverse applications, from drugs used as antitumor agents and enzyme inhibitors (Dell’Erba et al., 1992; De Angelis et al., 2005; Iida et al., 2005) to optical materials used in light-emitting diodes and conducting polymers (Cornil et al., 2001). For example, benzo[c]isoxazole derivatives are prescribed as antipsychotic risperidone drugs (Szarfman et al., 2006) and play a key role in many organic reactions (Loudon and Tennant, 1964), notably those leading to anthranilic acids. Also, acridine derivatives, such as acridones, pyridoacridines, and imidazoacridines, are one of the oldest classes of bioactive compounds that are widely used as antibacterial (Mitra et al., 2014), antiprion (Kukowska-Kaszuba and Dzierzbicka 2007), antimalarial (Joshi and Viswanathan, 2006; Winter et al., 2008) anticancer (Kamal et al., 2004; Belmont et al., 2007), and antitumor (Qiao et al., 2012; Lang et al., 2013) agents. Recently, various derivatives of the acridine series also demonstrated significant inhibitory activities toward Plasmodium (Girault et al., 2000, 2001), Trypanosoma (Gamage et al., 1997) and Leishmania (Werbovetz et al., 1994; Di Giorgio et al., 2003) parasites, as well as potent antiviral properties (Lowden and Bastow, 2003; Goodell et al., 2006).
Recently, we reported synthesis of new derivatives of imidazo[4,5-a]acridines as very effective antibacterial agents (Sadeghian et al., 2012; Rahimizadeh et al., 2009). In continuation of our research work on the synthesis of bioactive nitrogen heterocyclic compounds (Rahimizadeh et al., 2009, 2010; Sadeghian et al., 2010; Bakavoli et al., 2010; Pordel et al., 2013), in this study, we explored the preparation and investigation of some imidazo[4,5-a]acridones as potential antiviral agents against different viral strains. Furthermore, the cytotoxic activity of these compounds was also determined.
Experimental
Materials, methods, and instruments
Methanol, N,N-dimethylformamide (DMF), methyl iodide, n-propyl bromide, n-butyl bromide, isobutyl bromide, phenyl acetonitrile, 2-(4-chlorophenyl)acetonitrile, and 2-(4-bromophenyl)acetonitrile were purchased from Merck. Potassium hydroxide was purchased from Sigma–Aldrich. All solvents were dried according to standard procedures. Compounds 1a–d were synthesized as described in the literature (Preston, 2009).
Melting points were measured on an electrothermal type-9100 melting-point apparatus. The IR (as KBr disks) spectra were obtained on a Tensor 27 spectrometer, and only noteworthy absorptions are listed. The 13C NMR (100 MHz) and 1H NMR (400 MHz) spectra were recorded on a Bruker Avance DRX-400 FT spectrometer in CDCl3 and DMSO-d 6 . Chemical shifts are reported in ppm downfield from TMS as internal standard; coupling constant J is given in Hz. The mass spectra were recorded on a Varian Mat, CH-7 at 70 eV. Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyzer. All measurements were carried out at room temperature.
General procedure for the synthesis of compounds 3a–j
With stirring to a solution of KOH (13 g, 231 mmol) in methanol (50 mL), 1-alkyl-5-nitrobenzimidazole 1a–d (10 mmol) and aryl acetonitriles 2a–c (12 mmol) were added. The mixture was refluxed for 4 h and then poured into water. The precipitate was collected by filtration, washed with water, and air-dried to give 3a–j. Further purification was achieved by crystallization from suitable solvent such as EtOH.
3-Methyl-8-phenyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3a)
Pale yellow crystals (methanol); m.p.: 267–269 °C [lit.(Rahimizadeh et al., 2009) m.p.: 266–268 °C]; 1H NMR (400 MHz, CDCl3) δ = 3.43 (s, 3H, N–CH3), 7.41 (d, J = 8.0 Hz, 1H, Ar H), 7.55–7.81 (m, 7H, Ar H). 13C NMR (100 MHz, CDCl3): δ = 162.4 (C, C-5), 159.7 (C, C-8), 153.6 (C, C-2), 149.4 (CH, C-7), 132.5 (C, C-9), 130.9 (CH, C-14), 129.3 (CH, C-12, C-13), 128.4 (CH, C-10, C-11), 125.8 (C, C-1), 120.5 (CH, C-4), 115.6 (CH, C-6), 103.1 (C, C-3), 35.1 (CH3, N–CH3).
8-(4-Chlorophenyl)-3-methyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3b)
Pale yellow crystals (methanol); m.p.: 293–295 °C (lit. [Rahimizadeh et al., 2009] m.p.: 292–294 °C); 1H NMR (400 MHz, CDCl3) δ 3.92 (s, 3H, N-CH3), 7.42 (d, J = 9.5 Hz, 1H, Ar H), 7.58 (d, J = 9.5 Hz, 1H, Ar H), 7.67 (d, J = 8.8 Hz, 2H, Ar H), 7.89 (s, 1H, Ar H), 8.87 (d, J = 8.8 Hz, 2H, Ar H). 13C NMR (100 MHz, CDCl3): δ = 162.9 (C, C-5), 157.3 (C, C-8), 153.2 (C, C-2), 149.0 (CH, C-7), 135.3 (CH, C-14), 133.9 (C, C-9), 131.2 (CH, C-12, C-13), 129.9 (CH, C-10, C-11), 125.6 (C, C-1), 120.2 (CH, C-4), 115.5 (CH, C-6), 102.8 (C, C-3), 35.6 (CH3, N–CH3).
8-Phenyl-3-propyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3c)
Pale yellow crystals (methanol); m.p.: 121–122 °C [lit.(Rahimizadeh et al., 2009) m.p.: 119–122 °C]; 1H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.0 Hz, 3H, CH2–CH 3 ), 1.77–2.12 (m, 2H, CH 2 –CH3), 4.21 (t, J = 7.0 Hz, 2H, N–CH2), 7.47–7.69 (m, 6H, Ar H), 7.89 (s, 1H, Ar H), 8.89 (d, J = 8.0 Hz, 1H, Ar H). 13C NMR (100 MHz, CDCl3): δ = 163.7 (C, C-8), 162.7 (C, C-5), 148.4 (CH, C-7), 147.3 (C, C-2), 133.8 (C, C-9), 130.3 (CH, C-14), 129.5 (CH, C-12, C-13), 127.9 (CH, C-10, C-11), 123.0 (C, C-1), 120.4 (CH, C-4), 111.2 (CH, C-6), 102.8 (C, C-3), 49.3 (CH2, N–CH2), 21.9 (CH2, CH2–CH3), 13.0 (CH3, CH2–CH3).
8-(4-Chlorophenyl)-3-propyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3d)
Pale yellow crystals (methanol); m.p.: 160–163 °C [lit.(Rahimizadeh et al., 2009) m.p.: 158–160 °C]; 1H NMR (400 MHz, CDCl3) δ 1.05 (t, J = 7.3 Hz, 3H, CH2–CH 3 ), 1.85–2.21 (m, 2H, CH2–CH 2 –CH3), 4.18 (t, J = 7.3 Hz, 2H, N–CH2), 7.40 (d, J = 9.5 Hz, 1H, Ar H), 7.56 (d, J = 9.5 Hz, 1H, Ar H), 7.62 (d, J = 8.6 Hz, 2H, Ar H), 7.86 (s, 1H, Ar H), 8.89 (d, J = 8.6 Hz, 2H, Ar H). 13C NMR (100 MHz, CDCl3): δ = 162.7 (C, C-5), 158.73 (C, C-8), 148.9 (CH, C-7), 147.1 (C, C-2), 133.4 (CH, C-14), 130.5 (CH, C-12, C-13), 129.7 (CH, C-10, C-11), 129.5 (C, C-9), 122.7 (C, C-1), 120.4 (CH, C-4), 112.0 (CH, C-6), 103.3 (C, C-3), 49.5 (CH2, N–CH2), 22.3(CH2, CH2–CH3), 13.1 (CH3, CH2–CH3).
3-Butyl-8-phenyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3e)
Pale yellow crystals (methanol); m.p.: 113–115 °C [lit.(Rahimizadeh et al., 2009) m.p.: 110–112 °C]; 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.0 Hz, 3H, CH2–CH 3 ), 1.21–1.56 (m, 2H, CH2–CH 2 –CH3), 1.81–2.09 (m, 2H, CH2–CH 2 –CH2–CH3), 4.23 (t, J = 7.0 Hz, 2H, N–CH2), 7.47–7.69 (m, 6H, Ar H), 7.88 (s, 1H, Ar H), 8.89 (d, J = 8.0 Hz, 1H, Ar H). 13C NMR (100 MHz, CDCl3): δ = 162.3 (C, C-5), 159.6 (C, C-8), 148.6 (C, C-2), 146.0 (CH, C-7), 132.5 (C, C-9), 131.2 (CH, C-14), 129.2 (CH, C-12, C-13), 128.6 (CH, C-10, C-11), 121.1 (CH, C-4), 123.5 (C, C-1), 113.9 (CH, C-6), 103.2 (C, C-3), 48.3 (CH2, N–CH2), 31.0(CH2, CH2–CH2), 21.9 (CH2, CH2–CH2), 13.8 (CH3, CH2–CH3).
3-Butyl-8-(4-chlorophenyl)-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3f)
Pale yellow crystals(methanol); m.p.: 155–157 °C [lit.(Rahimizadeh et al., 2009) m.p.: 157–159 °C]; 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J = 7.0 Hz, 3H, CH2–CH 3 ), 1.23–1.58 (m, 2H, CH2–CH 2 –CH3), 1.82–2.10 (m, 2H, CH2–CH 2 –CH2–CH3), 4.24 (t, J = 7.0 Hz, 2H, N–CH2), 7.41 (d, J = 9.5 Hz, 1H, Ar H), 7.56 (d, J = 9.5 Hz, 1H, Ar H), 7.61 (d, J = 8.6 Hz, 2H, Ar H), 7.90 (s, 1H, Ar H), 8.87 (d, J = 8.6 Hz, 2H, Ar H). 13C NMR (100 MHz, CDCl3): δ = 162.8 (C, C-5), 157.5 (C, C-8), 155.0 (C, C-2), 149.8 (CH, C-7), 134.1 (CH, C-14), 132.0 (C, C-9), 131.0 (CH, C-12, C-13), 129.9 (CH, C-10, C-11), 122.7 (CH, C-4), 123.7 (C, C-1), 114.8 (CH, C-6), 103.2 (C, C-3), 48.7 (CH2, N–CH2), 31.5(CH2, CH2–CH2), 22.0 (CH2, CH2–CH2), 13.9 (CH3, CH2–CH3).
8-(4-Bromophenyl)-3-methyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3g)
Pale yellow crystals (ethanol); yield (79 %), m.p.: 277–280 °C; 1H NMR (400 MHz, CDCl3): δ 3.92 (s, 3H, N–CH3), 7.40 (d, J = 9.0 Hz, 1H, Ar H), 7.53 (d, J = 9.0 Hz, 1H, Ar H), 7.7 (d, J = 8.0 Hz, 2H, Ar H), 7.83 (s, 1H, Ar H), 8.75 (d, J = 8.0 Hz, 2H, Ar H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.8 (C, C-5), 153.5 (C, C-2), 153.2 (C, C-8), 149.7 (CH, C-7), 134.1 (CH, C-12, C-13), 130.7 (CH, C-10, C-11), 130.1 (C, C-9), 126.0 (C, C-1), 124.6 (CH, C-14), 120.1 (CH, C-4), 115.0 (CH, C-6), 100.8 (C, C-3), 35.3 (CH3, N–CH3). MS (70 eV): m/z 330 [M + 2] + (7), 91 (100). Anal. Calcd for C15H10BrN3O (328.2): C, 54.90; H, 3.07; N, 12.80. Found: C, 54.60; H, 3.02; N, 13.01.
8-(4-Bromophenyl)-3-propyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3h)
Pale yellow crystals (ethanol); yield (72 %), m.p.: 170–172 °C; 1H NMR (400 MHz, CDCl3): δ 0.97 (t, J = 7.2 Hz, 3H, CH2–CH 3 ), 1.95 (m, 2H, CH2–CH 2 –CH3), 4.18 (t, J = 7.2 Hz, 2H, N–CH2), 7.43 (d, J = 9.0 Hz, 1H, Ar H), 7.55 (d, J = 9.0 Hz, 1H, Ar H), 7.75 (d, J = 8.8 Hz, 2H, Ar H), 7.85 (s, 1H, Ar H), 8.75 (d, J = 8.8 Hz, 2H, Ar H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.5 (C, C-5), 156.1 (C, C-8), 148.1 (CH, C-7), 146.9 (C, C-2), 134.7 (CH, C-12, C-13), 130.8 (CH, C-10, C-11), 130.5 (C, C-9), 126.1 (C, C-1), 124.9 (CH, C-14), 120.1 (CH, C-4), 115.7 (CH, C-6), 100.5 (C, C-3), 49.3 (CH2, N–CH2), 22.1 (CH2, CH2–CH3), 13.3 (CH3, CH2–CH3). MS (70 eV): m/z 358 [M + 2] + (5), 91 (100). Anal. Calcd for C17H14BrN3O (356.2): C, 57.32; H, 3.96; N, 11.80. Found: C, 56.96; H, 3.93; N, 11.65.
8-(4-Bromophenyl)-3-butyl-3H-imidazo[4′,5′:3,4]benzo[c]isoxazole (3i)
Pale yellow crystals (ethanol); yield (75 %), m.p.: 155–157 °C; 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J = 7.0 Hz, 3H, CH2–CH 3 ), 1.4 (m, 2H, CH2–CH 2 –CH3), 1.95 (m, 2H, CH2–CH 2 –CH2–CH3), 4.23 (t, J = 7.0 Hz, 2H, N–CH2), 7.44 (d, J = 9.0 Hz, 1H, Ar H), 7.57 (d, J = 9.0 Hz, 1H, Ar H), 7.71 (d, J = 9.0 Hz, 2H, Ar H), 7.83 (s, 1H, Ar H), 8.78 (d, J = 9.0 Hz, 2H, Ar H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.3 (C, C-5), 156.3 (C, C-8), 148.0 (CH, C-7), 146.1 (C, C-2), 134.5 (CH, C-12, C-13), 131.1 (CH, C-10, C-11), 130.4 (C, C-9), 126.2 (C, C-1), 125.4 (CH, C-14), 120.3 (CH, C-4), 115.9 (CH, C-6), 100.3 (C, C-3), 49.0 (CH2, N–CH2), 31.4 (CH2, CH2–CH2), 22.5 (CH2, CH2–CH2), 13.7 (CH3, CH2–CH3). MS (70 eV): m/z 372 [M + 2] + (3), 91 (100). Anal. Calcd for C18H16BrN3O (370.2): C, 58.39; H, 4.36; N, 11.35. Found: C, 58.12; H, 4.32; N, 11.23.
8-(4-Bromophenyl)-3-isobutyl-3H-imidazo [4′,5′:3,4] benzo [c] isoxazole (3j)
Pale yellow crystals (ethanol); yield (78 %), m.p.: 153–155 °C; 1H NMR (400 MHz, CDCl3): δ 1.01 (d, J = 7.2 Hz, 6H, CH(CH 3 )2), 2.22 (m, 1H, CH(CH3)2), 4.04 (d, J = 7.2 Hz, 2H, N–CH2), 7.46 (d, J = 9.2 Hz, 1H, Ar H), 7.57 (d, J 2 = 9.2 Hz, 1H, Ar H), 7.75 (d, J = 8.8 Hz, 2H, Ar H), 7.86 (s, 1H, Ar H), 8.81 (d, J = 8.8 Hz, 2H, Ar H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.6 (C, C-5), 156.3 (C, C-8), 148.1 (CH, C-7), 146.3 (C, C-2), 134.7 (CH, C-12, C-13), 131.3 (CH, C-10, C-11), 130.5 (C, C-9), 126.7 (C, C-1), 125.0 (CH, C-14), 120.9 (CH, C-4), 116.3 (CH, C-6), 99.8 (C, C-3), 53.8 (CH2, N–CH2), 28.8 (CH, CH(CH3)2), 18.6 (CH3, CH(CH3)2). MS (70 eV): m/z 372 [M + 2] + (1), 91 (100). Anal. Calcd for C18H16BrN3O (370.2): C, 58.39; H, 4.36; N, 11.35. Found: C, 58.18; H, 4.31; N, 11.12.
General procedure for the synthesis of 4a–j
To a solution of 3a–j (10 mmol) in concentrated sulfuric acid (100 mL) maintained at −10 °C, sodium nitrite (5 g, 150 mmol) was added with stirring over a half-hour period. After the addition was completed, the mixture was allowed to warm to room temperature and to stand at room temperature for 48 h. After pouring this mixture into crushed ice and water (500 mL), the solid which precipitated was removed by filtration, was washed with water and then acetone, and dried to give 4a–j.
3-Methyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one (4a)
Yellowish needles (EtOH + CH3CN); m.p.: >300 °C [lit.(Rahimizadeh et al., 2009) m.p.: >300 °C]; IR (KBr): 3420 cm−1 (NH), 1660 cm−1 (C=O). 1H NMR (400 MHz, DMSO-d 6 ): δ 3.92 (s, 3H, N–CH3), 7.41 (d, J = 8.9 Hz, 1H, Ar H), 7.45–7.85 (m, 5H, Ar H), 8.33 (s, 1H, Ar H), 11.79 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.1 (C = O, C9), 141.6 (C, C-11), 140.3 (CH, C-7), 140.6 (C, C-1), 129.1 (CH, C-12), 127.7 (C, C-10), 126.7 (CH, C-15), 122.4 (C, C-2), 120.0 (CH, C-13), 119.3 (CH, C-6), 117.9 (CH, C-4), 117.5 (CH, C-14), 117.0 (CH, C-5), 107.7 (CH, C-3), 33.3 (CH3, N–CH3). MS (70 eV): m/z 249 [M] + (3), 91 (100); Anal. Calcd for C15H11N3O (249.3): C, 72.28; H, 4.45; N, 16.86. Found: C, 72.01; H, 4.42; N, 17.04.
8-Chloro-3-methyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one (4b)
Yellowish needles (EtOH + CH3CN); m.p.: >300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.: >300 °C]; IR (KBr): 3415 cm−1 (NH), 1660 cm−1 (C = O). 1H NMR (400 MHz, DMSO-d 6 ) δ 4.04 (s, 3H, N–CH3), 7.32 (dd, J = 9.5 Hz, J = 2.1 Hz, 1H, Ar H), 7.78 (d, J = 9.4 Hz, 1H, Ar H), 7.85 (d, J = 9.4 Hz, 1H, Ar H), 8.12 (d, J = 2.1 Hz, 1H, Ar H), 8.25 (d, J = 9.5 Hz, 1H, Ar H) 8.45 (s, 1H, Ar H), 11.83 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.1 (C = O, C9), 141.9 (C, C-11), 141.4 (CH, C-7), 140.6 (C, C-1), 138.2 (CH, C-12), 127.0 (C, C-10), 126.4 (CH, C-15), 122.2 (C, C-2), 119.9 (CH, C-13), 119.2 (CH, C-6), 117.9 (CH, C-4), 117.3 (CH, C-14), 117.0 (CH, C-5), 107.4 (CH, C-3), 33.4 (CH3, N–CH3). MS (70 eV): m/z 285 [M + 2] + (1), 91 (100); Anal. Calcd for C15H10ClN3O (283.7): C, 63.50; H, 3.55; N, 14.81. Found: C, 63.43; H, 3.52; N, 14.89.
3-Propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one (4c)
Yellowish needles (EtOH + CH3CN); m.p.: >300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.: >300 °C]; IR (KBr): 3415 cm−1 (NH), 1660 cm−1 (C=O). 1H NMR (400 MHz, DMSO-d 6 ) δ 0.79 (t, J = 7.0 Hz, 3H, CH2–CH 3 ), 1.71–2.06 (m, 2H, CH2–CH 2 –CH3), 4.26 (t, J = 7.0 Hz, 2H, N–CH2), 7.15–8.15 (m, 6H, Ar H), 8.30 (s, 1H, Ar H), 11.86 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.0 (C = O, C9), 140.2 (C, C-11), 139.4 (CH, C-7), 138.5 (C, C-1), 129.3 (CH, C-12), 127.1 (C, C-10), 126.1 (CH, C-15), 122.1 (C, C-2), 119.5 (CH, C-13), 118.8 (CH, C-6), 117.2 (CH, C-4), 117.0 (CH, C-14), 116.6 (CH, C-5), 106.9 (CH, C-3), 52.5 (CH2, N–CH2), 21.6 (CH2, CH2–CH3), 10.0 (CH3, CH2–CH3). MS (70 eV): m/z 277 [M] + (3), 91 (100); Anal. Calcd for C17H15N3O (277.3): C, 73.63; H, 5.45; N, 15.15. Found: C, 73.49; H, 5.41; N, 15.41.
8-Chloro-3-propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one (4d)
Yellowish needles (EtOH + CH3CN); m.p.: >300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.: >300 °C]; IR (KBr): 3415 cm−1 (NH), 1660 cm−1 (C=O). 1H NMR (400 MHz, DMSO-d 6 ) δ 0.83 (t, J = 7.1 Hz, 3H, CH2–CH 3 ), 1.69–1.95 (m, 2H, CH2–CH 2 –CH3), 4.29 (t, J = 7.1 Hz, 2H, N–CH2), 7.25 (dd, J = 9.5 Hz, J = 2.1 Hz, 1H, Ar H), 7.68 (d, J = 9.4 Hz, 1H, Ar H), 7.75 (d, J = 9.4 Hz, 1H, Ar H), 8.17 (d, J = 2.1 Hz, 1H, Ar H), 8.25 (d, J = 9.5 Hz, 1H, Ar H), 8.35 (s, 1H, Ar H), 11.80 (br s, 1H, NH);. 13C NMR (100 MHz, DMSO-d6): δ = 175.1 (C = O, C9), 140.2 (C, C-11), 140.0 (CH, C-7), 139.6 (C, C-1), 137.4 (CH, C-12), 128.4 (C, C-10), 126.1 (CH, C-15), 121.9 (C, C-2), 119.1 (CH, C-13), 119.0 (CH, C-6), 117.7 (CH, C-4), 117.1 (CH, C-14), 115.2 (CH, C-5), 106.7 (CH, C-3), 52.8 (CH2, N–CH2), 21.6 (CH2, CH2–CH3), 10.1 (CH3, CH2–CH3). MS (70 eV): m/z 313 [M + 2] + (1), 91 (100); Anal. Calcd for C17H14ClN3O (311.8): C, 65.49; H, 4.53; N, 13.48. Found: C, 65.23; H, 4.51; N, 13.69.
3-Butyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one (4e)
Yellowish needles (EtOH + CH3CN); m.p.: >300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.: >300 °C]; IR (KBr): 3415 cm−1 (NH), 1660 cm−1 (C=O). 1H NMR (400 MHz, DMSO-d 6 ) δ 0.87 (t, J = 7.0 Hz, 3H, CH2–CH 3 ), 1.16–1.51 (m, 2H, CH2–CH 2 –CH3), 1.75–2.03 (m, 2H, CH2–CH 2 –CH2–CH3), 4.30 (t, J = 7.0 Hz, 2H, N–CH2), 7.10–8.10 (m, 6H, Ar H), 8.31 (s, 1H, Ar H), 11.81 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.1 (C = O, C9), 140.3 (C, C-11), 138.9 (CH, C-7), 138.0 (C, C-1), 129.3 (CH, C-12), 127.2 (C, C-10), 126.2 (CH, C-15), 122.1 (C, C-2), 119.5 (CH, C-13), 118.9 (CH, C-6), 117.3 (CH, C-4), 117.0 (CH, C-14), 116.6 (CH, C-5), 107.0 (CH, C-3), 49.7 (CH2, N–CH2), 30.8 (CH2, CH2–CH2), 20.4 (CH2, CH2–CH2), 11.1 (CH3, CH2–CH3). MS (70 eV): m/z 291 [M] + (5), 91 (100); Anal. Calcd for C18H17N3O (291.3): C, 74.21; H, 5.88; N, 14.42. Found: C, 73.97; H, 5.85; N, 14.50.
3-Butyl-8-chloro-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one (4f)
Yellowish needles (EtOH + CH3CN); m.p.: >300 °C (decomp) [lit.(Rahimizadeh et al., 2009) m.p.: >300 °C]; 1H NMR (400 MHz, DMSO-d 6 ) δ 0.86 (t, J = 6.5 Hz, 3H, CH2–CH 3 ), 1.13–1.48 (m, 2H, CH2–CH 2 –CH3), 1.73–2.01 (m, 2H, CH2–CH 2 –CH2–CH3), 4.33 (t, J = 6.5 Hz, 2H, N–CH2), 7.21(dd, J = 9.5 Hz, J = 2.1 Hz, 1H, Ar H), 7.58 (d, J = 9.4 Hz, 1H, Ar H), 7.65 (d, J = 9.4 Hz, 1H, Ar H), 8.15 (d, J = 2.1 Hz, 1H, Ar H), 8.25 (d, J = 9.5 Hz, 1H, Ar H) 8.30 (s, 1H, Ar H), 11.91 (br s, 1H, NH); IR (KBr): 3415 cm−1 (NH), 1660 cm−1 (C = O).);13C NMR (100 MHz, DMSO-d6): δ = 175.1 (C = O, C9), 140.3 (C, C-11), 139.7 (CH, C-7), 139.1 (C, C-1), 137.4 (CH, C-12), 128.4 (C, C-10), 126.2 (CH, C-15), 121.9 (C, C-2), 119.2 (CH, C-13), 119.0 (CH, C-6), 117.7 (CH, C-4), 117.2 (CH, C-14), 115.2 (CH, C-5), 107.4 (CH, C-3), 49.9 (CH2, N–CH2), 30.7 (CH2, CH2–CH2), 20.4 (CH2, CH2–CH2), 11.1 (CH3, CH2–CH3). MS (70 eV): m/z 327 [M + 2] + (2), 91 (100); Anal. Calcd for C18H16ClN3O (325.8): C, 66.36; H, 4.95; N, 12.90. Found: C, 66.03; H, 4.94; N, 13.09.
8-Bromo-3-methyl-3H-imidazo[4,5-a]acridin-11(6H)-one (4g)
Yellowish needles (EtOH + CH3CN); yield (70 %), m.p.: >300 °C (decomp); IR(KBr): 3400 cm−1 (NH), 1632 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d 6 ): δ 3.93 (s, 3H, N–CH3), 7.24 (dd, J = 8.4 Hz, J′ = 1.2 Hz, 1H, Ar H), 7.66 (d, J = 9.2 Hz, 1H, Ar H), 7.85 (d, J = 9.2 Hz, 1H, Ar H), 7.94(s, 1H, Ar H), 8.05 (d, J = 1.2 Hz, 1H, Ar H), 8.43 (d, J = 8.4 Hz, 1H, Ar H), 11.8 (br s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 175.1 (C=O, C9), 148.7 (CH, C-10), 143.4 (C, C-11), 141.9 (CH, C-7), 140.2 (C, C-1), 138.8 (CH, C-12), 129.5 (C, C-14), 125.1 (CH, C-15), 124.2 (C, C-2), 117.1 (CH, C-13), 119.0 (CH, C-6), 117.1 (CH, C-4), 117.6 (CH, C-5), 107.8 (CH, C-3), 33.9 (CH3, N–CH3). MS (70 eV): m/z 330 [M + 2] + (5), 91 (100). Anal. Calcd for C15H10BrN3O (328.2): C, 54.90; H, 3.07; N, 12.80. Found: C, 54.70; H, 3.02; N, 12.69.
8-Bromo-3-propyl-3H-imidazo [4,5-a]acridin-11(6H)-one (4h)
Yellowish needles (EtOH + CH3CN); yield (65 %), m.p.: >300 °C (decomp); IR(KBr): 3392 cm−1 (NH), 1633 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d 6 ): δ 0.86 (t, J = 6.8 Hz, 3H, CH2–CH 3 ), 1.84 (m, 2H, CH2–CH 2 –CH3), 4.31 (t, J = 6.8 Hz, 2H, N–CH2), 7.38 (d, J = 8.8 Hz, 1H, Ar H), 7.41 (d, J = 8.8 Hz, 1H, Ar H), 7.74 (s, 1H, Ar H), 8.08 (dd, J = 8.4 Hz, J′ = 1.2 Hz, 1H, Ar H), 8.18 (d, J = 8.4 Hz, 1H, Ar H), 8.35 (d, J = 1.2 Hz, 1H, Ar H), 11.8 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.3 (C=O, C9), 148.5 (CH, C-10), 143.7 (C, C-11), 141.9 (CH, C-7), 140.5 (C, C-1), 138.4 (CH, C-12), 129.7 (C, C-14), 125.3 (CH, C-15), 124.4 (C, C-2), 117.4 (CH, C-13), 119.1 (CH, C-6), 117.2 (CH, C-4), 117.9 (CH, C-5), 107.8 (CH, C-3), 53.5 (CH2, N–CH2), 21.7 (CH2, CH2–CH3), 10.0 (CH3, CH2–CH3). MS (70 eV): m/z 358 [M + 2] + (4), 91 (100); Anal. Calcd for C17H14BrN3O (356.2): C, 57.32; H, 3.96; N, 11.80. Found: C, 57.70; H, 4.05; N, 11.56.
8-Bromo-3-butyl-3H-imidazo [4,5-a]acridin-11(6H)-one (4i)
Yellowish needles (EtOH + CH3CN); yield (67 %), m.p.: >300 °C (decomp); IR(KBr): 3423 cm−1 (NH), 1636 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d 6 ): δ 0.90 (t, J = 6.7 Hz, 3H, CH2–CH 3 ), 1.26 (m, 2H, CH2–CH 2 –CH3), 1.83 (m, 2H, CH2–CH 2 –CH2–CH3), 4.41 (t, J = 6.7 Hz, 2H, N–CH2), 7.43 (d, J = 7.0 Hz, 1H, Ar H), 7.53 (d, J = 7.0 Hz, 1H, Ar H), 7.8 (s, 1H, Ar H), 8.15 (dd, J = 8.4 Hz, J′ = 1.2 Hz, 1H, Ar H), 8.25 (d, J = 8.4 Hz, 1H, Ar H), 8.86 (d, J = 1.2 Hz, 1H, Ar H), 12.06 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.4 (C=O, C9), 148.6 (CH, C-10), 143.9 (C, C-11), 142.3 (CH, C-7), 140.6 (C, C-1), 138.3 (CH, C-12), 129.7 (C, C-14), 125.4 (CH, C-15), 124.6 (C, C-2), 117.8 (CH, C-13), 119.3 (CH, C-6), 117.1 (CH, C-4), 117.4 (CH, C-5), 107.0 (CH, C-3), 49.5 (CH2, N–CH2), 30.5 (CH2, CH2–CH2), 20.3 (CH2, CH2–CH2), 11.0 (CH3, CH2–CH3). MS (70 eV): m/z 372 [M + 2] + (3), 91 (100); Anal. Calcd for C18H16BrN3O (370.2): C, 58.39; H, 4.36; N, 11.35. Found: C, 58.67; H, 4.39; N, 11.25.
8-Bromo-3-isobutyl-3H-imidazo [4,5-a]acridin-11(6H)-one (4j)
Yellowish needles (EtOH + CH3CN); yield (72 %), m.p.: >300 °C (decomp); IR(KBr): 3391 cm−1 (NH), 1633 (C=O) cm−1. 1H NMR (400 MHz, DMSO-d 6 ): δ 0.67 (d, J = 7.0 Hz, 6H, CH(CH 3 )2), 1.98 (m, 1H, CH(CH3)2), 4.14 (d, J = 7.0 Hz, 2H, N–CH2), 7.27 (d, J = 8.8 Hz, 1H, Ar H), 7.31 (d, J = 8.8 Hz, 1H, Ar H), 7.62 (s, 1H, Ar H), 7.95 (dd, J = 8.4 Hz, J′ = 1.2 Hz, 1H, Ar H), 8.2 (d, J = 8.4 Hz, 1H, Ar H), 8.37 (d, J = 1.2 Hz, 1H, Ar H), 11.81 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): δ = 175.3 (C=O, C9), 148.5 (CH, C-10), 143.8 (C, C-11), 142.0 (CH, C-7), 140.4 (C, C-1), 138.7 (CH, C-12), 129.7 (C, C-14), 125.6 (CH, C-15), 124.9 (C, C-2), 117.8 (CH, C-13), 119.3 (CH, C-6), 117.0 (CH, C-4), 117.2 (CH, C-5), 107.4 (CH, C-3), 54.6 (CH2, N–CH2), 29.5 (CH, CH(CH3)2), 18.5 (CH3, CH(CH3)2). MS (70 eV): m/z 372 [M + 2] + (2), 91 (100); Anal. Calcd for C18H16BrN3O (370.2): C, 58.39; H, 4.36; N, 11.35. Found: C, 58.21; H, 4.33; N, 11.19.
Biological evaluations
Antiviral assay (MIC or EC50) (Clercq et al., 1980, 1987)
Confluent cell cultures in microtiter 96-well plates were inoculated with 100 CCID50 of virus, one CCID50 being the virus dose required to infect 50 % of the cell cultures. After 1–2 h of virus adsorption period, residual virus was removed, and the cell cultures were incubated at 37 °C in the presence of varying concentrations of the test compounds (dilutions were made based upon CTC50). Viral cytopathogenicity was recorded as soon as it reached completion in the control virus infected cell cultures that were not treated with the test compounds after 4–5 days of post infection, microscopically. The antiviral activity of the compounds 4a–j was expressed as the effective concentration required for inhibiting the viral cytopathic effect by 50 % (MIC or EC50). The CTC50 and MIC of the test compounds were compared with the standard drugs brivudine (BVDU), cidofovir, acyclovir, and ribavirin under similar conditions. By adopting the above procedure, the MIC or EC50 for all the compounds 4a–j was determined.
Cytotoxicity activity assay (Piotrowska et al., 2012)
Murine leukemia L1210, human T-lymphocyte CEM, human cervix carcinoma (HeLa), and human lung fibroblast (HEL) cells were suspended at 300,000–500,000 cells/mL of culture medium, and 100 μL of a cell suspension was added to 100 μL of an appropriate dilution of the test compounds in wells of 96-well microtiter plates. After incubation at 37 °C for two (L1210) or three (CEM, HeLa, HEL) days, the cell number was determined using a Coulter counter. The IC50 was defined as the compound concentration required to inhibit cell proliferation by 50 %.
Results and discussion
Chemistry
Initially, N-alkyl-5-nitrobenzimidazoles 1a–d were obtained from 5-nitrobenzimidazole using different alkyl halides treatment in DMF and KOH as previously described (Preston, 2009). 3H-imidazo[4′,5′:3,4]benzo [c] isoxazoles 3a–j were accessed through the nucleophilic substitution of hydrogen of N-alkyl-5-nitrobenzimidazoles 1a–d with aryl acetonitriles 2a–c under basic conditions (Rahimizadeh et al., 2009; Sahraei et al., 2013; Pordel 2012) (Scheme 1). Derivatives of 3a–j were converted to 3H-imidazo[4,5-a]acridones 4a–j in concentrated sulfuric acid containing nitrous acid at room temperature by Tanasescu reaction (Tanasescu 1927) in fairly good yields (Scheme 1). Compounds 3g–j and 4g–j are new heterocyclic compounds. The structures of compounds 3g–j and 4g–j were unambiguously characterized on the basis of their IR, 1H NMR and mass spectra.
Synthesis of compounds 3a–j and 4a–j
Antiviral and cytostatic evaluation
Compounds 4a–j were evaluated for antiviral and cytostatic activity using the method described in experimental section. The results of antiviral screening of compounds 4a–j against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, and herpes simplex virus-1 TK-KOS ACV r are shown in Table 1. The results of assay indicate that all the compounds have shown varying degree of cytotoxicity (i.e., from 90 to 200 μM). Based on the CTC50 non-toxic concentrations, all the synthesized compounds were subjected for antiviral activity determination against different viral strains. The results of antiviral activity (Table 1) indicated that all 3H-imidazo[4,5-a]acridones 4a–j exhibited good-to-moderate antiviral activity against mentioned organisms from approximately 8 to 150 μM which is comparable with the reference drug Ribavirin.
Also, the results revealed that compounds 4b, 4d, and 4f in which the R2 substituent is a chlorine function displayed greater antiviral activity than did others. Compound 4f (R2 = Cl and R1 = Bu) was the most potent of the tested compounds against viral strains. It might be due to the chain lengths and chlorine substituent that change the binding characteristics of ligands to their respective receptors and, thereby, improve the biological activities.
The cytotoxicity of the tested compounds toward the uninfected host cells was defined as the minimum compound concentration (MCC) that caused a microscopically detectable alteration of normal cell morphology. The 50 % cytostatic concentration (CC50), causing a 50 % decrease in cell proliferation, was determined against murine leukemia L1210, human lymphocyte CEM, human cervix carcinoma HeLa, and human lung fibroblast HEL cells. All of the tested compounds affected cell morphology of HEL, HeLa, Vero, MDCK, and CrFK cells at concentrations ranging from 60 to 200 μM for HeLa cells, L1210, CEM, and HEL cells (Table 2).
In conclusion, we synthesized a series of 3-alkyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one, 8-chloro-3-propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one, and new 8-bromo-3-propyl-6,11-dihydro-3H-imidazo[4,5-a]acridin-11-one, which were structurally confirmed by IR, 1H NMR, 13C NMR, elemental, and MS spectral analysis. The antiviral screening for all 3H-imidazo[4,5-a]acridones (4a–j) against a broad panel of DNA and RNA viral strains indicated that these compounds emerged as promising antiviral activity against different viral strains. Additionally, compounds 4a–j proved slightly cytostatic (middle to higher micromolar range: 60–200 μM).
Such compounds could be selected as lead compounds for the development of novel antiviral agents active against herpes simplex virus, vaccinia virus, and vesicular stomatitis virus.
References
Bakavoli M, Bagherzadeh G, Vaseghifar M, Shiri A, Pordel M, Mashreghi M, Pordeli P, Araghi M (2010) Molecular iodine promoted synthesis of new pyrazolo[3,4-d]pyrimidine derivatives as potential antibacterial agents. Eur J Med Chem 45:647–650
Belmont P, Bosson J, Godet T, Tiano M (2007) Acridine and acridone derivatives, anticancer properties and synthetic methods: Where are we now? Anti-Cancer Agents Med Chem 7:139–169
Clercq ED, Descamps J, Verhelst G, Walker RT, Jones AS, Torrence PF, Shuger D (1980) Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis 141:563–574
Clercq ED, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Holy A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8:261–272
Cornil J, Beljonne D, Calbert JP, Bredas JL (2001) Interchain interactions in organic π-conjugated materials: impact on electronic structure, optical response, and charge transport. Adv Mater 13:1053–1067
De Angelis M, Stossi F, Carlson KA, Katzenellenbogen BS, Katzenellenbogen JA (2005) Indazole estrogens: highly selective ligands for the estrogen receptor ß. J Med Chem 48:1132–1144
Dell’Erba C, Novi M, Petrillo G, Tavani C (1992) Behaviour of arylazo tert-butyl sulfides with ketone enolates. competition between srn1 α-arylation and azocoupling reactions. Tetrahedron 48:325–334
Di Giorgio C, Delmas F, Filloux N, Robin M, Seferian L, Azas N, Gasquet M, Timon-David P, Galy JP (2003) In vitro activities of 7-substituted 9-chloro and 9-amino-2-methoxyacridines and their bis- and tetra-acridine complexes against leishmania infantum. Antimicrob Agents Chemother 47:174–180
Gamage SA, Figgit DP, Wojcik SJ, Ralph RK, Ransijn A, Mauel J, Yardley V, Snowdon D, Croft SL, Denny W (1997) Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1′-substituted 9-anilinoacridines. J Med Chem 40:2634–2642
Girault S, Grellier P, Berecibar A, Maes L, Mouray E, Lemiere P, Debreu MA, Davioud-Charvet E, Sergheraert C (2000) Antimalarial, antitrypanosomal, and antileishmanial activities and cytotoxicity of bis (9-amino-6-chloro-2-methoxyacridines): influence of the linker. J Med Chem 43:2646–2654
Girault S, Delarue S, Grellier P, Berecibar A, Maes L, Quirijnen L, Lemiere P, Debreu-Fontaine MA, Sergheraert C (2001) Antimalarial in vivo activity of bis (9-amino-6-chloro-2-methoxyacridines. J Pharm Pharmacol 53:935–938
Goodell JR, Madhok AA, Hiasab H, Ferguson DM (2006) Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg Med Chem 14:5467–5480
Iida T, Satoh H, Maeda K, Yamamoto Y, Ki Asakawa, Sawada N, Wada T, Kadowaki C, Itoh T, Mase T, Weissman SA, Tschaen D, Krska S, Volante RP (2005) Practical synthesis of a neuropeptide y antagonist via stereoselective addition to a ketene. J Org Chem 70:9222–9229
Joshi AA, Viswanathan CL (2006) Recent developments in antimalarial drug discovery. Anti-Infect Agents Med Chem 5:105–122
Kamal A, Srinivas O, Ramulu P, Ramesh G, Kumar PP (2004) Synthesis of C8linked pyrrolo [2,1-c][1,4] benzodiazepine-acridone/acridine hybrids as potential DNA-binding agents. Bioorg Med Chem Lett 14:4107–4111
Kukowska-Kaszuba M, Dzierzbicka K (2007) Synthesis and structure-activity studies of peptide-acridine/acridone conjugates. Curr Med Chem 14:3079–3104
Lang X, Li L, Chen Y, Sun Q, Wu Q, Liu F, Tan Ch, Liu H, Gao Ch, Jiang Y (2013) Novel synthetic acridine derivatives as potent DNA-binding and apoptosis-inducing antitumor agents. Bioorg Med Chem 21:4170–4177
Loudon JD, Tennant G (1964) Substituent interactions in ortho-substituted nitrobenzenes. Quart Rev Chem Soc 18:389–413
Lowden CT, Bastow KF (2003) Cell culture replication of herpes simplex virus and or human cytomegalovirus is inhibited by 3,7-dialkoxylated, 1-hydroxyacridone derivatives. Antiviral Res 59:143–154
Mitra P, Chakraborty PK, Saha P, Ray P, Basu S (2014) Antibacterial efficacy of acridine derivatives conjugated with gold nanoparticles. Int J Pharm 473:636–643
Piotrowska DG, Balzarini J, Gowacka IE (2012) Design, synthesis, antiviral and cytostatic evaluation of novel isoxazolidine nucleotide analogues with a 1,2,3-triazole linker. Eur J Med Chem 47:501–509
Pordel M (2012) Synthesis of new fluorescent compounds from benzimidazole. J Chem Res 36:595–597
Pordel M, Abdollahi A, Razavi B (2013) Synthesis and biological evaluation of novel isoxazolo[4,3-e]indoles as antibacterial agent. Russ J Bioorg Chem 39:211–214
Preston PN (2009) The chemistry of heterocyclic compounds, benzimidazoles and cogeneric tricyclic compounds, Part 1, vol 40. Wiley, London, pp 87–105
Qiao X, Zeitany AE, Wright MW, Essader AS, Levine KE, Kucera GL, Bierbach U (2012) Analysis of the DNA damage produced by a platinum-acridine antitumor agent and its effects in NCI-H460 lung cancer cells. Metallomics 4:645–652
Rahimizadeh M, Pordel M, Bakavoli M, Bakhtiarpoor Z, Orafaie A (2009) Synthesis of imidazo[4,5-a]acridones and imidazo[4,5-a]acridines as potential antibacterial agents. Monatsh Chem 140:633–638
Rahimizadeh M, Pordel M, Bakavoli M, Rezaeian Sh, Sadeghian A (2010) Synthesis and antibacterial activity of some new derivatives of pyrazole. World J Microbiol Biotechnol 26:317–321
Sadeghian H, Sadeghian A, Pordel M, Rahimizadeh M, Jahandari P, Orafaie A, Bakavoli M (2010) Design, synthesis, and structure–activity relationship study of 5-amido-1-(2,4-dinitrophenyl)-1H-4-pyrazolecarbonitrils as DD carboxypeptidase/penicillin-binding protein inhibitors with Gram-positive antibacterial activity. Med Chem Res 19:103–119
Sadeghian A, Pordel M, Safdari H, Fahmidekar MA, Sadeghian H (2012) 11-Chloro-3-methyl-3H-imidazo[4,5-a]acridine (CMIA) as a potent and selective antimicrobial agent against clinical isolates of highly antibiotic-resistant Acinetobacter baumannii. Med Chem Res 21:3897–3901
Sahraei R, Pordel M, Behmadi H, Razavi B (2013) Synthesis of a new class of strongly fluorescent heterocyclic compounds: 3H-imidazo[4,5 a]acridine-11-carbonitriles. J Lumin 136:334–338
Szarfman A, Tonning J, Levine J, Doraiswamy P (2006) Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy 26:748–758
Tanasescu I (1927) Preparation of acridones (and 10-hydroxyacridones) from o-nitrobenzaldehyde and a halobenzene in the presence of concentrated sulfuric acid containing nitrous acid as catalyst. Bull Soc Chim Fr 41:528–532
Werbovetz KA, Spoors PG, Pearson RD, Macdonald TL (1994) Cleavable complex formation in Leishmania chagasi treated with anilinoacridines. Mol Biochem Parasitol 65:1–10
Winter RW, Kelly JX, Smilkstein MJ, Dodean R, Hinrichs D, Riscoe MK (2008) Antimalarial quinolones: synthesis, potency, and mechanistic studies. Exp Parasitol 118:487–497
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent
For this type of study, formal consent is not required.
Rights and permissions
About this article
Cite this article
Daghigh, L.R., Pordel, M., Davoodnia, A. et al. Synthesis, antiviral, and cytotoxic investigation of imidazo[4,5-a]acridones. Med Chem Res 24, 3912–3919 (2015). https://doi.org/10.1007/s00044-015-1438-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-015-1438-1