Translate this page into:
Synthesis and antibacterial activity of some new 4-anilino-5-phenyl-4H-1,2,4-triazole-3-thiol derivatives
⁎Corresponding author. Address: Postal code: 82524, Sohag, Egypt. Tel.: +20 1064382209; fax: +20 93601159. bahgat.ramadan@yahoo.com (Bahgat R.M. Hussein)
-
Received: ,
Accepted: ,
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
4-Anilino-5-phenyl-4H-1,2,4-triazole-3-thiol (1) reacted with formaldehyde and different amines to give Mannich bases 2a–i. Treatment of compound 1 with formaldehyde afforded the corresponding 2-hydroxymethyl derivative 3, which upon its reaction with thionyl chloride yielded the corresponding chloromethyl derivative 4. Treatment of compound 4 with some thiols gave the corresponding sulfides 5a–f. The ring closure reaction of chloromethyl derivative 4 with hydrazine hydrate, phenyl hydrazine, hydroxylamine, urea and thiourea afforded triazolo-, oxadiazolo- and triazinotriazoles 6–10, respectively.
Keywords
4-Anilino-5-phenyl-4H-1,2,4-triazole-3-thiol
Mannich bases
Triazolotriazoles
Oxadiazolotriazoles
Triazinotriazoles
Antibacterial activity
1 Introduction
Various 1,2,4-triazoles found extensive investigations due to their useful application in different areas of biological activity and as industrial intermediates such as antiasthmatic (Naito et al., 1996), antiviral (ribavirin) (De Clercq, 2004), antifungal (fluconazole) (Collin et al., 2003), antimicrobial (Kidwai et al., 2001), antibacterial (Papakonstantinou-Garoufalias et al., 2002), insecticidal (Ghorab et al., 1999), amoebicidal (Andotra and Sharma, 1988), hypnotic (Hester et al., 1971), cytotoxic (Milton, 2001) and hypotensive (Burell et al., 1994; Ghorab et al., 1996) activities. This moiety was also found in potent agonist and antagonist receptor ligands, (Wadsworth et al., 1992; Chen et al., 2001) in HIV-1 protease inhibitors (Thompson et al., 1994) and in thrombin inhibitors (Duncia et al., 1998). Along with these significant pharmaceutical uses, 1,2,4-triazole derivatives are effectively used in polymers, dyestuff, photographic chemicals and agricultural chemicals (Potts, 1961). In view of these findings and in continuation of our work in the same field (Ghattas and El-saraf, 1989; Ghattas et al., 1989, 2001, 2003; El-wassaimy et al., 1992; Abdel-Rahman et al., 1993; Moustafa, 2001), we report herein the synthesis of some new s-triazole derivatives and tested the latter for antibacterial activity.
2 Experimental
Melting points are uncorrected and were determined by Kofeler melting point apparatus. IR (cm−1) spectra were recorded (KBr disk) on a Nicolet 710 FT-IR spectrophotometer. 1H NMR (DMSO-d6) spectra were recorded at 300 MHz on a Varian Gremini NMR spectrometer at the Cairo University, the chemical shift is expressed in δ value (ppm) using TMS as an internal reference. Element analyses carried out on an elemental analyzer 240 °C. Mass spectra were performed on Micromass 7070 E spectrometer operating at 70 eV, using direct inlet.
2.1 Synthesis of Mannich bases 2a–i (general procedure)
Formaldehyde (1.5 mL, 40% solution) was added to a solution of compound 1 (0.5 g, 1.8 mmol) in ethanol (15 mL) and the reaction mixture was refluxed for 1 h. The appropriate amine (0.001 mol) was added and the reaction mixture was refluxed for 4 h. After cooling, the formed precipitate was filtered and recrystallized from the appropriate solvent to give the corresponding Mannich bases 2a–i.
2.1.1 4-Anilino-5-phenyl-2-[(1,3-thiazol-2-yl-amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2a)
White crystals from ethanol, yield 0.39 g (55%), m.p. 155 °C; IR (KBr): Vmax/cm−1: 3431 (NH), 3195 (NH), 3081 (Ar, CH), 2918 (Aliph., CH), 1592 (C⚌N); MS, m/z (Irel,%): 380 [M]+ (10.6), 312 (21.3), 239 (27.7), 178 (51), 135 (34), 103 (100), 77 (81), 51 (72.3). Anal. for C18H16N6S2 (380.48) Calcd. %: C 56.77; H 4.20; N 22.07; S 8.41. Found %: C 56.51; H 4.35; N 22.30; S 8.61.
2.1.2 4-Anilino-5-phenyl-2-[(1,3,4-thiadiazol-2-yl-amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2b)
White crystals from ethanol, yield 0.7 g (98%), m.p. 113 °C; IR (KBr): Vmax/cm−1: 3415 (NH), 3203 (NH), 3072 (Ar, CH), 2940 (Aliph., CH), 1568 (C⚌N); MS, m/z (Irel,%): 381 [M]+ (0.04), 312 (21.3), 103 (60.6), 60 (100). Anal. for C17H15N7S2 (381.47) Calcd. %: C 53.47; H 3.93; N 25.69; S 8.38. Found %: C 53.33; H 3.67; N 25.53; S 8.41.
2.1.3 4-Anilino-5-phenyl-2-[(pyridin-2-yl-amino)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (2c)
White-yellow crystals from ethanol, yield 0.65 g (94%), m.p. 175 °C; IR (KBr): Vmax/cm−1: 3428 (NH), 3240 (NH), 3015 (Ar, CH), 2954 (Aliph., CH), 1600 (C⚌N); MS, m/z (Irel,%): 374 [M]+ (0.07), 312 (37.7), 279 (19), 181(13.2), 149 (22.6), 103 (100), 55 (96.2). Anal. for C20H18N6S (374.46) Calcd. %: C 64.06; H 4.80; N 22.43; S 8.54. Found %: C 64.15; H 4.66; N 22.52; S 8.37.
2.1.4 1-[4-(4-Anilino-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione-2-yl-methylamino)phenyl]-1-ethanone (2d)
Yellow crystals from ethanol, yield 0.75 g (97%), m.p. 168 °C; IR (KBr): Vmax/cm−1: 3328 (NH), 3185 (NH), 3048 (Ar, CH), 2930 (Aliph., CH), 1657 (C⚌O), 1589 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.95–7.58 (m, 15H, Ar-H), 6.95 (s, 2H, 2NH), 5.54 (s, 2H, N–CH2–N), 2.39 (s, 3H, CH3). Anal. for C23H21N5OS (415.51) Calcd. %: C 66.42; H 5.05; N 16.84; S 7.70. Found %: C 66.31; H 5.22; N 16.75; S 7.53.
2.1.5 4-Anilino-2-[(diethylamino)methyl]-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (2e)
Brown crystals from ethanol, yield 0.37 g (56%), m.p. 92 °C; IR (KBr): Vmax/cm−1: 3369 (NH), 3055 (Ar, CH), 2966 (Aliph., CH), 1617 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.92–7.33 (m, 11H, Ar-H + NH), 3.07–3.04 (q, 4H, CH2, J = 7.8 Hz), 2.68 (s, 2H, CH2), 1.15–1.20 (t, 6H, CH3, J = 14.7 Hz). Anal. for C19 H23N5S (353.48) Calcd. %: C 64.50; H 6.50; N 19.80; S 9.00. Found %: C 64.31; H 6.72; N 19.63; S 9.12.
2.1.6 4-Anilino-2-{[ethyl(phenyl)amino]methyl}-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (2f)
White crystals from ethanol, yield 0.68 g (90%), m.p. 107 °C; IR (KBr): Vmax/cm−1: 3424 (NH), 3048 (Ar, CH), 2964 (Aliph., CH), 1606 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.91–6.92 (m, 10H, Ar-H), 5.68 (s, NH), 5.20 (s, 2H, N–CH2–N), 3.69–3.63 (q, 2H, N–CH2, J = 18.0 Hz), 1.21–1.19 (t, 3H, CH3, J = 6 Hz). Anal. for C23H23N5S (401.52) Calcd. %: C 68.73; H 5.72; N 17.43; S 7.97. Found %: C 68.61; H 5.83; N 17.35; S 7.81.
2.1.7 4-Anilino-2-(morpholin-4-yl-methyl)-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (2g)
White crystals from ethanol, yield 0.48 g (71%), m.p. 118 °C; IR (KBr): Vmax/cm−1: 3427.9 (NH), 3051.8 (Ar, CH), 2937, 2841 (Aliph., CH,), 1615 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.91–7.33 (m, 10H, Ar-H), 5.16 (s, NH), 5.01 (s, 2H, N–CH2–N), 3.58–3.36 (m, 4H, 2N–CH2), 2.79–2.49 (m, 4H, 2O–CH2). Anal. for C19H21N5OS (367.46) Calcd. %: C 62.04; H 5.71; N 19.05; S 8.70. Found %: C 62.23; H 5.82; N 19.31; S 8.65.
2.1.8 4-Anilino-5-phenyl-2-(piperidin-1-ylmethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (2h)
White crystals from ethanol, yield 0.63 g (92%), m.p. 93 °C; IR (KBr): Vmax/cm−1: 3422 (NH), 3058 (Ar, CH), 2925, 2845 (Aliph., CH), 1608 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.91–7.55 (m, 10H, Ar-H), 4.99 (s, 2H, N–CH2), 3.36 (s, 1H, NH), 2.72–2.50 (m, 4H, 2N–CH2), 1.48–1.44 (m, 4H, CH2CH2N), 1.33–1.32 (m, 2H, CH2CH2CH2). Anal. for C20H23N5S (365.49) Calcd. %: C 65.66; H 6.29; N 19.15; S 8.75. Found %: C 65.42; H 6.33; N 19.31; S 8.61.
2.1.9 4-Anilino-1-[4-(4-anilino-3-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazole-1-yl-methyl) piperazino methyl-3-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thione (2i)
White crystals from ethanol, yield 0.98 g (81%), m.p. 240 °C; IR (KBr): Vmax/cm−1: 3430 (NH), 3059 (Ar, CH), 2938, 2841 (Aliph., CH), 1615 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.89–7.56 (m, 20H, Ar-H), 5.0 (s, 4H, 2N–CH2–N), 3.21 (s, 2H, NH), 2.80 (m, 8H, 4N–CH2). Anal. for C34H34N10S2 (646.83): Calcd. %: C 63.07; H 5.25; N 21.64; S 9.89. Found %: C 63.19; H 5.11; N 21.55; S 9.97.
2.2 Synthesis of 4-anilino-2-hydroxymethyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (3)
Formaldehyde (1.5 mL, 40% solution) was added to a solution of compound 1 (1.34 g, 5 mmol) in ethanol (15 mL) and the reaction mixture was refluxed for 1 h. The solvent was evaporated to dryness, the formed solid was collected and recrystallized from ethanol to give compound 3. White crystals from ethanol, yield 1.4 g (94%), m.p. 132 °C; IR (KBr): Vmax/cm−1: 3418 (OH), 3107 (NH), 2944 (Ar, CH), 2768 (Aliph., CH), 1610 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.92–7.58 (m, 10H, Ar-H), 6.06 (s, 2H, CH2), 5.4 (s, 1H, NH), 4.99 (s, 1H, OH). Anal. for C15H14N4OS (298.36) Calcd. %: C 60.32; H 4.69; N 18.76; S 10.72. Found %: C 60.41; H 4.59; N 18.65; S 10.81.
2.3 Synthesis of 4-anilino-2-chloromethyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (4)
Thionyl chloride (10 mL) was added dropwise to compound 3 (2.98 g, 10 mol) and the reaction mixture was warmed on a water bath for 1 h. After cooling, the reaction mixture was poured into petroleum ether (100 mL, 80:100 °C). The formed precipitate was filtered and recrystallized from ethanol to give compound 4. White crystals from ethanol, yield 2.76 g (87%), m.p. 106 °C; IR (KBr): Vmax/cm−1: 3439 (NH), 3037 (Ar, CH), 2929 (Aliph., CH), 1616 (C⚌N), 767 (C–Cl); 1H NMR (DMSO-d6), δ, ppm: 7.91–7.28 (m, 10H, Ar-H), 5.41 (s, 1H, NH), 5.39 (s, 2H, CH2). Anal. for C15H13ClN4S (316.8) Calcd. %: C 56.81; H 4.10; N 17.67; S 10.10. Found %: C 56.57; H 4.13; N 17.54; S 10.21.
2.4 Synthesis of compounds 5a–f (general procedure)
To a solution of compound 4 (0.5 g 1.58 mmol) in dimethylformamide (30 mL) and triethylamine (1.58 mmol), the appropriate thiol (1.58 mmol) was added. The reaction mixture was refluxed for 3 h, the solvent was evaporated under reduced pressure. The formed precipitate was collected and recrystallized from the appropriate solvent to give the corresponding sulfides 5a–f.
2.4.1 4-Anilino-5-phenyl-2-[(propylthio) methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (5a)
Brown crystals from dioxane, yield 0.44 g (79%), m.p. 89 °C. IR (KBr): Vmax/cm−1: 3438 (NH), 3046 (Ar, CH), 2961, 2931 (Aliph., CH), 1615 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.87–7.54 (m, 10H, Ar-H), 6.15 (br, 3H, CH2–N + NH), 3.206–3.157 (t, 2H, S–CH2, J = 14.7 Hz), 1.70–1.60 (m, 2H, –CH2–), 0.99–0.97 (t, 3H, CH3–, J = 8.4 Hz). Anal. for C18H20N4S2 (356.5) Calcd. %: C 60.58; H 5.61; N 15.70; S 17.95. Found %: C 60.48; H 5.55; N 15.61; S 17.99.
2.4.2 4-Anilino-2-[(cyclohexylthio)methyl]-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b)
White crystals from dimethylformamide, yield 0.39 g (62%), m.p. 222 °C; IR (KBr): Vmax/cm−1: 3439 (NH), 3055 (Ar, CH), 2929 (Aliph., CH), 1608 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.89–7.57 (m, 11H, Ar-H + NH), 6.36 (s, 2H, CH2), 3.59–3.27 (m, 11H, cyclohexyl). Anal. for C21H24 N4S2 (396.56) Calcd. %: C 63.54; H 6.05; N 14.12; S 16.13. Found %: C 63.48; H 6.22; N 14.11; S 16.25.
2.4.3 4-Anilino-5-phenyl-2-[(phenylthio)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c)
White crystals from dimethylformamide, yield 0.41 g (67%), m.p. 98 °C; IR (KBr): Vmax/cm−1: 3433 (NH), 3054 (Ar, CH), 2928 (Aliph., CH), 1581 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.82–7.31 (m, 15H, Ar-H), 5.58 (br, 3H, NH + CH2). Anal. for C21H18N4S2 (390.52) Calcd. %: C 64.52; H 4.61; N 14.33; S 16.38. Found %: C 64.64; H 4.55; N 14.47; S 16.35.
2.4.4 4-Anilino-2-{[(4-chlorophenyl)thio]methyl}-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5d)
White crystals from dimethylformamide, yield 0.56 g (82.5%), m.p. 138 °C; IR (KBr): Vmax/cm−1: 3439 (NH), 3055 (Ar, CH), 2929 (Aliph., CH), 1608 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.89–7.57 (m, 11H, Ar-H + NH), 6.36 (s, 2H, CH2). Anal. for C21H17ClN4S2 (424.96) Calcd. %: C 59.29; H 4.00; N 13.17; S 15.06. Found %: C 59.41; H 4.12; N 13.32; S 15.12.
2.4.5 4-Anilino-2-{[(4-anilino-5-phenyl-4H-1,2,4-triazol-3-yl)thio]methyl}-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (5e)
Pale-pink crystals from dimethylformamide, yield 0.65 g (75.5%), m.p. 148 °C; IR (KBr): Vmax/cm−1: 3440 (2NH), 3028 (Ar, CH), 2932 (Aliph., CH), 1610 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.99–7.54 (m, 20H, Ar-H), 5.9 (br, 4H, N–CH2 + 2NH). Anal. for C29H24N8S2 (548.68) Calcd. %: C 63.42; H 4.37; N 20.41; S 11.66. Found %: C 63.35; H 4.43; N 20.37; S 11.81.
2.4.6 4-Anilino-5-phenyl-2-{[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]methyl}-2,4-dihydro-3H-1,2,4-triazole-3-thione (5f)
Pale-white crystals from dimethylformamide, yield 0.54 g (75%), m.p. 217 °C; IR (KBr): Vmax/cm−1: 3445 (NH), 3065 (Ar, CH), 2931 (Aliph., CH), 1612 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.95–7.11 (m, 16H, Ar-H + NH), 5.43 (s, 2H, N–CH2). Anal. for C23H18N6OS2 (458.55) Calcd. %: C 60.18; H 3.92; N 18.31; S 13.95. Found %: C 60.22; H 3.87; N 18.42; S 13.76.
2.5 Synthesis of compounds 6–10: (general procedure)
To a solution of compound 4 (2.2 mmol) and triethylamine (2.2 mmol) in xylene (40 mL) were added hydrazine hydrate, phenyl hydrazine, hydroxylamine hydrochloride, urea and/or thiourea (2.2 mmol), respectively. The reaction mixture was refluxed for 10 h. The solvent was evaporated under reduced pressure, the formed precipitate was collected and recrystallized from ethanol to give the corresponding compound 6–10.
2.5.1 7-Anilino-6-phenyl-2,7-dihydro-3H-1,2,4-triazolo[4,3-b]-1,2,4-triazole (6)
White crystals from ethanol, yield 0.68 g (97%), m.p. 200 °C; IR (KBr): Vmax/cm−1: 3106 (NH), 3015 (Ar, CH), 2932 (Aliph., CH), 1622 (C⚌N); MS, m/z (Irel,%): 276 [M]+ (7.7), 252 (58.5), 192 (69.2), 161 (100), 133 (32.3), 104 (66.2),77 (67.7), 51 (72.3). Anal. for C15 H12N6 (276.3) Calcd. %: C 67.34; H 4.48; N 31.42. Found %: C 67.21; H 4.35; N 31.27.
2.5.2 7-Anilino-2,6-diphenyl-2,7-dihydro-3H-1,2,4-triazolo[4,3-b]-1,2,4-triazole (7)
Dark brown crystals from ethanol, yield 0.56 g (72%), m.p. 115 °C; IR (KBr): Vmax/cm−1: 3414 (NH), 3045 (Ar, CH), 2928 (Aliph., CH), 1598 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 7.98–7.04 (m, 16H, Ar-H + NH), 5.54 (s, 2H, N–CH2–N). Anal. for C21H18N6 (354.41) Calcd. %: C 71.10; H 5.07; N 23.7. Found %: C 71.24; H 5.11; N 23.67.
2.5.3 7-Anilino-6-phenyl-7H-1,2,4-triazolo[5,1-c]-1,2,4-oxadiazole (8)
Brown crystals from ethanol, yield 0.55 g (90%), m.p. 138 °C; IR (KBr): Vmax/cm−1: 3422 (NH), 3022 (Ar, CH), 2932 (Aliph., CH), 1607 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 8.0–7.54 (m, 11H, Ar-H + NH), 5.9 (s, 2H, CH2). Anal. for C15H13N5O (279.3) Calcd. %: C 64.44; H 4.65; N 25.06. Found %: C 64.36; H 4.58; N 25.31.
2.5.4 1-Anilino-2-phenyl-1,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-1,3,5-triazin-7-one (9)
Pale-brown crystals from ethanol, yield 0.41 g (61%), m.p. 140 °C; IR (KBr): Vmax/cm−1: 3398 (NH), 3038 (Ar, CH), 2923 (Aliph., CH), 1720 (C⚌O), 1612 (C⚌N); 1H NMR (DMSO-d6), δ, ppm: 8.0–7.55 (m, 12H, Ar-H + 2NH), 5.9 (s, 2H, CH2). Anal. for C16H14N6O (306.32) Calcd. %: C 62.67; H 4.57; N 27.42. Found %: C 62.51; H 4.43; N 27.56.
2.5.5 1-Anilino-2-phenyl-1,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-1,3,5-triazine-7-thione (10)
Brown crystals from ethanol, yield 0.45 g (90%), m.p. 176 °C; IR (KBr): Vmax/cm−1: 3430 (2NH), 3091 (Ar, CH), 2924 (Aliph., CH), 1607 (C⚌N), 1175 (C⚌s); MS, m/z (Irel,%): 322 [M]+ (2.77), 253 (100), 194 (10.22), 149 (10.09), 126 (41.39), 118 (19.53), 103 (12.7), 91 (18.3), 77 (26.62), 51(6.5). Anal. for C16H14N6S (322.38) Calcd. %: C 59.55; H 4.34; N 26.05. Found %: C 59.64; H 4.27; N 26.22.
2.6 Antibacterial activity
The compounds were dissolved in DMSO. In order to ensure that the solvent per se had no effect on bacterial growth or enzymatic activity, negative control tests were performed using DMSO at the same concentrations. The inhibitory effect of compounds 2b, 2c, 2e, 2g, 2h, 2i, 4, 5a, 5b, 5d, 5e and 6 on the in vitro growth of broad spectrum of bacteria representing one gram positive bacterium, namely Bacillus cereus and two gram negative bacteria, namely; Pseudomonas aeruginosa and Escherichia coli was evaluated using agar diffusion method (cup and plate method) (Barry, 1976) by measuring the zone of inhibition on agar plates at three different concentrations 10,000, 30,000 and 50,000 ppm. DMSO was used as solvent control. All plates were incubated at 37 ± 0.5 °C for 24 h. The zone of inhibition of compounds was measured using cm scale. The results indicated in Table 1.
Types of bacteria
Bacillus cereus
Pseudomonas aeruginosa
Escherichia coli
Concentrations
Concentrations
Concentrations
Compound
10,000 ppm
30,000 ppm
50,000 ppm
10,000 ppm
30,000 ppm
50,000 ppm
10,000 ppm
30,000 ppm
50,000 ppm
2b
0.9 cm
2.3 cm
2.6 cm
0.7 cm
1.2 cm
1.4 cm
0.4 cm
0.8 cm
1.4 cm
2c
1.0 cm
1.7 cm
1.7 cm
–
0.5 cm
–
0.2 cm
0.4 cm
0.7 cm
2e
0.7 cm
1.3 cm
1.8 cm
0.7 cm
1.3 cm
1.8 cm
0.5 cm
1.1 cm
1.2 cm
2g
1.4 cm
3.1 cm
3.4 cm
0.8 cm
1.4 cm
1.9 cm
0.9 cm
1.8 cm
1.9 cm
2h
1.7 cm
2.6 cm
3.5 cm
1.1 cm
1.4 cm
2.3 cm
1.0 cm
1.2 cm
1.7 cm
2i
0.8 cm
0.9 cm
1.0 cm
0.8 cm
0.9 cm
1.3 cm
0.5 cm
0.8 cm
0.9 cm
4
1.0 cm
1.1 cm
2.0 cm
0.9 cm
1.2 cm
1.5 cm
1.1 cm
1.3 cm
2.3 cm
5a
0.5 cm
0.6 cm
0.7 cm
0.5 cm
0.7 cm
1.0 cm
0.5 cm
0.6 cm
0.8 cm
5b
0.6 cm
0.9 cm
1.1 cm
–
–
0.5 cm
0.5 cm
0.8 cm
0.4 cm
5d
0.7 cm
0.9 cm
0.9 cm
0.5 cm
0.7 cm
0.9 cm
0.6 cm
0.8 cm
1.0 cm
5e
0.3 cm
0.4 cm
0.8 cm
–
–
–
0.7 cm
0.8 cm
0.6 cm
6
0.4 cm
0.5 cm
0.7 cm
0.9 cm
1.3 cm
2.1 cm
0.5 cm
0.8 cm
0.9 cm
3 Results and discussion
3.1 Chemistry
Mannich reaction on 4-anilino-5-phenyl-4H-1,2,4-triazole-3-thiol (1) (Chande et al., 1993) using formaldehyde and different amines namely; 2-aminothiazole, 2-amino-1,3,4-thiadiazole, 2-aminopyridine, p-aminoacetophenone, diethylamine, N-ethylaniline, morpholine, piperidine and piperazine afforded the corresponding Mannich bases 2a–i. (cf. Scheme 1). The structure of these compounds was established on the basis of their elemental and spectral analyses. MS of compounds 2a, 2b and 2c showed the molecular ion peaks at m/z = 380 (M+, 10.6%), 381(M+, 0.04%) and 374(M+, 0.07%), respectively, (cf. experimental). 4-Anilino-2-hydroxymethyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (3) was obtained via the reaction of compound 1 with formaldehyde, which in turn reacted with thionyl chloride to give 4-anilino-2-chloromethyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (4). IR spectrum (KBr, cm−1) of compound 3 showed new absorption band corresponding to OH at 3418.3 cm−1. Treatment of compound 4 with the respective aliphatic, aromatic or heterocyclic thiols namely; propanethiol, cyclohexanethiol, thiophenol, 4-chlorothiophenol, 4-anilino-5-phenyl-4H-1,2,4-triazole-3-thiol and 5-phenyl-1,3,4-oxadiazole-2-thiol, in boiling dimethylformamide in the presence of triethylamine, yielded the corresponding sulfides 5a–f in good yields (cf. Scheme 1). The IR spectra (KBr, cm−1) of compounds 5a–f showed disappearance of absorption band corresponding to C–Cl at 767 cm−1. Condensation of chloromethyl derivative 4 with hydrazine hydrate, phenyl hydrazine, hydroxylamine, urea and thiourea in refluxing p-xylene and triethylamine gave; 7-anilino-6-phenyl-2,7-dihydro-3H-1,2,4-triazolo[4,3-b]-1,2,4-triazole (6), 7-anilino-2,6-diphenyl-2,7-dihydro-3H-1,2,4-triazolo[4,3-b]-1,2,4-triazole (7), 7-anilino-6-phenyl-7H-1,2,4-triazolo[5,1-c]-1,2,4-oxadiazole (8), 1-anilino-2-phenyl-1,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-1,3,5-triazin-7-one (9) and 1-anilino-2-phenyl-1,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-1,3,5-triazine-7-thione (10) respectively (cf. Scheme 2). The structure of these compounds was proved by elemental and spectral analyses (cf. experimental). MS of compounds 6 and 10 showed the molecular ion peak at m/z 276 (M+, 7.7%) and 322 (M+, 2.77%), respectively.
Synthesis of Mannich bases and sulfides.
Synthesis of triazolo-, oxadiazolo- and triazinotriazoles.
3.2 Antibacterial activity
The results of antibacterial activity are shown in Table 1. Mannich bases derivatives exhibited good activity, specially compounds 2g and 2h, showed the highest inhibitory effect against all types of bacteria excepting E. coli which effected highly by chloromethyl compound 4 (2.3 cm). Sulfides display good activity against Bacillus cereus and E. coli but possess moderate to poor activities against P. aeruginosa. Triazolotriazole 6 showed good activities against all types of bacteria. The zone of inhibition of all compounds was increased by increasing the concentrations excepting compound 2c that has activity against P. aeruginosa at 30,000 ppm only.
Acknowledgments
The authors are deeply grateful to the Chemistry Department, Faculty of Science, Sohag University in Egypt for supporting and facilitating this study. Also, we extend our thanks to Dr. Rehab Mostafa Mohamed and Miss. Dalia Ahmed Abd El Raheem, Botany Department, Faculty of Science, Sohag University in Egypt for Evaluation of bacterial inhibiting effects.
References
- Phosphorus, Sulfur and Silicon. 1993;85:183-192.
- Proc. Natl. Acad. Sci. India. 1988;58A:215.
- The Antimicrobial Susceptibility Test, Principles and Practices. Philadeliphia, PA, USA: Illus Lea and Febiger; 1976. p. 180
- Bioorg. Med. Chem. Lett.. 1994;4:1285.
- Indian J. Chem.. 1993;32B:1218-1228.
- Bioorg. Med. Chem. Lett.. 2001;11:3165.
- Bioorg. Med. Chem. Lett.. 2003;13:2601.
- J. Clin. Virol.. 2004;30:115.
- Bioorg. Med. Chem. Lett.. 1998;8:775.
- Phosphorus, Sulfur and Silicon. 1992;70:99.
- Sulfur Lett.. 1989;8:261.
- Rev. Roum. Chim.. 1989;34:1987.
- Synth. Commun.. 2001;31(16):57-66.
- Eygpt. J. Chem.. 2003;46:297-311.
- Pestic. Sci.. 1996;48:31.
- Acta Pharm.. 1999;49:1.
- J. Med. Chem.. 1971;14:1078.
- Bioorg. Med. Chem.. 2001;9:217.
- Neurotoxicology. 2001;22:767.
- Synth. Commun.. 2001;31(1):97.
- J. Med. Chem.. 1996;39:3019.
- Farmaco. 2002;57:973.
- Chem. Rev.. 1961;61:87.
- Bioorg. Med. Chem. Lett.. 1994;4:2441.
- J. Med. Chem.. 1992;35:1280.
