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Characterization and pharmacological evaluation of new pyridine analogs
*Corresponding author. Tel.: +91 0261 2264746; fax: +91 0261 2256012 drnavin@satyam.net.in (Navin B. Patel)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Available online 1 August 2010
Abstract
Reaction of 5-ethyl pyridine-2-ethanol 1 and methane sulphonyl chloride gives corresponding sulphonate 2; which on condensation with p-hydroxy benzaldehyde will give 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde 3. A series of chalcones 4a–o were prepared from 3 and substituted aromatic acetophenone. Chalcones 4a–o further react with guanidine nitrate to give a series of pyrimidines 5a–o which condense with 3,4-dichlorobenzylchloride to give amide derivatives 6a–o. Newly synthesized compounds have been examined on the basis of spectral analysis. All the compounds were screened against different gram-positive and gram-negative bacteria. Most of these compounds showed better inhibitory activity in comparison with the standard drugs.
Keywords
Chalcone
Pyrimidine
Amide
Microbial studies
1 Introduction
The number of life-threatening infections caused by multidrug-resistant gram-positive pathogens has reached an alarming level in hospitals and community. Infections caused by these organisms pose a serious challenge to the scientific community and the need for an effective therapy has led to a search for novel antibacterial agents.
Amides, thioamides and carbamates are versatile intermediates in the synthesis of natural products. A large number of antibiotics contain amide linkage. Several derivatives of amides were prepared and found to possess different activities like antimicrobial (Aytemir et al., 2003; Yildiz Oren et al., 2004; Temiz-Arpacı et al., 2005) antibacterial (Desai and Chikhalia, 2005) antifungal, antimycobacterial activities and photosynthesis inhibition activity (Dolezal et al., 2002, 2006). Amide also possessed anti-inflammatory and analgesic activities (Zhong et al., 2009; Banoglu et al., 2007; Geronikaki et al., 2003). Several amides also displayed brain antihypoxic activity (Mitkov et al., 2007), antinociceptive (Onkol et al., 2004) and insecticidal activity (De Paula et al., 2000).
Literature survey reveals that various drugs for e.g. penicillin, pyrazinamide, indinavir, and ritonavir contain particular activities due to the amide linkage present in their structures.
The present study is concerned with the synthesis of the series of heterocyclic amides prepared from pyrimidine derivatives. Considering these findings, we thought of synthesizing the amide derivatives.
2 Experimental
2.1 General
Laboratory Chemicals were supplied by Rankem India Ltd. and Ficher Scientific Ltd. Melting points were determined by the open tube capillary method and are uncorrected. The purity of the compounds was determined by thin layer chromatography (TLC) plates (silica gel G) in the toluene:ethyl acetate (7.5:2.5) solvent system. The spots were observed by exposure to iodine vapours or by UV light. The IR spectra were obtained on a Perkin–Elmer 1720 FT-IR spectrometer (KBr pellets). The 1H NMR and 13C NMR spectra were recorded on a Bruker Avance II 400 spectrometer using TMS as the internal standard in CDCl3. Elemental analysis of the newly synthesized compounds was carried out on a Carlo Erba 1108 analyzer.
2.2 General preparation of the compounds 4a–o
To a solution of 3 (4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde) (Gaonkar et al., 2006; Momose et al., 1991) (0.01 mol) in methanol (50 mL), different substituted aromatic acetophenones (0.01 mol) were added in the presence of 2% NaOH solution (5 mL) and the mixtures were stirred for 10–12 h at room temperature. The solvent was distilled off and crude product poured into ice water. The compound thus obtained was washed with water and recrystallized from ethanol to get the pure intermediate (Fig. 1).
Chalcones 4a–o.
2.2.1 5-Ethyl-2-{[4-(1-(2,4-dichloro-5-fluorophenyl)-2-propan-1-one-3-yl)]phenoxy ethyl} pyridine (4a)
m.p. 121–123 °C. Yield 80%. Rf: 0.58. IR (KBr): t = 3062 (Ar-H), 2953, 2836 (–CH2–), 1664 (–C⚌O), 1598(–CH⚌CH–), 1223, 1033 (C–O–C), 975 (C–F), 742 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.17 (t, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 7.00–7.84 (m, 6H, Ar–H), 7.10 (d, 1H, ⚌CH–CO), 7.18 (d, 1H, –CH), 7.36–8.28 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C-8), 25.1 (C-7), 38.0 (C-9), 67.5 (C-10), 115.5–156.0 (C-11–C-16), 117.3–161.5 (C-20–C-25), 119.2 (C-18), 122.4–160.5 (C-2–C-6), 144.5 (C-17), 190.5 (C-19). Anal. calcd for C24H20NO2Cl2F: C64.88, H4.54, N3.15. Found C64.84, H4.50, N3.10.
2.2.2 5-Ethyl-2-{[4-(1-(4-methoxyphenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4b)
m.p. 84–86 °C. Yield 72%. Rf: 0.56. IR (KBr): t = 3064 (Ar-H), 2947, 2835 (–CH2–), 1663 (–C⚌O), 1596 (–CH⚌CH–), 1220, 1028 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.19 (t, 3H, –CH3), 2.57 (q, 2H, –CH2), 3.19 (t, 2H, –CH2), 3.84 (s, 3H, –OCH3), 4.33 (t, 2H, –CH2–O), 7.12 (d, 1H, ⚌CH–CO), 7.20 (d, 1H, –CH), 7.38–8.27 (m, 3H, Pyridine-H), 7.05–8.11 (m, 8H, Ar-H); 13C NMR (100 MHz, CDCl3): δ = 15.3 (C-8), 25.5 (C-7), 37.0 (C-9), 55.5 (C-26), 66.4 (C-10), 115.0–116.4 (C-20–C-25), 115.2–155.5 (C-11–C-16), 118.5 (C-18), 124.0–160.0 (C-2–C-6), 143.5 (C-17), 189.5 (C-19). Anal. calcd for C25H25NO3: C77.49, H6.50, N3.61. Found C77.42, H6.42, N3.54.
2.2.3 5-Ethyl-2-{[4-(1-(2,4-dichlorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4c)
m.p. 95–97 °C. Yield 82%. Rf: 0.54. IR (KBr): t = 3066 (Ar-H), 2953, 2835 (–CH2–), 1660 (–C⚌O), 1592 (–CH⚌CH–), 1218, 1030 (C–O–C), 740 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.18 (t, 3H, –CH3), 2.56 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.35 (t, 2H, –CH2–O), 7.03–7.69 (m, 7H, Ar-H), 7.13 (d, 1H, ⚌CH–CO), 7.17 (d, 1H, –CH), 7.39–8.29 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C-8), 25.8 (C-7), 38.5 (C-9), 67.3 (C-10), 114.5–156.5 (C-11–C-16), 119.5 (C-18), 122.0–159.5 (C-2–C-6), 127.3–141.5 (C-20–C-25), 144.0 (C-17), 190.8 (C-19). Anal. calcd for C24H21NO2Cl2: C67.61, H4.96, N3.29. Found C67.60, H4.90, N3.23.
2.2.4 5-Ethyl-2-{[4-(1-(4-hydroxyphenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4d)
m.p. 178–179 °C. Yield 78%. Rf: 0.59. IR (KBr): t = 3057 (Ar-H), 2945, 2832 (–CH2–), 1660 (–C⚌O), 1595 (–CH⚌CH–), 1216, 1033 (C–O–C), 3375 (–OH). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.58 (q, 2H, –CH2), 3.15 (t, 2H, –CH2), 4.36 (t, 2H, –CH2–O), 5.15 (s, 1H, –OH), 7.01–8.05 (m, 8H, Ar-H), 7.12 (d, 1H, ⚌CH–CO), 7.19 (d, 1H, –CH), 7.37–8.31 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C-8), 25.1 (C-7), 38.0 (C-9), 67.5 (C-10), 115.5-156.0 (C-11–C-16), 116.3–132.0 (C-20–C-25), 119.2 (C-18), 122.4–160.5 (C-2–C-6), 144.5 (C-17), 190.5 (C-19). Anal. calcd for C24H23NO3: C77.19, H6.21, N3.75. Found C77.13, H6.16, N3.70.
2.2.5 5-Ethyl-2-{[4-(1-(2,6-chloro-5-fluorophenyl)-2-propan-1-one-3-yl)]phenoxy ethyl}pyridine (4e)
m.p. 101–103 °C. Yield 85%. Rf: 0.53. IR (KBr): t = 3065 (Ar-H), 2955, 2837 (–CH2–), 1657 (–C⚌O), 1589 (–CH⚌CH–), 1225, 1036 (C–O–C), 976 (C–F), 747 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 7.03–7.32 (m, 6H, Ar-H), 7.11 (d, 1H, ⚌CH–CO), 7.19 (d, 1H, –CH), 7.37–8.29 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C-8), 25.4 (C-7), 38.0 (C-9), 67.3 (C-10), 115.5–156.5 (C-11–C-16), 117.5–162.0 (C-20–C-25), 119.5 (C-18), 122.0–160.0 (C-2–C-6), 144.2 (C-17), 190.3 (C-19). Anal. calcd for C24H20NO2Cl2F: C64.88, H4.54, N3.15. Found C64.86, H4.50, N3.07.
2.2.6 5-Ethyl-2-{[4-(1-(4-methylphenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4f)
m.p. 115–120 °C. Yield 80%. Rf: 0.55. IR (KBr): t = 3060 (Ar-H), 2950, 2835 (–CH2–), 1662 (–C⚌O), 1599 (–CH⚌CH–), 1223, 1033 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H, –CH3), 2.34 (s, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 6.84–7.84 (m, 8H, Ar-H), 7.11 (d, 1H, ⚌CH–CO), 7.19 (d, 1H, –CH), 7.39–8.30 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C-8), 21.7 (C-26), 25.8 (C-7), 37.4 (C-9), 67.4 (C-10), 115.0–155.3 (C-11–C-16), 119.7 (C-18), 123.4–160.9 (C-2–C-6), 127.5–142.4 (C-20–C-25), 144.2 (C-17), 190.0 (C-19). Anal. calcd for C25H25NO2: C80.83, H6.78, N3.77. Found C80.81, H6.74, N3.71.
2.2.7 5-Ethyl-2-{[4-(1-(1-phenyl)-2-propan-1-one-3-yl)]phenoxyethyl}pyridine (4g)
m.p. 90–92 °C. Yield 83%. Rf: 0.53. IR (KBr): t = 3055 (Ar-H), 2947, 2832 (–CH2–), 1657 (–C⚌O), 1596 (–CH⚌CH–), 1217, 1029 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.18 (t, 3H, –CH3), 2.56 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.30 (t, 2H, –CH2–O), 7.01–7.81 (m, 9H, Ar-H), 7.13 (d, 1H, ⚌CH–CO), 7.18 (d, 1H, –CH), 7.38–8.32 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C-8), 25.5 (C-7), 38.2 (C-9), 67.3 (C-10), 115.5–156.2 (C-11–C-16), 119.5 (C-18), 122.4–160.5 (C-2–C-6), 127.8–138.0 (C-20–C-25), 144.5 (C-17), 190.2 (C-19). Anal. calcd for C24H23NO2: C80.64, H6.49, N3.93. Found C80.63, H6.45, N3.86.
2.2.8 5-Ethyl-2-{[4-(1-(4-fluorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl }pyridine (4h)
m.p. 100–103 °C. Yield 79%. Rf: 0.54. IR (KBr): t = 3062 (Ar-H), 2953, 2838 (–CH2–), 1661 (–C⚌O), 1594 (–CH⚌CH–), 1222, 1037 (C–O–C), 970 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.18 (t, 3H, –CH3), 2.56 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 7.05–7.79 (m, 8H, Ar-H), 7.14 (d, 1H, ⚌CH–CO), 7.19 (d, 1H, –CH), 7.39-8.29 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C-8), 25.3 (C-7), 38.0 (C-9), 67.0 (C-10), 115.5–156.5 (C-11–C-16), 116.5–168.0 (C-20–C-25), 119.5 (C-18), 122.5–160.3 (C-2–C-6), 144.2 (C-17), 190.3 (C-19). Anal. calcd for C24H22NO2F: C76.78, H5.91, N3.73. Found C76.74, H5.86, N3.66.
2.2.9 5-Ethyl-2-{[4-(1-(2,4-fluorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl }pyridine (4i)
m.p. 75–78 °C. Yield 81%. Rf: 0.57. IR (KBr): t = 3064 (Ar-H), 2949, 2834 (–CH2–), 1658 (–C⚌O), 1598 (–CH⚌CH–), 1217, 1030 (C–O–C), 973 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.15 (t, 2H, –CH2), 4.30 (t, 2H, –CH2–O), 6.87–7.77 (m, 7H, Ar-H), 7.12 (d, 1H, ⚌CH–CO), 7.17 (d, 1H, –CH), 7.38–8.32 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.3 (C-8), 25.6 (C-7), 38.4 (C-9), 67.5 (C-10), 105.5–169.5 (C-20–C-25), 115.1–156.2 (C-11–C-16), 119.2 (C-18), 122.4–160.5 (C-2–C-6), 144.0 (C-17), 190.1 (C-19). Anal. calcd for C24H21NO2F2: C73.27, H5.38, N3.56. Found C73.25, H5.34, N3.49.
2.2.10 5-Ethyl-2-{[4-(1-(4-bromophenyl)-2-propan-1-one-3-yl)]phenoxyethyl}-pyridine (4j)
m.p. 102–104 °C. Yield 85%. Rf: 0.56. IR (KBr): t = 3064 (Ar-H), 2953, 2830 (–CH2–), 1660 (–C⚌O), 1595 (–CH⚌CH–), 1225, 1032 (C–O–C), 858 (C-Br). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.34 (t, 2H, –CH2–O), 7.00–8.01 (m, 8H, Ar-H), 7.13 (d, 1H, ⚌CH–CO), 7.16 (d, 1H, –CH), 7.37–8.30 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.0 (C-8), 24.5 (C-7), 38.2 (C-9), 67.1 (C-10), 115.5–156.0 (C-11–C-16), 118.5 (C-18), 121.4–159.5 (C-2–C-6), 132.1–136.9 (C-20–C-25), 144.2 (C-17), 189.5 (C-19). Anal. calcd for C24H22NO2Br: C66.06, H5.08, N3.21. Found C66.03, H5.02, N3.15.
2.2.11 5-Ethyl-2-{[4-(1-(3,4-dichlorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4k)
m.p. 105–110 °C. Yield 84%. Rf: 0.55. IR (KBr): t = 3067 (Ar-H), 2947, 2829 (–CH2–), 1664 (–C⚌O), 1593 (–CH⚌CH–), 1220, 1031 (C–O–C), 744 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.19 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 7.01–7.76 (m, 7H, Ar-H), 7.11 (d, 1H, ⚌CH–CO), 7.18 (d, 1H, –CH), 7.38–8.32 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C-8), 25.1 (C-7), 37.2 (C-9), 66.5 (C-10), 114.5–155.2 (C-11–C-16), 119.8 (C-18), 122.4–160.5 (C-2–C-6), 130.4–139.5 (C-20–C-25), 143.5 (C-17), 188.9 (C-19). Anal. calcd for C24H21NO2Cl2: C67.61, H4.96, N3.29. Found C67.58, H4.90, N3.23.
2.2.12 5-Ethyl-2-{[4-(1-(4-chlorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4l)
m.p. 138–140 °C. Yield 88%. Rf: 0.53. IR (KBr): t = 3028 (Ar-H), 2944, 2827 (–CH2–), 1659 (–C⚌O), 1596 (–CH⚌CH–), 1224, 1037 (C–O–C), 746 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.57 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.30 (t, 2H, –CH2–O), 7.03–7.86 (m, 8H, Ar-H), 7.10 (d, 1H, ⚌CH–CO), 7.19 (d, 1H, –CH), 7.37–8.32 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C-8), 24.8 (C-7), 38.3 (C-9), 67.3 (C-10), 114.5–156.0 (C-11–C-6), 118.2 (C-18), 121.5–160.8 (C-2–C-6), 129.5–140.5 (C-20–C-25), 144.5 (C-17), 190.5 (C-19). Anal. calcd for C24H22NO2Cl: C73.56, H5.66, N3.57. Found C73.52, H5.61, N3.55.
2.2.13 5-Ethyl-2-{[4-(1-(3-methoxyphenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4m)
m.p. 75–80 °C. Yield 70%. Rf: 0.52. IR (KBr): t = 3066 (Ar-H), 2952, 2833 (–CH2–), 1664 (–C⚌O), 1594 (–CH⚌CH–), 1220, 1032 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.58 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 3.85 (s, 3H, –OCH3) 4.34 (t, 2H, –CH2–O), 6.96–8.11 (m, 8H, Ar-H), 7.11 (d, 1H, ⚌CH–CO), 7.16 (d, 1H, –CH), 7.39-8.30 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C-8), 25.5 (C-7), 38.5 (C-9), 55.5 (C-26), 68.5 (C-10), 115.3–156.5 (C-11–C-16), 117.3–161.5 (C-20–C-25), 119.2 (C-18), 122.6–161.5 (C-2–C-6), 144.1 (C-17), 190.1 (C-19). Anal. calcd for C25H25NO3: C77.49, H6.50, N3.61. Found C77.45, H6.48, N3.52.
2.2.14 5-Ethyl-2-{[4-(1-(3-fluorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4n)
m.p. 87–90 °C. Yield 80%. Rf: 0.54. IR (KBr): t = 3062 (Ar-H), 2956, 2835 (–CH2–), 1660 (–C⚌O), 1597 (–CH⚌CH–), 1219, 1032 (C–O–C), 976 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.11 (t, 3H, –CH3), 2.53(q, 2H, –CH2), 3.14 (t, 2H, –CH2), 4.31 (t, 2H, –CH2–O), 7.00–7.58 (m, 8H, Ar-H), 7.13 (d, 1H, ⚌CH–CO), 7.18 (d, 1H, –CH), 7.39-8.30 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.8 (C-8), 25.3 (C-7), 38.0 (C-9), 55.8 (C-26), 67.5 (C-10), 114.5–164.0 (C-20–C-25), 115.5–156.1 (C-11–C-16), 119.2 (C-18), 122.5–160.5 (C-2–C-6), 144.8 (C-17), 189.5 (C-19), Anal. calcd for C24H22NO2F: C76.78, H5.91, N3.73. Found C76.72, H5.86, N3.70.
2.2.15 5-Ethyl-2-{[4-(1-(3,4-difluorophenyl)-2-propan-1-one-3-yl)]phenoxyethyl} pyridine (4o)
m.p. limpid. Yield 82%. Rf: 0.55. IR (KBr): t = 3060 (Ar-H), 2950, 2835 (–CH2–), 1662 (–C⚌O), 1599 (–CH⚌CH), 1223, 1033 (C–O–C), 978 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.12 (t, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 7.02–7.56 (m, 7H, Ar-H), 7.14 (d, 1H, ⚌CH–CO), 7.19 (d, 1H, –CH), 7.37–8.28 (m, 3H, Pyridine-H); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C-8), 25.1 (C-7), 38.2 (C-9), 67.1 (C-10), 115.5–156.0 (C-11–C-16), 116.3–155.5 (C-20–C-25), 119.6 (C-18), 122.4–160.2 (C-2–C-6), 144.5 (C-17), 190.5 (C-19). Anal. calcd for C24H21NO2F2: C73.27, H5.38, N3.56. Found C73.21, H5.33, N3.48.
2.3 General preparation of the compounds 5a–o
A mixture of freshly prepared solution of sodium ethoxide (0.02 mol Na in 50 mL ethanol), 4a–o (0.01 mol) and guanidine nitrate (0.01 mol) was refluxed for 8–12 h; reaction progress was monitored by TLC (tolune:ethyl acetate, 7.5:2.5). After completion of reaction, the mixture was concentrated under vacuum and the remaining reaction mass was poured into crushed ice; the solid was separated out and stirred for 1 h to maintain neutral pH with dilute glacial acetic acid. The mass was filtered and washed with water, dried and recrystallized from ethanol (Fig. 2).
Pyrimidines 5a–o.
2.3.1 5-Ethyl-2-{[4-(6-(2,4-dichloro-5-fluorophenyl)-2-aminopyrimidin-4-yl)] phenoxyethyl} pyridine (5a)
m.p. 95–98 °C. Yield 74%. Rf: 0.42. IR (KBr): t = 3355, 3222 (–NH2), 3062 (Ar-H), 2954, 2837 (–CH2–), 1602 (–C⚌N), 1225, 1036 (C–O–C), 973 (C-F), 745 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 5.18 (s, 2H, –NH2), 6.90–7.82 (m, 8H, Ar-H), 7.39–8.32 (m, 3H, Pyridine-H), 7.84 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.3 (C-8), 25.2 (C-7), 38.0 (C-9), 67.0 (C-10), 103.5 (C-22), 114.0–154.4 (C-11–C-16), 118.7–161.4 (C-24–C-29), 123.5–160.5 (C-2–C-6), 160.7 (C-21), 163.2 (C-17), 165.0 (C-19) Anal. calcd for C25H21N4OCl2F: C62.12, H4.38, N11.59. Found C62.06, H4.32, N11.52.
2.3.2 5-Ethyl-2-{[4-(6-(4-methoxyphenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5b)
m.p. 100–102 °C. Yield 52%. Rf: 0.40. IR (KBr): t = 3352, 3224 (–NH2), 3065 (Ar-H), 2957, 2834 (–CH2–), 1609 (–C⚌N), 1223, 1033 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 3.83 (s, 3H, –OCH3) 4.34 (t, 2H, –CH2–O), 5.12 (s, 2H, –NH2), 6.89–7.84 (m, 8H, Ar-H), 7.40–8.32 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C-8), 25.0 (C-7), 37.5 (C-9), 55.8 (C-30), 67.3 (C-10), 103.4 (C-22), 114.5–160.5 (C-24–C-29), 115.3–155.5 (C-11–C-16), 123.8–161.0 (C-2–C-6), 160.5 (C-21), 164.5 (C-17), 165.1 (C-19), Anal. calcd for C26H26N4O2: C73.22, H6.14, N13.14. Found C73.14, H6.08, N13.07.
2.3.3 5-Ethyl-2-{[4-(6-(2,4-dichlorophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5c)
m.p. 115–118 °C. Yield 78%. Rf: 0.43. IR (KBr): t = 3358, 3227 (–NH2), 3057 (Ar-H), 2953, 2836 (–CH2–), 1607 (–C⚌N), 1227, 1037 (C–O–C), 746 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.52 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 5.22 (s, 2H, −NH2), 6.88–7.81 (m, 8H, Ar-H), 7.39–8.32 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C-8), 26.1 (C-7), 37.3 (C-9), 67.5 (C-10), 104.2 (C-22), 115.1–155.2 (C-11–C-16), 123.6–161.9 (C-2–C-6), 127.4–135.5 (C-24–C-29), 160.5 (C-21), 163.6 (C-17), 165.1 (C-19). Anal. calcd for C25H22N4OCl2: C64.52, H4.76, N12.04. Found C64.46, H4.69, N12.00.
2.3.4 5-Ethyl-2-{[4-(6-(4-hydroxyphenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5d)
m.p. >300 °C. Yield 50%. Rf: 0.44. IR (KBr): t = 3355, 3224 (–NH2), 3064 (Ar-H), 2955, 2832 (–CH2–), 1600 (–C⚌N), 1220, 1032 (C–O–C), 3357 (–OH). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.15 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 9.85 (s, 1H, –OH), 5.12 (s, 2H, –NH2), 6.84–7.78 (m, 8H, Ar-H), 7.39–8.30 (m, 3H, Pyridine-H), 7.85 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.7 (C-8), 25.5 (C-7), 37.6 (C-9), 67.3 (C-10), 103.5 (C-22), 115.7–155.7 (C-11–C-16), 116.3–158.5 (C-24–C-29), 122.9–159.9 (C-2–C-6), 160.3 (C-21), 163.8 (C-17), 165.2 (C-19), Anal. calcd for C25H24N4O2: C72.80, H5.86, N13.58. Found C72.74, H5.78, N13.52.
2.3.5 5-Ethyl-2-{[4-(6-(2,6-chloro-5-fluorophenyl)-2-aminopyrimidin-4-yl)] phenoxyethyl}pyridine (5e)
m.p. 105–108 °C. Yield 76%. Rf: 0.40. IR (KBr): t = 3348, 3219 (–NH2), 3062 (Ar-H), 2953, 2830 (–CH2–), 1606 (–C⚌N), 1220, 1034 (C–O–C), 975 (C–F), 747 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.12 (t, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.31 (t, 2H, –CH2–O), 5.24 (s, 2H, –NH2), 6.91–7.83 (m, 8H, Ar-H), 7.38–8.30 (m, 3H, Pyridine-H), 7.85 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C-8), 25.1 (C-7), 38.2 (C-9), 67.2 (C-10), 103.2 (C-22), 113.9–154.1 (C-11–C-16), 118.3–161.4 (C-24–C-29), 123.0–160.4 (C-2–C-6), 160.5 (C-21), 163.0 (C-17), 165.4 (C-19), Anal. calcd for C25H21N4OCl2F: C62.12, H4.38, N11.59. Found C62.04, H4.31, N11.55.
2.3.6 5-Ethyl-2-{[4-(6-(4-methylphenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5f)
m.p. 133–136 °C. Yield 78%. Rf: 0.42. IR (KBr): t = 3355, 3220 (–NH2), 3057 (Ar-H), 2952, 2834 (–CH2–), 1610 (–C⚌N), 1220, 1034 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.33 (s, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 5.15 (s, 2H, –NH2), 6.89–7.80 (m, 8H, Ar-H), 7.39–8.30 (m, 3H, Pyridine-H), 7.85 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C8), 21.7 (C30), 25.5 (C7), 37.5 (C9), 67.5 (C10), 103.2 (C22), 115.0–155.4 (C11–C16), 123.4–160.9 (C2–C6), 129.2–144.4 (C24–C29), 160.9 (C21), 163.5 (C17), 165.5 (C19), Anal. calcd for C26H26N4O: C76.07, H6.38, N13.65. Found C76.00, H6.32, N13.57.
2.3.7 5-Ethyl-2-{[4-(6-(1-phenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl}pyridine (5g)
m.p. 110–115 °C. Yield 65%. Rf: 0.44. IR (KBr): t = 3356, 3225 (–NH2), 3058 (Ar-H), 2952, 2832 (–CH2–), 1605 (–C⚌N), 1227, 1038 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.52 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.30 (t, 2H, –CH2–O), 5.20 (s, 2H, –NH2), 6.89–7.82 (m, 8H, Ar-H), 7.38–8.31 (m, 3H, Pyridine-H), 7.87 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.3 (C8), 25.1 (C7), 38.2 (C9), 67.2 (C10), 103.7 (C22), 114.9–154.1 (C11–C16), 118.7–161.4 (C24–C29), 123.6–160.4 (C2–C6), 160.5 (C21), 163.2 (C17), 164.9 (C19), Anal. calcd for C26H24N4O: C75.73, H6.10, N14.13. Found C75.68, H6.04, N14.10.
2.3.8 5-Ethyl-2-{[4-(6-(4-fluorophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5h)
m.p. 244–246 °C. Yield 70%. Rf: 0.45. IR (KBr): t = 3356, 3222 (–NH2), 3064 (Ar-H), 2950, 2835 (–CH2–), 1602 (–C⚌N), 1226, 1036 (C–O–C), 975 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.31 (t, 2H, –CH2–O), 5.16 (s, 2H, –NH2), 6.88–7.80 (m, 8H, Ar-H), 7.39-8.32 (m, 3H, Pyridine-H), 7.84 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 14.9 (C8), 25.4 (C7), 38.3 (C9), 67.4 (C10), 103.9 (C22), 114.1–154.3 (C11–C16), 116.0–163.0 (C24–C29), 123.9–160.9 (C2–C6), 160.7 (C21), 163.0 (C17), 164.5 (C19), Anal. calcd for C25H23N4OF: C72.45, H5.59, N13.52. Found C72.35, H5.54, N13.48.
2.3.9 5-Ethyl-2-{[4-(6-(2,4-fluorophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5i)
m.p. 135–139 °C. Yield 72%. Rf: 0.41. IR (KBr): t = 3347, 3225 (–NH2), 3066 (Ar-H), 2945, 2832 (–CH2–), 1604 (–C⚌N), 1220, 1034 (C–O–C), 978 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 5.18 (s, 2H, –NH2), 6.90–7.83 (m, 8H, Ar-H), 7.37–8.30 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.1 (C8), 25.4 (C7), 38.1 (C9), 67.8 (C10), 103.5 (C22), 114.2–153.9 (C11–C16), 116.6–164.5 (C24–C29), 123.5–160.8 (C2–C6), 160.5 (C21), 163.2 (C17), 164.4 (C19), Anal. calcd for C25H22N4OF2: C69.43, H5.13, N12.96. Found C69.37, H5.08, N12.92.
2.3.10 5-Ethyl-2-{[4-(6-(4-bromophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5j)
m.p. 115–117 °C yield. 77%. Rf: 0.40. IR (KBr): t = 3354, 3225 (–NH2), 3057 (Ar-H), 2952, 2837 (–CH2–), 1608 (–C⚌N), 1224, 1032 (C–O–C), 860 (C-Br). 1H NMR (CDCl3, 400 MHz): δ = 1.15(t, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 5.14 (s, 2H, –NH2), 6.86–7.81 (m, 8H, Ar-H), 7.38–8.33 (m, 3H, Pyridine-H), 7.85(s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C8), 25.1 (C7), 38.8 (C9), 67.7 (C10), 103.9 (C22), 114.1–154.2 (C11–C16), 123.1–132.1 (C24–C29), 123.8–160.6 (C2–C6), 160.7 (C21), 163.1 (C17), 164.5 (C19), Anal. calcd for C25H23N4OBr: C63.16, H4.88, N11.79. Found C63.11, H4.82, N11.73.
2.3.11 5-Ethyl-2-{[4-(6-(3,4-dichlorophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5k)
m.p. 125–130 °C. Yield 73%. Rf: 0.43. IR (KBr): t = 3356, 3227 (–NH2), 3066 (Ar-H), 2955, 2838 (–CH2–), 1605 (–C⚌N), 1225, 1037 (C–O–C), 748 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.15 (t, 2H, –CH2), 4.35 (t, 2H, –CH2–O), 5.17 (s, 2H, –NH2), 6.92-7.83 (m, 8H, Ar-H), 7.41–8.30 (m, 3H, Pyridine-H), 7.84 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.8 (C8), 25.4 (C7), 38.3 (C9), 67.5 (C10), 103.8 (C22), 114.1–154.3 (C11–C16), 123.6–160.8 (C2–C6), 127.0–133.5 (C24–C29), 160.5 (C21), 160.5 (C21), 163.1 (C17), 164.5 (C19), Anal. calcd for C25H22N4OCl2: C64.52, H4.76, N12.04. Found C64.48, H4.71, N12.00.
2.3.12 5-Ethyl-2-{[4-(6-(4-chlorophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5l)
m.p. 92–95 °C. Yield 74%. Rf: 0.42. IR (KBr): t = 3356, 3227 (–NH2), 3066 (Ar-H), 2955, 2838 (–CH2–), 1611 (–C⚌N), 1225, 1037 (C–O–C), 748 (C–Cl). 1H NMR (CDCl3, 400 MHz):δ = 1.17 (t, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.14 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 5.10 (s, 2H, –NH2), 6.91–7.82 (m, 8H, Ar-H), 7.40–8.31 (m, 3H, Pyridine-H), 7.83 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.7 (C8), 25.7 (C7), 38.5 (C9), 67.4 (C10), 103.7 (C22), 114.2–154.1 (C11–C16), 123.9–161.0 (C2–C6), 128.9–134.5 (C24–C29), 160.5 (C21), 163.4 (C17), 164.1 (C19), Anal. calcd for C25H23N4OCl: C69.68, H5.38, N13.00. Found C69.63, H5.34, N12.98.
2.3.13 5-Ethyl-2-{[4-(6-(3-methoxyphenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5m)
m.p. 98–111 °C. Yield 54% Rf: 0.44. IR (KBr): t = 3356, 3225 (–NH2), 3066 (Ar-H), 2956, 2838 (–CH2–), 1609 (–C⚌N), 1220, 1033 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.53 (q, 2H, –CH2) 3.17 (t, 2H, –CH2), 3.82 (s, 3H, –OCH3), 5.22 (s, 2H, –NH2), 4.34 (t, 2H, –CH2–O), 6.90–7.85 (m, 8H, Ar-H), 7.40–8.33 (m, 3H, Pyridine-H), 7.85 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C8), 25.6 (C7), 38.5 (C9), 55.7 (C30), 67.8 (C10), 103.2 (C22), 113.9–154.5 (C11–C16), 114.9–160.0 (C24–C29), 123.1–160.5 (C2–C6), 160.1 (C21), 163.2 (C17), 164.3 (C19). Anal. calcd for C26H26N4O2: C73.22, H6.14, N13.14. Found C73.18, H6.10, N13.10.
2.3.14 5-Ethyl-2-{[4-(6-(3-fluorophenyl)-2-aminopyrimidin-4-yl)]phenoxyethyl} pyridine (5n)
m.p. 95–100 °C. Yield 72%. Rf: 0.43. IR (KBr): t = 3352, 3225 (–NH2), 3065 (Ar-H), 2957, 2838 (–CH2–), 1601 (–C⚌N), 1218, 1029 (C–O–C), 976 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.52 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 5.14 (s, 2H, –NH2), 6.88–7.84 (m, 8H, Ar-H), 7.40–8.32 (m, 3H, Pyridine-H), 7.84 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 25.4 (C7), 38.3 (C9), 67.4 (C10), 103.5 (C22), 114.1–154.3 (C11–C16), 115.5–163.5 (C24–C29), 123.8–161.8 (C2–C6), 160.7 (C21), 163.0 (C17), 164.3 (C19), Anal. calcd for C25H23N4OF: C72.45, H5.59, N13.52. Found C72.40, H5.54, N13.49.
2.3.15 5-Ethyl-2-{[4-(6-(3,4-difluorophenyl)-2-aminopyrimidine-4-yl)]phenoxyethyl} pyridine (5o)
m.p. 115–118 °C. Yield 74%. Rf: 0.44. IR (KBr): t = 3357, 3218 (–NH2), 3062 (Ar-H), 2957, 2832 (–CH2–), 1602 (–C⚌N), 1225, 1034 (C–O–C), 975 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.17(t, 2H, –CH2), 4.34 (t, 2H, –CH2–O), 5.20 (s, 2H, –NH2), 6.89–7.85 (m, 8H, Ar-H), 7.39–8.33 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H); 13C NMR (100 MHz, CDCl3): δ = 14.6 (C8), 25.9 (C7), 37.9 (C9), 68.0 (C10), 102.9 (C22), 114.0–154.1 (C11–C16), 115.0–149.5 (C24–C29), 123.6–160.9 (C2–C6), 160.6 (C21), 162.9 (C17), 163.5 (C19). Anal. calcd for C25H22N4OF2: C69.43, H5.13, N12.96. Found C69.38, H5.06, N12.92.
2.4 General preparation of the compounds 6a–o
A solution of the 5a–o (0.01 mol) and the appropriate benzoyl chloride (0.02 mol) in pyridine (10 mL) was heated under reflux for 6–8 h and continued till the reaction completed. The progress of reaction was monitored by TLC (tolune:ethyl acetate, 7.5:2.5). After completion of the reaction, the mass was dumped into ice cold water; the solid obtained was filtered, washed with cold water until neutral pH and dried and recrystallized from ethanol Fig. 3.
Benzamido pyrimidines 6a–o.
2.4.1 5-Ethyl-2-{[4-(6-(2,4-dichloro-5-fluorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]pheno-xyethyl} pyridine (6a)
m.p. 135–137 °C. Yield 67%. Rf: 0.61. IR (KBr): t = 3064 (Ar-H), 2957, 2832 (–CH2–), 1610 (–C⚌N), 1225, 1033 (C–O–C), 1674 (Amide-1), 1533 (Amide-2), 1246 (Amide-3), 975 (C–F), 747 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.32 (s, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.15 (t, 2H, –CH2), 4.35 (t, 2H, –CH2–O), 7.05–8.14 (m, 11H, Ar-H), 7.32–8.32 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H), 9.32 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.7 (C8), 21.5 (C37), 25.8 (C7), 37.6 (C9), 67.3 (C10), 103.7 (C22), 115.3–155.6 (C11–C16), 123.3–160.6 (C2–C6), 127.2–144.6 (C24–C35), 161.4 (C21), 161.0 (C19), 163.2 (C17), 165.1 (C36), Anal. calcd for C32H23N4O2Cl4F: C58.56, H3.53, N8.54. Found C58.56, H3.53, N8.54.
2.4.2 5-Ethyl-2-{[4-(6-(4-methoxyphenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)] phenoxyethyl}pyridine (6b)
m.p. 70–72 °C. Yield 63%. Rf: 0.63. IR (KBr): t = 3063 (Ar-H), 2956, 2838 (–CH2–), 1612 (–C⚌N), 1675 (Amide-1), 1534 (Amide-2), 1245 (Amide-3) 1226, 1038 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.29 (s, 3H, –CH3), 2.50 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 7.03–8.14 (m, 11H, Ar-H), 7.33–8.31 (m, 3H, Pyridine-H), 7.82 (s, 1H, Pyrimidine-H), 9.31 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C8), 21.8 (C37), 25.5 (C7), 37.4 (C9), 67.4 (C10), 103.7 (C22), 115.3–155.2 (C11–C16), 123.8–161.0 (C2–C6), 127.0–144.6 (C24–C35), 161.3 (C21), 161.7 (C19), 163.4 (C17), 165.5 (C36), Anal. calcd for C33H28N4O3Cl2: C66.11, H4.71, N9.35. Found C66.09, H4.73, N9.35.
2.4.3 5-Ethyl-2-{[4-(6-(2,4-dichlorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)] phenoxyethyl} pyridine (6c)
m.p. 112–115 °C. Yield 65%. Rf: 0.64. IR (KBr): t = 3061 (Ar-H), 2954, 2833 (–CH2–), 1677 (Amide-1), 1604 (–C⚌N), 1535 (Amide-2), 1246 (Amide-3), 1224, 1036 (C–O–C), 746 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.17 (t, 3H, –CH3), 2.34 (s, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.32 (t, 2H, –CH2–O), 7.00–8.10 (m, 11H, Ar-H), 7.33–8.33 (m, 3H, Pyridine-H), 7.82 (s, 1H, Pyrimidine-H), 9.30 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.4 (C8), 21.5 (C37), 25.4 (C7), 37.6 (C9), 67.8 (C10), 103.3 (C22), 115.2–155.0 (C11–C16), 123.0–160.4 (C2–C6), 127.4–144.0 (C24–C35), 161.2 (C21), 161.4 (C19), 163.3 (C17), 165.6 (C36). Anal. calcd for C32H24 N4O2Cl4: C60.21, H3.79, N8.78. Found C60.22, H3.73, N8.78.
2.4.4 5-Ethyl-2-{[4-(6-(4-hydroxyphenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6d)
m.p. 116–118 °C. Yield, 61%. Rf: 0.59. IR (KBr): t = 3367 (–OH), 3057 (Ar-H), 2953, 2835 (–CH2–), 1671 (amide-1), 1604 (–C⚌N), 1534 (amide-2), 1245 (amide-3), 1223, 1034 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.15 (t, 3H, –CH3), 2.33 (s, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.17(t, 2H, –CH2), 4.34 (t, 2H, –CH2–O), 7.08–8.20 (m, 11H, Ar-H), 7.33–8.32(m, 3H, Pyridine-H), 7.83 (s, 1H, Pyrimidine-H), 9.33 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C8), 21.7 (C37), 25.6 (C7), 37.5 (C9), 67.5 (C10), 103.4 (C22), 115.2–155.6 (C11–C16), 123.5–160.9 (C2–C6), 127.5–144.1 (C24–C35), 161.4 (C21), 161.6 (C19), 163.1 (C17), 165.7 (C36). Anal. calcd for C32H26N4O3Cl2: C65.65, H4.48, N9.57. Found C65.62, H4.43, N9.55.
2.4.5 5-Ethyl-2-{[4-(6-(2,6-chloro-5-fluorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]pheno-xyethyl} pyridine (6e)
m.p. 122–124. Yield, 69%. Rf: 0.64. IR (KBr): t = 3063 (Ar-H), 2955, 2836 (–CH2–), 1676 (Amide-1), 1610 (–C⚌N), 1533 (Amide-2), 1245 (Amide-3), 1217, 1036 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.28 (s, 3H, –CH3), 2.57 (q, 2H, –CH2), 3.20 (t, 2H, –CH2), 4.35 (t, 2H, –CH2–O), 7.09–8.09 (m, 11H, Ar-H), 7.34–8.32 (m, 3H, Pyridine-H), 7.80 (s, 1H, Pyrimidine-H), 9.33 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.6 (C8), 21.6 (C37), 25.8 (C7), 37.7 (C9), 67.9 (C10), 103.7 (C22), 115.2–155.1 (C11–C16), 123.7–160.8 (C2–C6), 127.6–144.6 (C24–C35), 161.0 (C21), 161.5 (C19), 163.4 (C17), 165.4 (C36). Anal. calcd for C32H23N4O2Cl4F: C58.56, H3.53, N8.54. Found C58.53, H3.50, N8.55.
2.4.6 5-Ethyl-2-{[4-(6-(4-methylphenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6f)
m.p. 132–134 °C. Yield 71%. Rf: 0.67. IR (KBr): t = 3063 (Ar-H), 2954, 2832 (–CH2–), 1672 (Amide-1), 1614 (–C⚌N), 1537 (Amide-2), 1250 (Amide-3), 1222, 1031 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.16 (t, 3H, –CH3), 2.30 (s, 3H, –CH3), 2.53 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.30 (t, 2H, –CH2–O), 7.05–8.16 (m, 11H, Ar-H), 7.34–8.30 (m, 3H, Pyridine-H), 7.84 (s, 1H, Pyrimidine-H), 9.30 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.5 (C8), 21.7 (C37), 25.6 (C7), 37.5 (C9), 67.6 (C10), 103.5 (C22), 115.0–155.4 (C11–C16), 123.3–160.8 (C2–C6), 127.5–144.4 (C24–C35), 161.0 (C21), 161.5 (C19), 163.5 (C17), 165.3 (C36), Anal. calcd for C33H28N4O2Cl2: C67.93, H4.84, N9.60. Found C67.90, H4.83, N9.58.
2.4.7 5-Ethyl-2-{[4-(6-(1-phenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxyethyl} pyridine (6g)
m.p. 128–130 °C. Yield 65%. Rf: 0.64. IR (KBr): t = 3063 (Ar-H), 2954, 2835 (–CH2–), 1677 (Amide-1), 1606 (–C⚌N), 1534 (Amide-2), 1245 (Amide-3), 1223, 1033 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.17 (t, 3H, –CH3), 2.35 (s, 3H, –CH3), 2.51 (q, 2H, –CH2), 3.18 (t, 2H, –CH2), 4.35 (t, 2H, –CH2–O), 7.00–8.18 (m, 11H, Ar-H), 7.35–8.31 (m, 3H, Pyridine-H), 7.83 (s, 1H, Pyrimidine-H), 9.33 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.8 (C8), 21.4 (C37), 25.9 (C7), 37.3 (C9), 67.9 (C10), 103.4 (C22), 115.3–155.7 (C11–C16), 123.0–160.5 (C2–C6), 127.1–144.0 (C24–C35), 161.2 (C21), 161.2 (C19), 163.6 (C17), 165.4 (C36), Anal. calcd for C32H26N4O2Cl2: C67.49, H4.60, N9.84. Found C67.45, H4.63, N9.82.
2.4.8 5-Ethyl-2-{[4-(6-(4-fluorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6h)
m.p. 190–192 °C. Yield 63%. Rf: 0.68. IR (KBr): t = 3066 (Ar-H), 2956, 2838 (–CH2–), 1677 (Amide-1), 1608 (–C⚌N), 1533 (Amide-2), 1250 (Amide-3), 1220, 1034 (C–O–C), 974 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.13(t, 3H, –CH3), 2.32 (s, 3H, –CH3), 2.52 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.34 (t, 2H, –CH2–O), 7.10–8.12 (m, 11H, Ar-H), 7.34–8.34 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H), 9.36 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.3 (C8), 21.5 (C37), 25.4 (C7), 37.2 (C9), 67.5 (C10), 103.8 (C22), 115.2–155.8 (C11–C16), 123.9–161.3 (C2–C6), 127.9–145.4 (C24–C35), 161.4 (C21), 162.0 (C19), 163.9 (C17), 166.0 (C36), Anal. calcd for C32H25N4O2Cl2F: C65.42, H4.29, N9.54. Found C65.43, H4.25, N9.53.
2.4.9 5-Ethyl-2-{[4-(6-(2,4-fluorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6i)
m.p. 98–100 °C. Yield, 71%. Rf: 0.62. IR (KBr): t = 3062 (Ar-H), 2952, 2836 (–CH2–), 1676 (Amide-1), 1612 (–C⚌N), 1536 (Amide-2), 1247 (Amide-3), 1224, 1034 (C–O–C), 976 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.14 (t, 3H, –CH3), 2.34 (s, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.15 (t, 2H, –CH2), 4.31 (t, 2H, –CH2–O), 7.07–8.12 (m, 11H, Ar-H), 7.36–8.36 (m, 3H, Pyridine-H), 7.87 (s, 1H, Pyrimidine-H), 9.40 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C8), 21.5 (C37), 25.3 (C7), 37.2 (C9), 67.0 (C10), 103.8 (C22), 115.0–156.1 (C11–C16), 123.8–160.2 (C2–C6), 127.5–144.8 (C24–C35), 161.3 (C21), 161.2 (C19), 163.6 (C17), 165.1 (C36), Anal. calcd for C32H24N4O2Cl2F2: C63.48, H4.00, N9.25. Found C63.45, H4.01, N9.23.
2.4.10 5-Ethyl-2-{[4-(6-(4-bromophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6j)
m.p. 183–184 °C. Yield, 66%. Rf: 0.68. IR (KBr): t = 3065 (Ar-H), 2956, 2837(–CH2–), 1673 (Amide-1), 1604 (–C⚌N), 1536 (Amide-2), 1246 (Amide-3), 1222, 1037 (C–O–C), 858 (C–Br). 1H NMR (CDCl3, 400 MHz): δ = 11.20 (t, 3H, –CH3), 2.38 (s, 3H, –CH3), 2.50 (q, 2H, –CH2), 3.19 (t, 2H, –CH2), 4.38 (t, 2H, –CH2–O), 7.15–8.20 (m, 11H, Ar-H), 7.37–8.36 (m, 3H, Pyridine-H), 7.82 (s, 1H, Pyrimidine-H), 9.32 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.7 (C8), 21.6 (C37), 25.4 (C7), 37.4 (C9), 67.2 (C10), 104.0 (C22), 115.8–155.7 (C11–C16), 123.3–161.8 (C2–C6), 127.8–144.2 (C24–C35), 161.4 (C21), 161.2 (C19), 163.0 (C17), 165.6 (C36). Anal. calcd for C32H25N4O2Cl2Br: C59.28, H3.89, N8.64. Found C59.21, H3.84, N8.60.
2.4.11 5-Ethyl-2-{[4-(6-(3,4-dichlorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6k)
m.p. 150–151 °C. Yield 59%. Rf: 0.62. IR (KBr): t = 3068 (Ar-H), 2954, 2839 (–CH2–), 1675 (Amide-1), 1606 (–C⚌N), 1535 (Amide-2), 1246 (Amide-3), 1227, 1034 (C–O–C), 750 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.19 (t, 3H, –CH3), 2.33 (s, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.14 (t, 2H, –CH2), 4.34 (t, 2H, –CH2–O), 7.10–8.10 (m, 11H, Ar-H), 7.32–8.28 (m, 3H, Pyridine-H), 7.80 (s, 1H, Pyrimidine-H), 9.34 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.1 (C8), 21.5 (C37), 25.8 (C7), 37.8 (C9), 67.6 (C10), 103.7 (C22), 115.3–155.6 (C11–C16), 123.8–160.6 (C2–C6), 127.5–145.0 (C24–C35), 161.3 (C21), 161.4 (C19), 163.8 (C17), 165.3 (C36). Anal. calcd for C32H24N4O2Cl4: C60.21, H3.79, N8.78. Found C60.26, H3.74, N8.71.
2.4.12 5-Ethyl-2-{[4-(6-(4-chlorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6l)
m.p. 163–165 °C. Yield 62%. Rf: 0.64. IR (KBr): t = 3063 (Ar-H), 2955, 2834 (–CH2–), 1672 (Amide-1), 1611 (–C⚌N), 1533 (Amide-2), 1243 (Amide-3), 1224, 1036 (C–O–C), 745 (C–Cl). 1H NMR (CDCl3, 400 MHz): δ = 1.19 (t, 3H, –CH3), 2.33 (s, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.14 (t, 2H, –CH2), 4.34 (t, 2H, –CH2–O), 7.10–8.10 (m, 11H, Ar-H), 7.32–8.28 (m, 3H, Pyridine-H), 7.80 (s, 1H, Pyrimidine-H), 9.34 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.1 (C8), 21.5 (C37), 25.8 (C7), 37.8 (C9), 67.6 (C10), 103.7 (C22), 115.3–155.6 (C11–C16), 123.8–160.6 (C2–C6), 127.5–145.0 (C24–C35), 161.3 (C21), 161.4 (C19), 163.8 (C17), 165.3 (C36), Anal. calcd for C32H25N4O2Cl3: C63.64, H4.17, N9.28. Found C63.60, H4.15, N9.25.
2.4.13 5-Ethyl-2-{[4-(6-(3-methoxyphenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6m)
m.p. 95–96 °C. Yield 67%, Rf: 0.66. IR (KBr): t = 3064 (Ar-H), 2956, 2836 (–CH2–), 1673 (Amide-1), 1605 (–C⚌N), 1536 (Amide-2), 1244 (Amide-3) 1221, 1034 (C–O–C). 1H NMR (CDCl3, 400 MHz): δ = 1.13 (t, 3H, –CH3), 2.30 (s, 3H, –CH3), 2.54 (q, 2H, –CH2), 3.16 (t, 2H, –CH2), 4.31 (t, 2H, –CH2–O), 7.05–8.17 (m, 11H, Ar-H), 7.34–8.33 (m, 3H, Pyridine-H), 7.85 (s, 1H, Pyrimidine-H), 9.31 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C8), 25.6 (C7), 38.5 (C9), 55.7 (C30), 67.8 (C10), 103.2 (C22), 113.9–154.5 (C11–C16), 114.9–160.0 (C24–C29), 123.1–160.5 (C2–C6), 160.1 (C21), 163.2 (C17), 164.3 (C19), Anal. calcd for C33H28N4O3Cl2: C66.11, H4.71, N9.35; found C66.08, H4.70, N9.34.
2.4.14 5-Ethyl-2-{[4-(6-(3-fluorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6n)
m.p. 98–100 °C. Yield 65%, Rf: 0.61. IR (KBr): t = 3066 (Ar-H), 2954, 2836 (–CH2–), 1675 (Amide-1), 1606 (–C⚌N), 1536 (Amide-2), 1245 (Amide-3), 1224, 1036 (C–O–C), 977 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.21(t, 3H, –CH3), 2.32 (s, 3H, –CH3), 2.56(q, 2H, –CH2), 3.18(t, 2H, –CH2), 4.35(t, 2H, –CH2–O), 7.12–8.20 (m, 11H, Ar-H), 7.35–8.32 (m, 3H, Pyridine-H), 7.86 (s, 1H, Pyrimidine-H), 9.32 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.6 (C8), 21.4 (C37), 25.9 (C7), 37.4 (C9), 67.3 (C10), 103.7 (C22), 115.3–155.4 (C11–C16), 123.6–160.5 (C2–C6), 127.8–144.2 (C24–C35), 161.4 (C21), 161.4 (C19), 163.2 (C17), 165.2 (C36), Anal. calcd for C32H25N4O2Cl2F: C65.42, H4.29, N9.54. Found C65.44, H4.26, N9.53.
2.4.15 5-Ethyl-2-{[4-(6-(3,4-fluorophenyl)-2-(3,4-dichlorobenzamidopyrimidin-4-yl)]phenoxy ethyl} pyridine (6o)
m.p. 178–180 °C. Yield 67%, Rf: 0.65. IR (KBr): t = 3065 (Ar-H), 2953, 2835 (–CH2–), 1676 (Amide-1), 1610 (–C⚌N), 1533 (Amide-2), 1246 (Amide-3), 1221, 1032 (C–O–C), 974 (C–F). 1H NMR (CDCl3, 400 MHz): δ = 1.19 (t, 3H, –CH3), 2.35 (s, 3H, –CH3), 2.55 (q, 2H, –CH2), 3.17 (t, 2H, –CH2), 4.33 (t, 2H, –CH2–O), 7.11–8.16 (m, 11H, Ar-H), 7.34–8.31 (m, 3H, Pyridine-H), 7.87 (s, 1H, Pyrimidine-H), 9.34 (s, 1H –NHCO); 13C NMR (100 MHz, CDCl3): δ = 15.2 (C8), 21.5 (C37), 25.5 (C7), 37.3 (C9), 67.3 (C10), 103.3 (C22), 115.2–155.0 (C11–C16), 123.7–160.6 (C2–C6), 127.2–144.7 (C24–C35), 161.5 (C21), 161.4(C19), 163.5(C17), 165.5(C36), Anal. calcd for C32H24N4O2Cl2F2: C63.48, H4.00, N9.25. Found C63.42, H4.02, N9.24.
3 Results and discussion
3.1 Chemistry
The synthesis of chalcones, pyrimidines and amide derivatives is outlined in Scheme 1. First the chalcones (4a–o) were prepared from 5-ethyl-2-[4-(carboxalehyde)phenoxyethyl]pyridine with different substituted aromatic acetophenones in diluted methanolic sodium hydroxide solution at room temperature. The compounds (5a–o) were synthesized from different chalcones with guanidine nitrate and sodium hydroxide in methanol. The compounds (6a–o) were prepared from different pyrimidines and 3,4-dichloro benzoyl chloride. The purity of the compounds was determined by TLC and elemental analysis and all the synthesized heterocycles were confirmed by 1H NMR, 13C NMR and IR spectra.
Synthesis of the compounds 4a–o, 5a–o and 6a–o. Reagents and conditions: (A) methane sulphonyl chloride, toluene, triethylamine; (B) 4-hydroxy benzaldehyde, ethanol, NaOH; (C) substituted acetophenone, methanol, 2% NaOH; (D) guanidine nitrate, sodium ethoxide, Ethanol; (E) 3,4-dichloro benzoyl choride, pyridine.
From the IR sharp band was observed at 1662 cm−1 for –C⚌O and at 1599 cm−1 for –CH⚌CH– of chalcones 4a–o. The 1H NMR spectra exhibited one doublet at δ 7.11 attributed to the ⚌CH–CO– protons. In the 13C NMR spectra of chalcones, –CH⚌CH– carbon appeared at the δ 144.2 and 119.7 ppm, respectively. The higher field resonances at δ 190.0 ppm were attributed to the carbonyl group present in chalcone. The structures of compounds 5a–o and 6a–o were also established by using IR and NMR spectroscopy. The IR of pyrimidine, disappearance of –C⚌O band at 1662 cm−1 and appearance of asymmetric and symmetric new broad bands at 3355 cm−1 and 3220 cm−1 for –NH2, respectively. A new signal was observed at δ 5.15 and δ 7.85 for the –NH2 and –CH in pyrimidine ring, respectively. From the 13C NMR, pyrimidine –CH carbon appeared at δ 103.2. The three bands were observed at 1672 cm−1, 1537 cm−1 and 1250 cm−1 of amide –C⚌O, –NH– and C–N, respectively. Similarly the disappearance of NH2 and the appearance of a signal at δ 9.25 due to –NHCO provided further evidence for the conversion of compound 5–6 and also 13C NMR spectra showing the amide signal at δ 165.3 ppm confirmed this.
On the basis of the above-mentioned spectral data, compounds 4a–o, 5a–o and 6a–o were confirmed.
3.2 Antimicrobial activity
The MICs of synthesized compounds were carried out by broth micro dilution method as described by Rattan (2000).
3.3 Antibacterial activity
The minimal bactericidal concentrations (MBCs) of the tested compounds are shown in Table 1. The different compounds 4a–o, 5a–o and 6a–o were tested in vitro against two gram-positive (S. aureus MTCC 96, S. pyogenus MTCC 443) and two-gram negative (E. coli MTCC 442, P. aeruginosa MTCC 441) bacteria. From the screening data, most of the compounds possessed very good antibacterial activity (MBC, 50–250 μg/ml) against S. aureus; some of them showed excellent activity with ampicillin. Chalcones 4b (4-OCH3), 4f (4-CH3) and 4h (4-F) showed MBC in the range between 62.5 and 100 μg/ml while ampicillin has MBC 100 μg/ml against E. coli which indicates that these compounds have excellent activity, while other chalcones 4c (2,4-Cl), 4d (4-OH) and 4o (3,4-F) possessed MBC 125–150 μg/ml against E. coli and 4h (4-F) exhibited very good activity against P. aeruginosa. Compounds 4f (4-CH3) and 4h (4-F) displayed excellent activity in the range of 100–150 μg/ml while remaining 4b (4-OCH3), 4d (4-OH) and 4n (3-F) were comparable against S. aureus with ampicillin. Compound 4h (4-F) has MBC 150 μg/ml which was comparatively good against S. pyogenus. The remaining chalcones possessed moderate to poor activity against all four bacterial species. For pyrimidines, 5b (4-OCH3) possessed MBC 62.5 μg/ml against E. coli and MBC 150 μg/ml against P. aeruginosa comparable with ampicillin. Compound 5e (2,6-Cl,5-F) exhibited MBC 150 μg/ml against P. aeruginosa. Compound 5h (4-F) possessed MBC 100 μg/ml against S. aureus and S. pyogeneus. Compound 5i (2,4-F) possessed MBC 62.5 μg/ml against E. coli and MBC 150 μg/ml against S. aureus and showed good activity as that of ampicillin. Compound 5l (4-Cl) showed MBC 100 μg/ml against P. aeruginosa and MBC 150 μg/ml against S. aureus. Other pyrimidines displayed moderate to poor activities against all four bacterial species. Amides 6i (2,4-F) and 6j (4-Br) showed MBC 100 μg/ml against E. coli which is same as ampicillin. Compound 6b (4-OCH3) showed MBC 100 μg/ml against P. aeruginosa; comparable with ampicillin. Compounds 6a (2,4-Cl, 5-F), 6b (4-OCH3) and 6i (2,4-F) showed MBC 100–150 μg/ml against S. aureus while ampicillin itself showed MBC 250 μg/ml which indicates that these compounds are highly active. Compound 6i (2,4-F) showed MBC 100–150 μg/ml against S. pyogeneus. Remaining amides possessed moderate to poor activities against all four bacterial species.
Comp.
R
Minimal bactericidal concentration μg/ml
Minimal fungicidal concentration μg/ml
Gram negative
Gram positive
E. coli
P. aeruginosa
S. aureus
S. pyogenus
C. albicans
A. niger
A. clavatus
4a
2,4-Cl,5-F
200
250
1000
1000
1000
500
500
4b
4-OCH3
100
150
250
250
1000
1000
1000
4c
2,4-Cl
150
500
500
500
500
500
1000
4d
4-OH
150
200
250
250
500
500
1000
4e
2,6-Cl,5-F
500
250
500
1000
1000
500
500
4f
4-CH3
100
150
100
250
1000
1000
1000
4g
H
500
1000
1000
1000
200
500
500
4h
4-F
62.5
100
150
150
250
>1000
>1000
4i
2,4-F
250
250
500
500
1000
1000
1000
4j
4-Br
500
500
500
250
1000
>1000
>1000
4k
3,4-Cl
500
500
1000
1000
1000
>1000
>1000
4l
4-Cl
500
250
500
250
1000
500
500
4m
3-OCH3
500
500
1000
1000
500
500
500
4n
3-F
250
500
250
500
500
1000
1000
4o
3,4-F
125
250
500
500
1000
1000
1000
5a
2,4-Cl,5-F
150
250
500
500
500
500
1000
5b
4-OCH3
62.5
150
250
250
500
>1000
>1000
5c
2,4-Cl
500
500
250
500
500
>1000
>1000
5d
4-OH
250
200
500
500
500
500
1000
5e
2,6-Cl,5-F
250
150
1000
1000
500
500
500
5f
4-CH3
200
200
250
250
500
500
500
5g
H
250
250
500
500
500
500
500
5h
4-F
250
250
100
100
500
250
250
5i
2,4-F
62.5
150
150
200
500
1000
1000
5j
4-Br
250
250
200
200
1000
1000
1000
5k
3,4-Cl
250
250
250
250
1000
500
500
5l
4-Cl
250
100
150
250
500
500
500
5m
3-OCH3
250
250
500
500
1000
500
500
5n
3-F
500
500
250
250
500
1000
1000
5o
3,4-F
250
500
500
250
200
200
200
6a
2,4-Cl,5-F
250
500
150
250
500
500
500
6b
4-OCH3
250
100
150
150
1000
500
500
6c
2,4-Cl
500
250
250
250
1000
>1000
>1000
6d
4-OH
250
200
500
500
500
500
500
6e
2,6-Cl,5-F
250
250
500
250
500
>1000
>1000
6f
4-CH3
200
250
250
500
100
200
200
6g
H
500
1000
500
500
1000
500
500
6h
4-F
150
200
500
500
500
1000
1000
6i
2,4-F
100
250
100
100
500
500
500
6j
4-Br
100
500
500
500
1000
>1000
>1000
6k
3,4-Cl
500
250
500
500
100
100
100
6l
4-Cl
250
250
250
500
1000
500
500
6m
3-OCH3
500
500
1000
1000
1000
1000
1000
6n
3-F
500
500
1000
500
500
1000
1000
6o
3,4-F
250
500
250
250
>1000
>1000
>1000
Gentamycin
0.05
1
0.25
0.5
–
–
–
Ampicillin
100
100
250
100
–
–
–
Chloroamphenicol
50
50
50
50
–
–
–
Ciprofloxacin
25
25
50
50
–
–
–
Norfloxacin
10
10
10
10
–
–
–
Nystatin
–
–
–
–
100
100
100
Greseofulvin
–
–
–
–
500
100
100
3.4 Antifungal activity
Minimal fungicidal concentrations (MFCs) of the synthesized compounds are shown in Table 1. For in vitro antifungal activity, three fungal species C. albicans MTCC 227, A. niger MTCC 282 and A. clavatus MTCC 1323 were used and compared with the standard drug greseofulvin. Chalcones 4g (–H) and 4h (4-F) showed excellent activity of 200–250 μg/ml; 4c (2,4-Cl), 4d (4-OH), 4m (3-OCH3) and 4n (3-F) possessed very good activity of 500 μg/ml with greseofulvin (500 μg/ml) against C. albicans whereas chalcones possessed moderate to poor activity against A. niger and A. clavatus. Pyrimidines 5o (3,4-F) possessed good activity of 200 μg/ml against C. albicans, which is comparable with greseofulvin (500 μg/ml). Amides 6f (4-CH3) and 6k (3,4-Cl) displayed excellent activity of 100 μg/ml against C. albicans and comparable with greseofulvin and nystatin. Compound 6k (3,4-Cl) possessed very good activity of 100 μg/ml against A. niger and A. clavatus. From the antifungal results it can be concluded that compound 6k (3,4-Cl) is very active like the standard drugs.
4 Conclusions
Chalcones 4b, 4f and 4h are found to be excellent against all bacteria; where as pyrimidines 5b and 5i are very effective and comparable with the standard drug. Amides 6i, 6j, 6b and 6a are more active and are comparable with the standard drugs.
Antifungal activities of chalcones 4g and 4h are more effective against all three fungal species. For pyrimidines, 5o was found comparable against C. albicans, while amides 6f and 6k are more effective against three fungal species. These results make new chalcone, pyrimidine and amide derivatives interesting for further synthetic and biological evaluation.
Acknowledgements
The authors thank the Professor and Head, Department of Chemistry for laboratory facilities, Dhanji Rajani, Microcare Laboratory, Surat, for antimicrobial activity; Atul Ltd. for IR spectra; C.D.R.I., Lucknow for elemental analysis and S.A.I.F., Chandigarh for 1H NMR and 13C NMR spectral analyses.
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