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Indian Journal of Pharmaceutical Sciences logoLink to Indian Journal of Pharmaceutical Sciences
. 2010 Sep-Oct;72(5):613–620. doi: 10.4103/0250-474X.78531

Synthesis and Antibacterial and Antifungal Studies of Novel Nitrogen Containing Heterocycles from 5-Ethylpyridin-2-ethanol

N B Patel 1,*, H R Patel 1
PMCID: PMC3116307  PMID: 21694994

Abstract

A novel series of chalcones, pyrimidines and imidazolinone is described; chalcones (4a-o) were prepared from the lead molecule 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde. Pyrimidine (5a-o) derivatives were prepared from the reaction of chalcones and guanidine nitrate in alkali media. Imidazolinones (6a-o) were synthesized from reaction of pyrimidine and oxazolone derivatives (prepared by Erlenmeyer azlactone synthesis). The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, 1H and 13C NMR spectral data. All the products were screened against different strains of bacteria and fungi. Most of these compounds showed better inhibitory activity in comparison to the standard drugs.

Keywords: Antibacterial, antifungal, chalcone, imidazolinone, pyrimidine

Chalcones, both natural or synthetic have been reported to exert a variety of biological activities such as antifungal[1], antibacterial[1,2], antimalarial[3,4], antiinflammatory[5], and anticancer[6]. Antimicrobial activity of these chalcones is attributed to the presence of a reactive α,β-unsaturated keto function that can be altered depending on the type and position of substituent on the aromatic rings. Pyrimidines, which are important constituents of nucleic acids, are of great importance due to their role in the current chemotherapy of AIDS. Derivatives of pyrimidines are of interest due to their antiHIV[7], antimalarial[8], analgesic[9], and antiinflammatory[10], activities.

The basic imidazole nucleus, present in azlactone containing oxazolone moiety, is of great importance for generating penicillin type of drug intermediates and synthetic hormonal compounds. Imidazolones or ketodihydroimidazoles are also known as oxoimidazolines contain a five- membered heterocyclic ring system with nitrogen atoms at positions 1 and 3 and carbonyl group at position 5. Oxoimidazolines have been reported to exhibit antibacterial[11,12], antifungal[13] and antimicrobial activites[14–17]. Imidazolinones have also been reported to possess fungicidal[18,19], herbicidal[19], and vasodilator activities[20].

Recently we have prepared chalcone, pyrimidine and amide derivatives and reported their antibacterial and antifungal activities[21–23]. All these observations and the essential role of heterocyclic chalcone, pyrimidine and imidazolinone derivatives in certain biological importance prompted us to synthesize these compounds for their antimicrobial activity.

MATERIALS AND METHODS

Laboratory chemicals were supplied by Rankem India Ltd. and Fisher Scientific Ltd. Melting points were determined using the open tube capillary method and were uncorrected. Purity of the compounds was determined by thin layer chromatography (TLC) plates (silica gel G) in the solvent system toluene:ethyl acetate (75:25). 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 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 were carried out on Carlo Erba 1108 analyzer.

Procedure for the synthesis of 4-[2-(5-ethylpyridin-2-yl)ethoxy]benzaldehyde (3):

4-[2-(5-Ethylpyridin-2-yl)ethoxy]benzaldehyde (3) was synthesized by the method described in the literature[24,25]. Chalcones and pyrimidines were synthesized and characterized by the reported method[21–23].

General Process of oxazol-5(4H)-one (Erlenmeyer azlactone synthesis) (C):

A mixture of p-fluoro benzaldehyde (0.33 mol), hippuric acid (0.33 mol) and potassium acetate (0.33 mol) in acetic anhydride (0.83 mol) was refluxed with stirring for 15 min (reaction progress was monitored by TLC using (3:1 isohexane-ethyl acetate as eluent). The mixture was then cooled down and neutralised by addition of solid potassium carbonate. The solid product was separated by filtration, dried and purified by crystallization. The synthetic route has been shown in scheme 1.

Scheme 1.

Scheme 1

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Synthetic protocol of oxazol-5(4H)-one (Erlenmeyer azlactone synthesis) (C)

General preparation of the compounds 6a-o:

A mixture of 5a-o (0.01 mol) and an appropriate oxazolone (0.01 mol) in 50 ml acetic acid was refluxed for 6-8 h (reaction progress was monitored by TLC using 7.5:2.5 toluene-ethyl acetate as eluent). After completion of reaction; cooled and was poured into ice cold water. The precipitate was filtered and washed with water till pH neutral. The raw product was crystallized from ethanol. The synthetic route is shown in scheme 2. and general structure of 6a-o is represented in fig. 1.

Scheme 2.

Scheme 2

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Synthetic protocol of 4a-o, 5a-o amd 6a-o

Fig. 1.

Fig. 1

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General structures of imidazolinones 6a-o

1-(4-(2,4-dichloro-5-fluorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6a):

Brown solid, m.p. 110-112°, yield 56%, Rf: 0.60; IR (KBr, cm-1) ν: 3062 (Ar-H), 2953, 2833 (-CH 2- ), 1795 (-C=O of imidazolinone), 1654 (-C=N imidazolinone), 1612 (-C=N of pyrimidine), 1222, 1036 (C-O-C), 972 (C-F), 743 (C-Cl).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.17 (t, 3H, -CH3), 2.35(s, 3H, -CH3), 2.51 (q, 2H, -CH2), 3.22 (t, 2H, -CH2), 4.33 (t, 2H, -CH2-O), 7.05-7.55 (m, 16H, Ar-H), 7.31 (s, 1H, -CH), 7.39-8.30 (m, 3H, pyridine-H), 7.81 (s, 1H, pyrimidine-H). 13C NMR (100 MHz, CDCl3) δ(ppm): 170.4(C31), 165.3(C19), 164.5(C34), 163.1(C17), 161.0(C21), 126.3-135.5 (C36-C41), 126.3-130.5 (C42-C47), 122.0-157.3 (C2-C6), 118.7-161.4 (C23-C28), 115.0-157.3 (C11-C16), 108.5 (C35), 103.3 (C22), 67.2 (C10), 37.3 (C9), 25.4 (C7), 15.3 (C8). Anal. calcd for C41H29N5O2Cl2F2: C 67.22, H 3.99, N 9.56; found C 67.20, H 3.95, N 9.54.

1-(4-(4-methoxyphenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6b):

Pale yellow solid, m.p. 109-113°, yield 60%, Rf: 0.62; IR (KBr, cm-1) ν: 3064 (Ar-H), 2950, 2832 (-CH2-), 1790 (-C=O of imidazolinone), 1653 (-C=N imidazolinone), 1614 (-C=N of pyrimidine), 1225, 1030 (C-O-C).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.15 (t, 3H, -CH3), 2.30 (s, 3H, -CH3), 2.52 (q, 2H, -CH2) , 3.26 (t, 2H, -CH2), 3.83, (s, 3H, -OCH3), 4.35 (t, 2H, -CH2-O), 7.03-7.55 (m, 18H, Ar-H), 7.15 (s, 1H, -CH), 7.40-8.33 (m, 3H, pyridine-H), 7.89 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.6 (C31), 165.2 (C19), 164.2 (C34), 163.3 (C17), 160.4 (C21), 126.7-135.3 (C36-C41), 126.3-130.5 (C42-C47), 122.2-157.3 (C2-C6), 115.2-157.1 (C11-C16),114.8-160.6 (C23-C28), 108.1 (C35), 103.5 (C22), 67.2 (C10), 55.3 (C29), 37.4 (C9), 25.1 (C7), 15.3 (C8). Anal. calcd for C42H34N5O3F: C 74.65, H 5.07, N 10.36; found C 74.66, H 5.09, N 10.33.

1-(4-(2,4-dichlorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6c):

Pale yellow solid, m.p. 105-108°, yield, 62%, Rf: 0.61; IR (KBr, cm-1) ν: 3058 (Ar-H), 2950, 2832 (-CH2-), 1791 (-C=O of imidazolinone), 1653 (-C=N imidazolinone), 1615 (-C=N of pyrimidine), 1225, 1037 (C-O-C), 743 (C-Cl).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.13 (t, 3H, -CH3), 2.35 (s, 3H, -CH3), 2.54 (q, 2H, -CH2), 3.23 (t, 2H, -CH2), 4.36 (t, 2H, -CH2-O), 7.05-8.03 (m, 17H, Ar-H), 7.32 (s, 1H, -CH), 7.35-8.32 (m, 3H, pyridine-H), 7.83 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.6 (C31), 165.3 (C19), 163.9 (C34), 163.1 (C17), 160.5 (C21), 127.4-135.7 (C23-C28), 126.0-135.5 (C36-C41), 126.2-130.5 (C42-C47), 122.8-157.4 (C2-C6), 114.5-157.6 (C11-C16), 108.7 (C35), 103.5 (C22), 67.7 (C10), 37.7 (C9), 25.1 (C7), 15.1 (C8). Anal. calcd for C41H30N5O2Cl2F: C 68.91, H 4.23, N 9.80; found C 68.92, H 4.25, N 9.81.

1-(4-(4-hydroxyphenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6d):

Yellow solid, m.p. 205-207°, yield, 54%, Rf: 0.63; IR (KBr, cm-1) ν: 3065(Ar-H), 3354 (-OH), 2953, 2833 (-CH2-), 1794 (-C=O of imidazolinone), 1652(-C=N imidazolinone), 1612(-C=N pyrimidine), 1223, 1032(C-O-C).1H NMR (CDCl3, 400 MHz) δ(ppm):1.20 (t, 3H, -CH3), 2.37 (s, 3H, -CH3), 2.51 (q, 2H, -CH2) , 3.24 (t, 2H, -CH2), 4.34 (t, 2H, -CH2-O), 6.79-7.55 (m, 18H, Ar-H), 7.26 (s, 1H, -CH), 7.37-8.35 (m, 3H, pyridine-H), 7.86 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 169.9 (C31), 165.0 (C19), 164.2 (C34), 163.8(C17), 160.2 (C21), 126.5-135.6(C36-C41), 126.2-130.0 (C42-C47), 122.2-157.3 (C2-C6), 116.4-158.5 (C23-C28), 115.1-157.2 (C11-C16), 108.3 (C35), 103.6 (C22), 67.6 (C10), 37.2 (C9), 25.3 (C7), 15.9(C8). Anal. calcd for C41H32N5O3F: C 74.42, H 4.87, N 10.58; found C 74.40, H 4.85, N 10.55.

1-(4-(2,6-dichloro-5-fluorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6e):

Brown solid, m.p. 110-112°, yield 55%, Rf: 0.61; IR (KBr, cm-1) ν: 3057 (Ar-H), 2958, 2837 (-CH2-), 1789 (-C=O of imidazolinone), 1653 (-C=N imidazolinone), 1616 (-C=N of pyrimidine), 1223, 1035 (C-O-C), 972 (C-F), 744 (C-Cl) .1H NMR (CDCl3, 400 MHz) δ(ppm): 1.16 (t, 3H, -CH3), 2.32 (s, 3H, -CH3), 2.56 (q, 2H, -CH2) , 3.26 (t, 2H, -CH2), 4.33 (t, 2H, -CH2-O), 6.81-7.55 (m, 16H, Ar-H), 7.30 (s, 1H, -CH), 7.35-8.34 (m, 3H, pyridine-H), 7.80 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.1 (C31), 165.2 (C19), 164.3 (C34), 163.8 (C17), 160.5 (C21), 126.2-135.5 (C36-C41), 126.1-130.5 (C42-C47), 122.7-157.3 (C2-C6), 118.3-161.4 (C23-C28), 114.6-157.5 (C11-C16), 108.9 (C35), 103.5 (C22), 67.1 (C10), 37.4 (C9), 25.8 (C7), 15.7 (C8). Anal. calcd for C41H29N5O2Cl2F2: C 67.22, H 3.99, N 9.56; found C 67.21, H 3.96, N 9.54.

1-(4-(4-methylphenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluoro- benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6f):

Pale yellow solid, m.p. 92-94°, yield 64%, Rf: 0.64; IR (KBr, cm-1) ν: 3062 (Ar-H), 2953, 2836 (-CH2-), 1798 (-C=O of imidazolinone), 1658 (-C=N imidazolinone), 1612 (-C=N of pyrimidine), 1222, 1035 (C-O-C).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.19 (t, 3H, -CH3), 2.33 (s, 3H, -CH3), 2.54 (q, 2H, -CH2) , 3.20 (t, 2H, -CH2), 4.32 (t, 2H, -CH2-O), 7.05-7.59 (m, 18H, Ar-H), 7.25 (s, 1H, -CH), 7.39-8.32 (m, 3H, pyridine-H), 7.85 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.3 (C31), 165.5(C19), 164.0(C34), 163.5(C17), 160.9 (C21), 127.4-138.4 (C23-C28), 126.4-135.2 (C36-C41), 126.1-130.2 (C42-C47), 122.5-157.1 (C2-C6), 114.9-157.4 (C11-C16), 108.0 (C35), 103.2 (C22), 67.5 (C10), 37.5 (C9), 25.5 (C7), 21.2 (C29), 15.4 (C8). Anal. calcd for C42H34N5O2F: C 76.46, H 5.19, N 10.62; found C 76.43, H 5.17, N 10.63.

1-(4-(1-phenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluoro- benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6g):

Brown solid, m.p. 86-88° yield 53%, Rf: 0.58; IR (KBr, cm-1) ν: 3063 (Ar-H), 2957, 2836 (-CH2-), 1794 (-C=O of imidazolinone), 1655 (-C=N imidazolinone), 1615 (-C=N of pyrimidine), 1229, 1034 (C-O-C).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.14 (t, 3H, -CH3), 2.34 (s, 3H, -CH3), 2.51 (q, 2H, -CH2) , 3.22 (t, 2H, -CH2), 4.35 (t, 2H, -CH2-O), 7.05-7.85 (m, 19H, Ar-H), 7.23 (s, 1H, -CH), 7.32-8.40 (m, 3H, pyridine-H), 7.82 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.8(C31), 165.9 (C19), 164.3(C34), 163.0(C17), 160.5 (C21), 127.5-133.0 (C23-C28), 126.1-135.1 (C36-C41), 126.4-130.5 (C42-C47), 122.2-157.3 (C2-C6), 114.2-157.6 (C11-C16), 108.1 (C35), 103.6 (C22), 67.3 (C10), 37.6 (C9), 25.7 (C7), 15.3 (C8). Anal. calcd for C41H32N5O2F: C 76.26, H 5.00, N 10.85; found C 76.21, H 5.01, N 10.82.

1-(4-(4-fluorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluoro- benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6h):

Dark brown solid, m.p. 160-162°, yield 57%, Rf: 0.63; IR (KBr, cm-1) ν: 3068 (Ar-H), 2955, 2832 (-CH2-), 1793 (-C=O of imidazolinone), 1653 (-C=N imidazolinone), 1618 (-C=N of pyrimidine), 1226, 1039 (C-O-C), 974 (C-F).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.20 (t, 3H, -CH3), 2.36 (s, 3H, -CH3), 2.56 (q, 2H, -CH2) , 3.23 (t, 2H, -CH2), 4.36 (t, 2H, -CH2-O), 7.05-8.15 (m, 18H, Ar-H), 7.28 (s, 1H, -CH), 7.37-8.38 (m, 3H, pyridine-H), 7.86 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.4 (C31), 165.6 (C19), 164.6 (C34), 163.6 (C17), 160.3 (C21), 126.0-135.0 (C36-C41), 126.1-130.7 (C42-C47), 122.3-157.7 (C2-C6), 116.0-162.9 (C23-C28), 114.3-157.6 (C11-C16), 108.6 (C35), 103.5 (C22), 67.5 (C10), 37.4 (C9), 25.6 (C7), 15.1 (C8). Anal. calcd for C41H31N5O2F2: C 74.19, H 4.71, N 10.55; found C 74.15, H 4.69, N 10.50.

1-(4-(2,4-fluorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluoro benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6i):

Brown solid, m.p. 105-107° yield 59%, Rf: 0.64; IR (KBr, cm-1) ν: 3066 (Ar-H), 2953, 2833 (-CH2-), 1795 (-C=O of imidazolinone), 1654 (-C=N imidazolinone), 1613 (-C=N of pyrimidine), 1225, 1035 (C-O-C), 975 (C-F).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.22 (t, 3H, -CH3), 2.39 (s, 3H, -CH3), 2.58 (q, 2H, -CH2) , 3.19 (t, 2H, -CH2), 4.37 (t, 2H, -CH2-O), 6.74-7.55 (m, 17H, Ar-H), 7.30 (s, 1H, -CH), 7.35-8.35 (m, 3H, pyridine-H), 7.84 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.7 (C31), 165.7 (C19), 164.3 (C34), 163.3 (C17), 160.4 (C21), 105.2-164.5 (C23-C28), 126.3-135.6 (C36-C41), 126.3-130.6 (C42-C47), 122.2-157.5 (C2-C6), 114.5-157.7 (C11-C16), 108.3 (C35), 103.7 (C22), 67.2 (C10), 37.4 (C9), 25.8 (C7), 15.9 (C8). Anal. calcd for C41H30N5O2F3: C 72.24, H 4.44, N 10.27; found C 72.21, H 4.42, N 10.22.

1-(4-(4-bromophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6j):

Brown solid, m.p. 102-104° yield 63%, Rf: 0.61; IR (KBr, cm-1) ν: 3063 (Ar-H), 2954, 2836 (-CH2-), 1794 (-C=O of imidazolinone), 1656 (-C=N imidazolinone), 1610 (-C=N of pyrimidine), 1225, 1033 (C-O-C), 864 (C-Br) .1H NMR (CDCl3, 400 MHz) δ(ppm): 1.18 (t, 3H, -CH3), 2.31 (s, 3H, -CH3), 2.53 (q, 2H, -CH2) , 3.24 (t, 2H, -CH2), 4.33 (t, 2H, -CH2-O), 7.05-7.78 (m, 18H, Ar-H), 7.31 (s, 1H, -CH), 7.41-8.39 (m, 3H, pyridine-H), 7.87 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.4 (C31), 165.3 (C19), 164.7 (C34), 163.2 (C17), 160.5 (C21), 123.1-132.1 (C23-C28), 126.6-135.4 (C36-C41), 126.6-130.3 (C42-C47), 122.2-157.6 (C2-C6), 115.2-157.2 (C11-C16), 108.4 (C35), 103.5 (C22), 67.2 (C10), 37.2 (C9), 25.4 (C7), 15.6 (C8). Anal. calcd for C41H31N5O2FBr: C 67.96, H 4.31, N 9.66; found C 67.90, H 4.30, N 9.68.

1-(4-(3,4-dichlorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6k):

Brown solid, m.p. 75-78° yield 61%, Rf: 0.62; IR (KBr, cm-1) ν: 3060 (Ar-H), 2952, 2834 (-CH2-), 1798 (-C=O of imidazolinone), 1658 (-C=N imidazolinone), 1609 (-C=N of pyrimidine), 1220, 1034 (C-O-C), 748 (C-Cl) .1H NMR (CDCl3, 400 MHz) δ(ppm): 1.20 (t, 3H, -CH3), 2.36 (s, 3H, -CH3), 2.50 (q, 2H, -CH2) , 3.23 (t, 2H, -CH2), 4.35 (t, 2H, -CH2-O), 7.05-7.86 (m, 17H, Ar-H), 7.21 (s, 1H, -CH), 7.33-8.35 (m, 3H, pyridine-H), 7.82 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.6 (C31), 165.0 (C19), 164.1 (C34), 163.1 (C17), 161.0 (C21), 127.0-133.8 (C23-C28), 126.7-135.4 (C36-C41), 126.5-130.6 (C42-C47), 122.1-157.4 (C2-C6), 114.3-157.3 (C11-C16), 108.5 (C35), 103.0 (C22), 67.1 (C10), 37.2 (C9), 25.7 (C7), 15.1 (C8). Anal. calcd for C41H30N5O2Cl2F: C 68.91, H 4.23, N 9.80; found C 68.88, H 4.20, N 9.79.

1-(4-(4-chlorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluoro benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6l):

Pale yellow solid, m.p. 135-138°, yield 67%, Rf: 0.58; IR (KBr, cm-1) ν: 3061(Ar-H), 2951, 2837(-CH2-), 1792(-C=O imidazolinone), 1652 (-C=N imidazolinone), 1615(-C=N pyrimidine), 1227, 1037(C-O-C), 742(C-Cl) .1H NMR (CDCl3, 400 MHz) δ(ppm): 1.15(t, 3H, -CH3), 2.34(s, 3H, -CH3), 2.52(q, 2H, -CH2) , 3.22(t, 2H, -CH2), 4.34 (t, 2H, -CH2-O), 7.05-7.98(m, 18H, Ar-H), 7.32(s, 1H, -CH), 7.36-8.29(m, 3H, pyridine-H), 7.82 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 171.2(C31), 164.9(C19), 164.3 (C34), 163.2 (C17), 160.4 (C21), 128.9-134.3 (C23-C28), 126.4-135.4 (C36-C41), 126.6-130.0 (C42-C47), 122.2-157.4 (C2-C6), 114.5-157.6 (C11-C16), 108.2 (C35), 103.6 (C22), 67.8 (C10), 37.8 (C9), 25.1 (C7), 15.5 (C8). Anal. calcd for C41H31N5O2ClF: C 72.40, H 4.59, N 10.30; found C 72.39, H 4.57, N 10.32.

1-(4-(3-methoxyphenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6m):

Yellow solid, m.p. 84-87° yield 59%, Rf: 0.63; IR(KBr, cm-1) ν: 3063(Ar-H), 2952, 2831(-CH2-), 1797 (-C=O imidazolinone), 1657 (-C=N imidazolinone), 1616 (-C=N pyrimidine), 1220, 1036 (C-O-C).1H NMR (CDCl3, 400 MHz) δ(ppm): 1.18(t, 3H, -CH3), 2.36(s, 3H, -CH3), 2.57(q, 2H, -CH2) , 3.24(t, 2H, -CH2), 3.73(s, 3H, -OCH3), 4.36(t, 2H, -CH2-O), 6.73-7.55(m, 18H, Ar-H), 7.24(s, 1H, -CH), 7.40-8.35(m, 3H, pyridine-H), 7.84 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.0 (C31), 165.2 (C19), 164.4(C34), 163.8(C17), 160.3(C21), 126.3-135.5(C36-C41), 126.4-130.6(C42-C47), 122.3-157.3 (C2-C6), 111.2-161.1(C23-C28), 114.5-157.6(C11-C16), 108.1(C35), 103.4(C22), 67.2 (C10), 55.8(C29), 37.3(C9), 25.2(C7), 15.7(C8). Anal. calcd for C42H34N5O3F: C 74.65, H 5.07, N 10.36; found C 74.63, H 5.04, N 10.34.

1-(4-(3-fluorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluoro benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6n):

Brown solid, m.p. 115-118°, yield 56%, Rf: 0.64; IR (KBr, cm-1) ν: 3067(Ar-H), 2955, 2835(-CH2-), 1795 (-C=O imidazolinone), 1653 (-C=N imidazolinone), 1613(-C=N pyrimidine), 1225, 1030(C-O-C), 973(C-F) .1H NMR (CDCl3, 400 MHz) δ(ppm): 1.16(t, 3H, -CH3), 2.38(s, 3H, -CH3), 2.56(q, 2H, -CH2), 3.24 (t, 2H, -CH2), 4.35 (t, 2H, -CH2-O), 6.93-7.55 (m, 18H, Ar-H), 7.21 (s, 1H, -CH), 7.39-8.38 (m, 3H, pyridine-H), 7.87 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.4 (C31), 165.8 (C19), 164.9 (C34), 163.0 (C17), 160.0 (C21), 126.0-135.2 (C36-C41), 126.7-130.7 (C42-C47), 122.3-157.4 (C2-C6), 115.5-163.4 (C23-C28), 114.3-157.6 (C11-C16), 108.7 (C35), 103.5 (C22), 67.4 (C10), 37.2 (C9), 25.8 (C7), 15.3 (C8). Anal. calcd for C41H31N5O2F2: C 74.19, H 4.71, N 10.55; found C 74.20, H 4.72, N 10.53.

1-(4-(3,4-difluorophenyl)-6-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)pyrimidin-2-yl)-4-(4-fluorobenzylidene)-2-phenyl-1H-imidazol-5(4H)-one (6o):

Brown solid, m.p. 137-140° yield 58%, Rf: 0.62; IR (KBr, cm-1) ν: 3064 (Ar-H), 2956, 2835 (-CH2-), 1794 (-C=O of imidazolinone), 1653 (-C=N imidazolinone), 1613 (-C=N of pyrimidine), 1223, 1037 (C-O-C), 970 (C-F) .1H NMR (CDCl3, 400 MHz) δ(ppm): 1.23 (t, 3H, -CH3), 2.34 (s, 3H, -CH3), 2.51 (q, 2H, -CH2) , 3.25 (t, 2H, -CH2), 4.39 (t, 2H, -CH2-O), 7.01-7.92 (m, 17H, Ar-H), 7.27 (s, 1H, -CH), 7.38-8.33 (m, 3H, pyridine-H), 7.82 (s, 1H, pyrimidine-H).13C NMR (100 MHz, CDCl3) δ(ppm): 170.6 (C31), 165.2 (C19), 164.3 (C34), 163.2 (C17), 160.4 (C21), 126.2-135.5 (C36-C41), 126.3-130.5 (C42-C47), 122.3-157.4 (C2-C6), 117.6-150.0 (C23-C28), 114.2-157.5 (C11-C16), 108.8 (C35), 103.7 (C22), 67.8 (C10), 37.5 (C9), 25.0 (C7), 15.1 (C8). Anal. calcd for C41H30N5O2F3: C 72.24, H 4.44, N 10.27; found C 72.26, H 4.42, N 10.25.

RESULTS AND DISCUSSION

The MICs of synthesized compounds were carried out by broth microdilution method as described by Rattan[26]. Antibacterial activity was screened against two gram positive (Staphylococcus aureus MTCC 96, Streptococcus pyogenus MTCC 443) and two gram negative (Escherichia coli MTCC 442, Pseudomonas aeruginosa MTCC 2488) bacteria, ampicillin was used as a standard antibacterial agent. Antifungal activity was screened against three fungal species Candida albicans MTCC 227, Aspergillus niger MTCC 282 and Aspergillus clavatus MTCC 1323, greseofulvin was used as a standard antifungal agent. All MTCC cultures were collected from Institute of Microbial Technology, Chandigarh, India.

The minimum bactericidal concentrations (MBCs) of 4a-o, 5a-o and 6a-o are shown in Table 1. From the screening data, most of the compounds possessed better antibacterial activity (MBC, 50-250 mg/ml) against S. aureus; chalcones 4b, 4f and 4h with 4-OCH3,4-CH3 and 4-F group showed MBC value in the range between 62.5-100 mg/ml against E. coli; 4h at 100 mg/ml against P. aeruginosa; 4f and 4h bearing 4-CH3 and 4-F at 100-150 mg/ml while remaining 4b, 4d and 4n having 4-OCH3,4-OH and 3-F showed comparable activity against S. aureus with ampicillin. The remaining chalcones showed less activity against all four bacterial species. The pyrimidine 5b and 5i containing 4-OCH3 and 2,4-F possessed more activity of 62.5 mg/ml against E. coli; 5h having 4-F at 100 mg/ml against S. aureus and S. pyogeneus; 5i containing 2,4-F at 150 mg/ml against S. aureus; 5l having 4-Cl at 100 mg/ml against P. aeruginosa and at 150 mg/ml against S. aureus. The remaining pyrimidines displayed less activity against all four bacterial species comparable to ampicillin. Imidazolinones 6j having 4-Br at 100 mg/ml against E. coli and 250 mg/ml against S. aureus; 6a, 6d, 6f, 6h, 6i, 6j, 6k, 6n and 6o containing 2,4-Cl, 5-F, 4-OH, 4-CH3,4-F, 2,4-F, 4-Br, 3,4-Cl, 3-F and 3,4-F grpups at 200-250 mg/ml against S. aureus were comparable with ampicillin.

TABLE 1.

ANTIBACTERIAL ACTIVITY OF COMPOUND 4A-O, 5A-O AND 6A-O

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Minimum fungicidal concentrations (MFCs) are shown in Table 2. Most of the compounds possessed very good antifungal activity against C. albicans; their MFC range between 100-500 mg/ml. In chalcones, 4c, 4d, 4g, 4h, 4m and 4n containing 2,4-Cl, 4-OH, phenyl, 4-F, 3-OCH3and 3-F at 200-500 mg/ml; 5o having 3,4-F at 200 mg/ml against C. albicans, while remaining pyrimidines are less active against A. niger and A. clavatus compared with greseofulvin. Imidazolinones, 6c containing 2,4-Cl displayed more at 100 mg/ml against C. albicans, A. niger and A. clavatus with greseofulvin and nystatin; 6e and 6h having 2,6-Cl, 5-F and 4-F at 250 mg/ml against C. albicans, while other imidazolinones show moderate activity against C. albicans with greseofulvin. Remainning imidazolinones are less active against two fungal A. niger and A. clavatus.

TABLE 2.

ANTIFUNGAL ACTIVITY OF COMPOUND 4A-O, 5A-O AND 6A-O

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In overall microbial analysis; all compounds are comparable with S. aureus and C. albicans. Chalcones having methoxy methyl hydroxy and fluoro groups, pyrimidines with methoxy, difluoro and chloro substitutents and imidazolinones having, chloro, dichloro, fluoro and difluoro are more active group against S. aureus and C. albicans. Imidazolinone 6c 2,4-Cl is comparable with both nystatin and greseofulvin.

Acknowledgments

The authors thank Professor and Head, Department of Chemistry for extending laboratory facilities; the librarian, Veer Narmad South Gujarat University, Surat for library facilities and D. Rajani, Microcare Laboratory, Surat for carrying out antimicrobial activity. We also thank the CDRI, Lucknow for elemental analysis and SAIF, Chandigarh for 1H NMR and 13C NMR spectral analysis.

Footnotes

Patel and Patel: Heterocyclic Antibacterial and Antifungal compounds

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