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Document Type : Original Article

Authors

Department of Chemistry, College of Sciences, University of Baghdad, Iraq

Abstract

A new methodology was applied to the synthesis of new imidazolones and oxyazepine derivatives containing imidazo thiazole fused rings. Starting with 5-(4-bromo phenyl) imidazo (2, 1-b) thiazole, which was synthesized using the standard procedure, the Carbaldehyed group was introduced at position 6 of 5-(4-bromo phenyl) imidazo (2, 1-b) thiazole. Then, this 6-carbaldehyed derivative was condensed with different substituted aromatic amines to afford new Schiff bases. The latter were cyclized into new oxazepine and imidazolone derivatives by using phthalic anhydride and glycine, respectively. These new derivatives were characterized by using FT-IR, 1HHNMR, and 13CNMR spectra, as well as examined (evaluated) for anti-bacterial and anti-fungal activities.

Graphical Abstract

Design, Synthesis of Imidazolone and Oxazepine Derivatives Bearing Imidazo (2, 1-b) Thiazole along with its Antimicrobial Activity

Keywords

Main Subjects

Introduction

Researchers are interested in the design and development of fused heterocyclic systems because of the wide range of pharmacological and biological activities they can perform [1]. Because of their broad range of pharmacological activity, imidazo [2,1-b] thiazole derivatives are particularly important among these heterocyclic compounds [2]. The imidazo [2,1-b] thiazole derivatives have been documented in the literature for their antibacterial, antitubercular, antifungal, antitumoral, antiviral, anthelmintic, and analgesic effects [3-10].

The Vilsmeier-Haack (V-H) reagent is a chloromethyleneiminium salt that has been widely used in formylation, cyclization, and ring annulation reactions [11]. This reagent is made in situ by mixing excess N-dimethyl formamide (DMF) with phosphorus oxychloride (POCl3) [12]. In this work, this reagent was used to introduce the formyl group at position 5 of 6-(4-bromophenyl) imidazo [2,1-b] thiazole to form 6-(4-bromophenyl) imidazo [2,1-b] thiazole-5-carbaldehyde. After that, this 5-carbaldehyde reacted with different amines in the presence of a few drops of glacial acetic acid to form Schiff bases as intermediate compounds. Finally, treating these intermediate compounds with different reagents and under different conditions leads to their cyclization to form certain novel heterocyclic compounds (oxazepine and imidazole) bearing an imidazo [2,1-b] thiazole core.

The structural cores of many natural products and biologically active substances are Nitrogen bridge head used seven-membered heterocycles [13-15]. Among them, N-fused 1, 3-oxazepine derivatives are an important class of seven-membered heterocycles that have attracted considerable attention in drug discovery as peptidomimetics, as shown in Figure 1 [16]. They are useful building blocks that mimic the interaction of biologically active peptides with their targets [17].

Figure 1: Imidazo [2,1-b] thiazoles in drug discovery

 

1,3-oxazepines are a seven-member ring compound with two hetro atoms for nitrogen and oxygen atoms at the 1- and 3-positions, respectively [18]. Oxazepines and their derivatives have been linked to a variety of biological and pharmacological activities, including antiepileptic, antifungal, anti-inflammatory, hypnotic muscle relaxant, antagonist, analgesic, and antibacterial [19-22]. On the other hand, one of the most fundamental classes of five-member nitrogen-containing heterocycles is the imidazole moiety and its derivatives [23]. They are found in a wide range of pharmaceutical and biological molecules, including histamine, histidine, Olmesartan, miconazole, biotin, clotrimazole, losartan, ketoconazole, eprosartan, and trifenagrel [24]. Furthermore, imidazole derivatives are occasionally used as green solvents in the form of ionic liquids and in organometallic chemistry to involve N-heterocyclic carbenes [25]. In general, they also have excellent pharmacological activities, such as antitumor, antifungal, antiplasmodium, antibacterial, and anti-inflammatory [26–31].

Material and Methods

All the used materials and solvents were obtained from Sigma/Aldrich, BDH and Merck chemicals and purchased from CDH and Reagent world companies respectively. Pre-coated aluminum sheets with silica gel 60, provided by Merck Company, were used in thin-layer chromatography (TLC), and iodine vapors were used to mark spots.

Instrumentation

  • Melting points were recorded using the Gallenkamp capillary melting point apparatus and were uncorrected. 
  • The Shimadzu Fourier Transform Infrared (FT-IR-8400S) Spectrophotometer was used to record infrared spectra at the University Of Baghdad College Of Science.
  • The Varian model ultra-shield nuclear magnetic resonance spectrometer at 400 and 499.67 MHz and 125 MHz was used to record 1H NMR and 13C NMR spectra, respectively, using deuterated dimethyl sulfoxide solvent (DMSO-d6). The chemical shifts are measured in parts per million (ppm) relative to the internal reference tetra-methyl silane (TMS) at the University of Mashhad in Iran.

Synthesis 6-(4-bromophenyl) imidazo [2, 1-b] thiazole (compound 1A) [32]

A mixture of 2-aminothiazole (0.01 mole) and 4-bromophenacilbromide (0.01 mole) was heated in abs. ethanol (80 mL) under reflux for 18–20 hours. The reaction was monitored by TLC using (2:1) ethyl acetate and petroleum ether, Rf. (0.67). A mixture was filtered, and then a solution (5% NaOH) was added to make the pH of the mixture around 10–11. Then, the mixture was left for 4 hours to obtain the largest amount of precipitate during the digestion process. After the precipitate was filtered, washed with distilled water, and then left to dry and recrystallized with EtOH to produce yellowish-orange crystals with an 89.7% yield [21]. The physical properties of this compound (1A) are shown in Table 1.

FT-IR (KBr, ν, cm-1):3132, 3050 (C-H) aromatic, 1662 (C=N), 1583, 1535, 1492 (C=C) aromatic, 1276 (C-N), 748 (C-S-C), 723 (C-Br). 1HNMR (ppm) (DMSO-d6, 400MHz) δ: 8.14 - 7. 3 (m, Ar-H); 13CNMR (ppm) (DMSO-d6, 400MHz) δ: 145.50 (S-C-N), 140.5 (C=N), 140.2 - 121.4, (5 C=C) aromatic, 138.05 (C=S), 123.78 (C-Br).

Synthesis of 6-(4-bromophenyl) imidazo [2, 1-b] thiazole-5-carbaldehyde compound (2A) [32]

The Vilsmeier reagent was prepared at (0–5) °C by dropping phosphorus oxychloride (POCl3) (0.012 mol) into a stirred solution of DMF (0.012 mol). Compound 1A (0.012 mol) in 1, 4-dioxane (20 ml) was added drop-wise to the Vilsmeier reagent while maintaining stirring and cooling. The reaction mixture was heated at 50–60 °C for 8–10 h. The reaction was monitored by TLC using (2:1) ethyl acetate, petroleum ether, and Rf (0.72). Then, the reaction mixture was cooled and poured into crushed ice. After that, the crude product was collected by filtration, washed with an excess of water, and then purified with ethanol to produce white crystals with an 85% yield. The physical properties of this compound (2A) are shown in Table 2.

FT-IR (cm-1):  3089.75 (C-H) aromatic, 2885.31 (C-H aldehyde), 1645.17 (C=O), 1587.31 (C=N), 1454.23 (C=C) aromatic, 1263.29 (C-N), 771.47 (C-S), 700.11 (C-Br); 1H-NMR (ppm): 10.00 (s, 1H,-CHO), 7.17-8.70 (m, 6H, Ar-H); 13CNMR (ppm): 183.87 (C-H) aldehyde, 168.2-147.3(C=N), 163.2               (S-C=N, 2- thiazole), 146.7-109.5(C=C), 137.75 - 128.70 (C-H) aromatic, 123 (C-Br).

Synthesis of Schiff bases derivatives from compounds (3-7) A [33]

A (0.003mol) of compound (2A) and (0.003 mol) of different amines were refluxed in absolute ethanol (30 mL) in the presence of (4-5) drops of glacial acetic acid for (9-21) h. TLC has been used to check the reaction completion. Then, the reaction mixture was cooled to room temperature, the product separated, filtered and poured into crushed ice, then purified by recrystallization by using EtOH. The physical properties of these compounds are shown in Table 3.


(E)-1-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -N – (2-chloro-4-nitrophenyl) methanimine compound (3A)

Spectra data were follows: C18H10BrClN4O2S FT-IR (KBr/cm-1): 3197.76 (CH aromatic), 2979.82 (CH aliphatic), 1639.38 (C=N) imine for Schiff base, 1575.73 (C=N) imidazo, 1504.37, 1371.29 (NO2), 1452.30 (C=C) aromatic, 1423.37 (C-N), 775.33 (C-S), 698.18 (C-Br), 671.18 (C-Cl); 1H-NMR (DMSO, 499.67 MHZ) δ: 7.97-6.93 (9, Ar-H) ,7.1(s,1H, HC=N) imine; 13C-NMR (DMSO, 499.67 MHZ) δ: 144.5-118.6 (m, C aromatic), 137.5 (C-NO2), 135.34(C=N Schiff base), 122.6 (C-Cl), 123.1 (C-Br).

(E)-4-(((6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) methylene) amino) phenol compound (4A)

Spectra data were follows: C18H12BrN3OS FT-IR (KBr/cm-1): 3429.20 (C-OH), 3093.61(CH aromatic), 1641.31 (C=N), 1562.23 (C=C) aromatic, 1475.44 (C-N), 777.26 (C-S), 644.18 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 9.35 (s, 1H, OH), 7.90-6.65 (m, Ar-H), 7.2 (s, 1H, HC=N) Schiff base; 13C-NMR (DMSO, 499.67 MHZ) δ: 146.9-116.7 (m, C aromatic), 135.34(C=N Schiff base), 123.1 (C-Br).

(E)-N-(4-(((6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) methylene) amino) phenyl) acetamide compound (5A)

Spectra data was follows: C20H15BrN4OS FT-IR (KBr/cm-1): 3390.63 (Sym) and 3446.56 (Asym) (N-H), 3118.68 (CH aromatic), 2929.67 (CH aliphatic), 1681.81(C=O), 1641.31(C=N) imine, 1577.66 (C=N) imidazo, 1477.37 (C=C) aromatic, 1454.23 (C-N), 773.40 (C-S), 698.18 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 7.97-6.85 (m, Ar-H), 7.3 (s,1H,HC=N) imine; 13C-NMR (DMSO, 499.67 MHZ) δ: 178.24 (C=O), 145.5-118.6 (m, C aromatic), 133.34 (C=N Schiff base), 122.1                              (C-Br), 35.55 (CH3) .

(E)-2-((6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) methylene) hydrazine-1-carboxamide compound (6A)

Spectra data was follows: C13H10BrN5OS FT-IR (KBr/cm-1): 3438.84(NH2), 3261.40 (Sym) and 3128.32 (Asym) (N-H), 3089.75 (CH aromatic), 2933.53 (CH aliphatic), 1647.10 (C=N) imine, 1575.73 (C=N) imidazo, 1475.44 (C=C) aromatic, 1423.37 (C-N), 1255.30 (C=S), 775.33 (C-S), 700.11 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 9.56(s,1H,NH), 8.6(s, 2H,NH2), 8.2-7.5 (m, Ar-H), 7.1 (s,1H,HC=N) imine; 13C-NMR (DMSO, 499.67 MHZ) δ: 176.94 (C=S), 135.33 (C=N Schiff base), 148.9, 132.4(C=N), 131.6 – 114.4 (C=C) aromatic.

(E)-1-(4-(((6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) methylene) amino) phenyl) ethan-1-one compound (7A).

Spectra data was as follows: C20H14BrN3OS FT-IR (KBr/cm-1): 3184.28 (CH aromatic), 2972.10 (C-H aliphatic),1683.44(C=O), 1649.02(C=N) imine, 1575.73(C=N) imidazo, 1473.51 (C=C) aromatic, 1411.80 (C-N), 777.46 (C-S), 644.18(C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 7.85-6.3 (m, Ar-H), 7.4 (s,1H, HC=N) imine; 13C-NMR (DMSO, 499.67 MHZ) δ: 178.24 (C=O), 145.5-118.6 (m, C aromatic), 132.47(C=N Schiff base), 121.1 (C-Br), 34.75(CH3).

Synthesis of Imidazolidone derivatives compounds (8-12) A [34]

A mixture of Schiff bases (0.001 mol), thioglycolic acid (0.001 mol), and (0.0016 mol). were dissolved in 10 mL dry pyridine and refluxed (18-23) h). TLC has been used to check the reaction completion, then filtered in cooled water and dried. All the formed products were recrystallized from ethanol. Physical properties of compounds (8-12) are listed in Table 4.

2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -3 – (2-chloro-4-nitrophenyl)-3, 5-dihydro-4H-imidazol-4-one compound (8A)

Spectra data was follows: C20H11BrClN5O3S  FT-IR (KBr/cm-1): 3197.76 (CH aromatic), 2979.82 (CH aliphatic),1685.67 (C=O) cyclic amid, 1641.31 (C=N) imidazolone ,1560.30 (C=N) imidazo, 1504.37,1371.29 (NO2), 1479.30 (C=C) aromatic, 1413.72 (C-N), 761.83 (C-S), 649.97 (C-Br), 621.04 (C-Cl); 1H-NMR (DMSO, 499.67 MHZ) δ: 7.97-6.93 (9, Ar-H) ,2.95,3.36 (s, 2H,CH2-C=O) of imidazoline ring, 2.3(C-H) aliphatic ; 13C-NMR (DMSO, 499.67 MHZ) δ:169.1(C=O) amide, 144.9 (C-NO2), 144.5-118.6 (17, C aromatic), 131.4 (C-Cl), 123.1 (C-Br), 52.7(CH2) aliphatic of imidazoline ring.

2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -3 – (4-hydroxyphenyl)-3, 5-dihydro-4H-imdazol-4-one compound (9A)

Spectra data was as follows: C20H13BrN4O2S FT-IR (KBr/cm-1): 3434.98 (C-OH), 3037.68 (CH aromatic), 2974.03, 2813.95 (CH) aliphatic, 1703.03 (C=O) cyclic amid, 1639.38 (C=N) imidazolone, 1554.52 (C=N) imidazo, 1470.65  (C=C) aromatic, 1413.72 (C-N), 775.33 (C-S), 642.25 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 9.42 (s, 1H, OH), 8.45-6.90 (10, Ar-H), 2.3(s, 2H, CH2CO); 13C-NMR (DMSO, 499.67 MHZ) δ: 169 (C=O) amide, 157.8 (C=N) imine, 154.1 (C-OH), 146.8-116.6 (m, C aromatic), 123.1 (C-Br), 52.7 (CH2) aliphatic of imidazolone ring.

2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -3–(2-chloro-4-nitrophenyl)-3,5-dihydro-4H-imidazol-4-one compound (8A)

Spectra data was follows: C20H11BrClN5O3S  FT-IR (KBr/cm-1): 3197.76 (CH aromatic), 2979.82 (CH aliphatic),1685.67 (C=O) cyclic amid, 1641.31 (C=N) imidazolone, 1560.30 (C=N) imidazo, 1504.37, 1371.29 (NO2), 1479.30 (C=C) aromatic, 1413.72 (C-N), 761.83 (C-S), 649.97 (C-Br), 621.04 (C-Cl); 1H-NMR (DMSO, 499.67 MHZ) δ: 7.97-6.93 (9, Ar-H), 2.95, 3.36 (s, 2H, CH2-C=O) of imidazoline ring, 2.3(C-H) aliphatic; 13C-NMR (DMSO, 499.67 MHZ) δ:169.1 (C=O) amide, 144.9 (C-NO2), 144.5-118.6 (17, C aromatic), 131.4 (C-Cl), 123.1 (C-Br), 52.7(CH2) aliphatic of imidazoline ring.

2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -3 – (4-hydroxyphenyl)-3, 5-dihydro-4H-imdazol-4-one compound (9A)

Spectra data was as follows: C20H13BrN4O2S FT-IR (KBr/cm-1): 3434.98 (C-OH), 3037.68 (CH aromatic),2974.03,2813.95(C-H)aliphatic, 1703.03(C=O) cyclic amid, 1639.38 (C=N) imidazolone, 1554.52 (C=N) imidazo, 1470.65  (C=C) aromatic, 1413.72 (C-N), 775.33 (C-S), 642.25 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 9.42 (s, 1H, OH), 8.45-6.90 (10, Ar-H), 2.3(s,2H,CH2CO); 13C-NMR (DMSO, 499.67 MHZ) δ: 169 (C=O) amide, 157.8(C=N) imine, 154.1(C-OH), 146.8-116.6 (m, C aromatic), 123.1 (C-Br), 52.7 (CH2) aliphatic of imidazolone ring.

N-(4-(2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) - 5-oxo-4, 5-dihydro-1H-imidazol-1-yl) phenyl) acetamide compound (10A)

Spectra data was follows: C22H16BrN5O2S FT-IR (KBr/cm-1): 3292.26 (NH), 3182.33 (CH aromatic), 2972.10 (CH aliphatic),1710(C=O), 1683.78(C=O) cyclic amid, 1641.31 (C=N) imidazolone, 1554.52 (C=N) imidazo, 1477.37 (C=C) aromatic, 1413.72 (C-N), 775.33 (C-S), 642.25 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 9.78 (N-H), 8.45-7.3 (m, Ar-H), 2.3 (s, 2H, CH2-C=O) of imidazoline ring, 2.06 (C-H) aliphatic; 13C-NMR (DMSO, 499.67 MHZ) δ: 169.1(C=O) amide, 168.9(C=O), 157.7-119.6 (m, C aromatic), 123.1 (C-Br), 52.7(CH2) aliphatic of imidazoline ring, 24(CH3) aliphatic.

1-(2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) - 5-oxo-4, 5-dihydro-1H-imidazol-1-yl) urea compound (11A)

Spectra data was follows: C15H11BrN6O2S FT-IR (KBr/cm-1): 3434.98 (NH2), 3290.33 (NH), 3184.26 (CH aromatic), 2975.96 (CH aliphatic), 1706.88 (C=O), 1689.53 (C=O) cyclic amid, 1641.31 (C=N) imidazolone, 1556.45 (C=N) imidazo, 1477.37 (C=C) aromatic, 1456.16 (C-N), 773.40 (C-S), 673.11 (C-Br).

3-(4-acetylphenyl)-2-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl)-3, 5-dihydro-4H-imidazol-4-one compound (12A)

Spectra data was follows: C15H11BrN6O2S FT-IR (KBr/cm-1): 3431.13 (NH2), 3286.48 (NH), 3191.97 (CH aromatic), 2975.96 (CH aliphatic), 1704.96 (C=O), 1676.03 (C=O) cyclic amid, 1641.31 (C=N) imidazolone, 1519.80 (C=N) imidazo, 1477.37 (C=C) aromatic, 1454.23 (C-N), 773.40 (C-S), 698.18 (C-Br).

Synthesis of Oxazepine derivatives compounds (13-17) A [35]:

Mixture of Schiff bases compound [3-7] A (0.004 mol) and 0.004 mol of phthalic anhydride were dissolved in dry benzene (25ml). The mixture was then refluxed for (15-20) h. at 55-60 °C to yield oxazepine derivatives (13-17) A. The products were cooled, filtered and purified by recrystallization use EtOH. The physical properties of these derivatives are shown in Table 5.

3-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -4-(2-chloro-4-nitrophenyl)-3, 4-dihydrobenzo [e] [1,3] oxazepin-1,5-dione compound (13A)

Spectra data was follows: C26H14BrClN4O5S FT-IR (KBr/cm-1): 3176.54 (CH aromatic), 2977.89 (CH aliphatic), 1699.17, 1683.74 (2C=O, oxazepine), 1639.38 (C=N) imidazole), 1508.23 asym, 1338.51 sym (NO2), 1473.51 (C=C) aromatic, 1413.72 (C-N), 795.55 (C-S), 667.32 (C-Br), 644.18 (C-Cl); 1H-NMR (DMSO, 499.67 MHZ) δ: 8.05(s,1H, CH-oxazepine ring), 8.33-7.28 (m, Ar-H) 13C-NMR (DMSO, 499.67 MHZ) δ: 167, 165.8 (2C=O), 144.9-119.6 (m, C aromatic), 89.4(CH) aliphatic.

3-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -4-(4-hydroxyphenyl)-3, 4-dihydrobenzo [e] [1, 3] oxazepin-1, 5-dione compound (14A)

Spectra data was follows: C26H16BrN3O4S FT-IR (KBr/cm-1): 3436.91(OH), 3170 (CH aromatic), 2975.96 (CH aliphatic), 1703.03, 1685.67 (2C=O, oxazepine), 1558.38 (C=N), 1506.30 asym, 1338.51sym (NO2), 1477.37 (C=C) aromatic, 1413.72 (C-N),779.19 (C-S), 667.32 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ:9.4 (s,1H, OH), 8.03(s,1H, CH-oxazepine), 8.10-6.95 (m, Ar-H); 13C-NMR (DMSO, 499.67 MHZ) δ: 167.3, 165.5 (2C=O, oxazepine), 154.2 (C-OH), 143.2-116.1 (m, C aromatic), 88.9 (CH) aliphatic.

N-(4-(3-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -1, 5-dioxo-1, 5-dihydrobenzo [e] [1, 3] oxazepin-4(3H)-yl) phenyl) acetamide compound (15A)

Spectra data was follows: C28H19BrN4O4S FT-IR (KBr/cm-1): 3174.61 (CH aromatic), 2970.85 (CH aliphatic), 1701.10 (C=O), 1683.74, 1641.31 (2C=O, oxazepine), 1595.02 (C=N), 1544.88 (C=N), 1475.44 (C=C) aromatic,1413.72 (C-N), 773.40 (C-S), 671.18 (C-Br); 1H-NMR (DMSO, 499.67 MHZ) δ: 9.78 (NH), 8.04 (s,1H, CH-oxazepine), 8.10-7.28 (m, Ar-H), 2.05(CH3); 13C-NMR (DMSO, 499.67 MHZ) δ: 168.9 (C=O) ,166.9, 165.7 (2C=O, oxazepine), 143.2-119.6 (m, C aromatic), 89.9 (CH) aliphatic, 24(CH3).

1-(3-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -1, 5-dioxo-1, 5-dihydrobenzo[e] [1, 3] oxazepin-4(3H)-yl) urea compound (16A)

Spectra data was follows: C21H14BrN5O4S FT-IR (KBr/cm-1): 3440.77 (NH2), 3290.33 (NH), 3172.68 (CH aromatic), 2972.10 (CH aliphatic), 1701.10 (C=O), 1689.74, 1639.38 (2C=O, oxazepine), 1556.45(C=N), 1473.51 (C=C) aromatic, 1413.72 (C-N), 777.26 (C-S), 667.32 (C-Br).

4-(4-acetylphenyl)-3-(6-(4-bromophenyl) imidazo [2, 1-b] thiazol-5-yl) -3, 4-dihydrobenzo [e] [1, 3] oxazepin-1, 5-dione compound (17A)

Spectra data was as follows: C28H18BrN3O4S FT-IR (KBr/cm-1): 3176.54 (CH aromatic), 2974.03     (CH aliphatic), 1699.17 (C=O), 1685.65, 1639.38 (2C=O, oxazepine), 1558.38 (C=N), 1475.44 (C=C) aromatic, 1413.72 (C-N), 781.12 (C-S), 644.18 (C-Br).

 

Biological Activity [36]

Antimicrobial susceptibility tests of some synthesized compounds were performed according to the "well diffusion method". The compounds were tested on two different bacterial strains, one gram-positive (staphylococcus aureus) and one gram-negative (Klebsiella pneumonia). Samples were cultured on Muller Hinton agar medium at a temperature of 37 °C for a period of 24 hours, and the results were good for some compounds, as shown in Table 6. They were also evaluated for one fungal strain, like pathogenic fungal (Candida), where samples were planted on the medium of PDA at a temperature of 28 °C for a period of 3-5 days, and some of the results were good, as shown in Table 6.

Scheme 1: Total Synthesis of Imidazolone & Oxazepine derivatives (8-17) A

 

Results and Discussion 

The formation of compound (1A) was established as a known procedure in literature [33], and is approved by FT-IR spectrum data, which includes the disappearance of the (NH2) band at (3400)        cm-1 and the (C=O) band at (1700) cm-1 and the appearance of new bands of (C=N) imidazo at (1679-1662) cm-1 due to the formation of the imidazole ring. 1H-NMR spectrum data of compound (1A) showed the appearance of multiple signals of aromatic ring protons at (7.36–8.14). The 13C-MR data of compound (1A) included the appearance of (N-CH=C imidazole) at 108.70 ppm and (C=N) at 146.50 ppm. These spectra data agreed well with the literature.

Aldehyde derivative was performed in the second step by Vilsmeier Huck reaction and confirmed its structure by FT-IR spectrum, including the appearance of a new band at 1645.17 (C=O) cm-1 belonging to the formation of aldehyde and 2885.31 (C-H) aldehyde. Singlet 1H-NMR (ppm) signal of a (-CH=O) proton at = (10.00) ppm.13CNMR (ppm) shows the new band at 183.87 (C-H) aldehyde.

The third step was the formation of Schiff bases (3-7) A; these Imine derivatives were characterized for their structure by FT-IR spectrum data including disappearance of carbonyl band and appearance of new band at 2979.82-2933.53 (CH) aliphatic and 1639.38-1649.02 (C=N) imine for all derivatives); 1H-NMR shown new band at 7.1(s, 1H, HC=N) imine and 13C-NMR appear 135.34 (C=N Schiff base).

In the fourth step, Schiff bases were cyclized by using glycine and phthalic anhydride to form the desired Imidazolidone and oxyazepine derivatives. As for compound (8-12), their formation was confirmed by FT-IR spectra through the appearance of (C=O lactone) peaks that ranged from 1703.03 to 1676.03 cm-1 for all derivatives. Its 1HNMR spectrum showed a signal at 7.3-7.1 (s, 1H, HC=N) imine, while its 13CNMR spectrum showed a signal at 169.1-168.9 (C=O) amide, and 52.7 (CH2) aliphatic of the imidazoline ring.

As for compound (13-17), A for Oxazepine derivatives was approved by FT-IR spectrum including the appearance of new bands at 1703.03, 1685.67 (C=O) belonging to the carbonyl of oxazepine and 2974.03 (CH aliphatic). 1H-NMR showed a new band at 8.03 (s, 1H, CH-oxazepine ring) and also 13C-NMR had new bands at 167.3 (C carboxyl), 165.5 (C amide) and 88.9 (CH) aliphatic.

Biological Activity

The findings revealed that the majority of the compounds tested had good antibacterial and antifungal activity. These bacteria and fungi were chosen because of their wide importance in the clinical field, as they cause a variety of diseases in addition to their various antibiotic and chemical drug resistance. Table 6 reveals that the produced compounds have biological activity against the selected fungus and bacteria because they may suppress the bacteria and fungi by varying the amounts of the compounds. This difference in toxicity is due to change in functional group or structures, as shown in Figures 2, 3, and 4.

 

Conclusion

New five-membered rings of Imidazolidone and seven-membered rings of Oxazepine bearing imidazo thiazole fused rings were synthesized by sequence steps through Schiff bases. These new derivatives were identified by FT-IR, 1H NMR, and 13CNMR spectra. Finally, Schiff bases and their cyclized rings were tested against two types of bacteria and fungi and found to have strong to moderate inhibitory activity against these bacteria and fungi.

As a result, these imidazo thiazole derivatives demonstrated good antibacterial agent agreement with the metronidazole (Flagyl) drug.

 

Key to symbols

Well diameter is 6 mm.

[conc.] = 0.02 g/mL; solvent: dimethylsolfoxide (DMSO).

Inhibition Zone: (-) no inhibition; (6-10) mm weak; (11-18) mm moderate; (19-30) mm strong;

Figures (2, 3, 4) show biological activities of some prepared compounds on Staphylococcus aureus, Klebsiella pneumonia and Candida albicans.

 

Acknowledgments

Special thanks to Senior Chemist Minera Khalid Ahmed Al-Mashhdani and Andy N. S. Shamaya for doing FT-IR spectra at the University of Baghdad.

 

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

 

Authors' contributions

All authors contributed toward data analysis, drafting, and revising the paper and agreed to be responsible for all the aspects of this work.

 

Conflict of Interest

We have no conflicts of interest to disclose.

 

ORCID

Mais Saad Hussein

https://www.orcid.org/0000-0002-7012-475X

Naeemah Al-Lami

https://www.orcid.org/0000-0003-0111-5435

HOW TO CITE THIS ARTICLE

Ali J. Al-Saray, Israa M. Al-Mussawi, Taghreed H. Al-Noor. Design, Synthesis of Imidazolone and Oxazepine Derivatives Bearing Imidazo    (2, 1-b) Thiazole along with its Antimicrobial Activity. Chem. Methodol., 2022, 6(4) 319-330

https://doi.org/10.22034/CHEMM.2022.329943.1443

URL: http://www.chemmethod.com/article_146436.html

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