Antibacterial Activity of Hydroxyimidazole Derivatives

Suaad M. Abuskhuna, Talal H. Zeglam, Omran N. R. Fhid, Asma O. Jebril

Department of Medicinal and Pharmaceutical Chemistry, Faculty of Pharmacy University of Tripoli,

Tripoli, Libya

*Corresponding Author E-mail: sudskhun@hotmail.com

ABSTRACT:

The imidazole ring is containing one of the important heterocyclic compounds found in endogenous biomolecules and pharmaceutical preparations. Different methods have been reported for the synthesis of 1-Hydroxyimidazoles and a number of them reported to possess significant biological activity, thus synthesis of some new derivatives are introduced for better antibacterial activity

KEYWORDS: Imidazole, Hydroxyimidazole derivatives, antibacterial activity

1. INTRODUCTION:

The imidazole ring is containing five membered ring systems have been described for their biological activity against various micro organisms^1,2 It is commonly found as a part of structure substances such as histamine and purine, also in a number of pharmaceutical drugs, such as antifungal agent¹ (ketoconazole), antiprotozoal agents metronidazole⁴ (1) and antihistamine cimetidine³ (2). N-hydroxyimidazoles are analogous of imidazole, have been prepared and tested biologically. Besides this, a pesticidal screening was carried out by Allan⁶ on a series of N-hydroxyimidazoles (3) and found them to have herbicide and insecticide activities. Antihypertensive⁷ activity was observed in some N‑hydroxyimidazole‑5‑methanamine derivatives such as (4). (Fig. 1). They have been also applied to coloring materials.⁸

Figure 1. Biologically active imidazole derivative

1-Hydroxyimidazoles were prepared by condensation reaction of monoximes of 1,2-diketones with an aldehyde in presence of ammonia⁶ (Scheme 1). They were prepared by reduction of 3-hydroxy-imidazole-1-oxide, and by cyclization of a 1,2-diketone, and an aldehyde in the presence of hydroxyl-amine.^8,9 N‑hydroxyimidazole has also been synthesized by N-oxidation of imidazole with 3‑chloroperbenzoic acid⁸ or peroxyphethalic acid.^9,10 The compounds in the present work have been synthesized by using Akagane method⁸ (Table 1). The reproduced compounds and the new derivatives (10, 11) were identified by means of physical and spectrophotometric analysis and evaluated in vitro for their antimicrobial activity. 

2. MATERIALS AND METHODS:

All solvents and reagents were used as received from various vendors. Infrared spectra were recorded by using KBr disc in the region 4000–400 cm^-1 on a Nicolet FT-IR Impact 400D

infrared spectrometer. ¹H NMR and ¹³C NMR spectra were run as solutions in CDCl₃ or DMSO-d₆ on a Bruker Avance 300 MHz instrument. Mass spectra were carried out on a Kratos Profile mass spectrometer. The melting points were determined by open capillary method and were uncorrected.

2.1 General procedure for preparation of 1H-imidazole-1-ol:

4,5-Dimethyl-2-(pyridine-2-yl)-1H-imidazole-1-ol⁶ (5).

The general procedure of Akagane and coworkers was used.  A 250-mL, round-bottomed flask, equipped with a magnetic stirrer was charged with diacethyl monoxime (1.5 g, 15 mmol) dissolved in a mixture of ammonia and water (1:1). Picolinaldehyde (1.5 g, 14 mmol) was added and the mixture was stirred overnight a room temperature. The solvent was removed under reduced pressure and the product was extracted with chloroform. The chloroform extract was dried over magnesium sulphate, filtered and evaporated under vacuum. The residue was crystallised from toluene to give (1) as yellow crystals (1 g, 30%), mp = 139-141 °C.

¹H NMR (CDCl₃): 2.22 (6H, s), 7.21-7.16 (1H, m), 7.82-7.76 (1H, dt, J = 7.8, 1.7 Hz), 8.19 (1H, s), 8.38 (1H, d, J = 7.5 Hz).

¹³C NMR (CDCl₃): 7.6, 13.0, 119.7, 122.2, 122.8, 131.0, 138.4, 146.5, 149.3.

IR (KBr): 3382, 2421, 1639, 1588, 1524, 1488, 1310, 1231, 1154, 1115, 964, 794, 742, 610, 505 cm^-1.

m/z: 189 (M⁺, 16%), 172 (64), 105 (56), 95 (8), 79 (100), 69 (28), 51 (58).

4,5-Diphenyl-2-(pyridine-2-yl)-1H-imidazole-1-ol⁶ (6):

The product was prepared in a similar method to (1) using α-benzil monoxime (2 g, 8.8 mmol) and picolinaldehyde (1g, 9 mmol). The product was crystallised from toluene giving (2) as yellow crystals (2.5 g, 89%), mp = 163-164 °C.

¹H NMR (CDCl₃): 7.30-7.19 (4H, m), 7.52-7.38 (3H, m), 7.61-7.56 (4H, m), 7.92-7.86 (1H, dt, J = 7.8 Hz), 8.27 (1H, d, J = 8 Hz), 8.44 (1H, d, J = 5 Hz).

¹³C NMR (CDCl₃): 120 2, 122.5, 125.8, 126.9, 127.4, 128.2, 128.30, 128.37, 128.4, 129.9, 132.2, 134.6, 134.9, 138.4, 145.7, 149.8.

IR (KBr): 3063, 1606, 1562, 1531, 1476, 1439, 1402, 1309, 1148, 959, 783, 730, 700 cm^-1.

m/z: 313 (M⁺, 26%), 296 (28), 284 (18), 193 (22), 176 (8), 165 (36), 148 (14), 105 (58), 89 (58), 79 (92), 63 (54), 51 (100).

4,5-Dimethyl-1H, 3′H-[2,4′-biimidazol]-1-ol¹¹ (7):

The white solid was prepared in a similar method to (1) using diacethyl monoxime (0.5 g, 5 mmol) and 4(5)-imidazole carboxaldehyde (0.5 g, 5 mmol). The solid was crystallised from ethyl acetate to afford (3) as white crystals (0.75 g, 80%), mp 155 °C.

¹H NMR (DMSO-d₆): 1.91 (3H, s), 2.01 (3H, s), 7.64 (2H, s).

¹³C NMR (DMSO-d₆): 7.2, 10.9, 118.5, 121.9, 123.2, 126.2, 131.3, 135.9.

IR (KBr): 3079, 1646, 1461, 1295, 1221, 1172, 1129, 1086, 1006, 870, 704, 633 cm^-1.

m/z: 178 (M⁺, 28%), 161 (82), 147 (4), 120 (18), 94 (100), 81 (10), 68 (66), 64 (26), 60 (10), 55 (48).

2-(2,4-Dimethoxyphenyl)-4,5-diphenyl-1H-imidazol-1-ol¹² (8):                                        

This solid was prepared in a similar mehod of (1) using 2,4‑dimethoxybenzaldehyde (1.47 g, 8.84 mmol) and a-benzilmonoxime (2.0 g, 8.88 mmol). The product was crystallised from toluene giving a white solid (2.1 g, 63%), mp 196-197 °C.

¹H NMR (CDCl₃): 3.75 (3H, s), 3.85 (3H, s), 6.50-6.47 (2H, d, J = 8.9 Hz), 7.38-7.25 (11H, m).

¹³C NMR (CDCl₃): 27.3, 55.8, 56.55, 99.3, 105.6, 127.3, 128.5, 129.4, 130.7, 162.0.

IR (KBr): 3413, 3070, 2943, 2845, 1619, 1585, 1541, 1468, 1302, 1214, 1165, 1136, 1034, 973, 919, 835, 804, 764, 701, 654, 517 cm^-1.

m/z: 372 (M⁺, 10%), 355 (18), 178 (1), 165 (2), 103 (4), 91 (100), 84 (26), 77 (6), 65 (14), 56 (36).

2-(2-Hydroxyphenyl)-4,5-dimethyl-1H-imidazol-1-ol⁶ (9):

This solid was prepared in a similar way to (1) using diacetyl monoxime (1.0 g, 10 mmol) and salicyladehyde (1.2 g, 10 mmol). The solid was crystallised from ethanol/acetonitrile giving colourless crystals (1.3 g, 64%), mp 245 °C.

¹H NMR (DMSO-d₆): 2.10 (3H, s), 2.20 (3H, s), 6.82-6.88 (2H, m), 7.27-7.33 (1H, dt, J = 7.7 Hz), 7.46 (1H, d, J = 7.5 Hz).

¹³C NMR (DMSO-d₆): 7.25, 10.0, 113.3, 118.4, 119.8, 122.5, 124.1, 127.6, 131.7, 134.2, 158.6.

IR (KBr): 2927, 1646, 1609, 1436, 1307, 1276, 1166, 972, 910, 849, 753, 541 cm^-1.

m/z: 204 (M⁺, 60%), 187 (100), 159 (68), 145 (16), 121 (40), 105 (16), 91 (14), 80 (20), 77 (38), 68 (28), 51 (52).

4,5-Dimethyl-2-[(E)-2-phenylvinyl]-1H-imidazol-1-ol (10):

The yellow solid was prepared in a similar way to (1) using cinnamaldehyde (0.26 g, 1.96 mmol) and diacetyl monoxime (0.2 g, 1.97 mmol). The solid was crystallised from acetonitrile/ethanol giving yellow crystals (0.36 g, 85%), mp 94-95 °C.

¹H NMR (DMSO-d₆): 1.82 (6H, s), 6.73 (1H, d, J = 16.4 Hz), 7.05 (2H, m), 7.14 (2H, t, J = 7.4 Hz), 7.26 (2H, d, J = 7.4 Hz).

¹³C NMR (DMSO-d₆): 7.6, 126.6, 128.1, 128.2, 129.1, 136.9, 162.8.

IR (KBr): 3035, 1648, 1477, 1320, 1199, 1138, 1024, 966, 891, 748, 689, 561, cm^-1. m/z: 214 (M⁺, 34%), 197 (100), 182 (26), 128 (26), 115 (42), 103 (30), 98 (12), 89 (14), 77 (42), 68 (12), 63 (26), 58 (14), 51 (42).

4,5-Bis(4-fluorophenyl)-2-pyridin-2-yl-1H-imidazol-1-ol (11):

This solid was prepared in a similar way to (1) using pyridine‑2‑carboxaldehyde (0.15 g, 1.40 mmol) and 4,4¢-difluorobenzilmonoxime (0.24 g, 0.91 mmol). The solid was recrystallised from cyclohexane/ethylacetate giving yellow crystals (0.3 g, 74%), mp 163-164°C.

¹H NMR (CDCl₃): 6.99 (2H, t, J = 8.7 Hz), 7.13 (2H, t, J = 8.7 Hz), 7.33 (1H, t, J = 6 Hz), 7.51-7.56 (4H, m), 7.92 (1H, t, J = 9 Hz), 8.24 (1H, d, J = 8 Hz), 8.46 (1H, d, J = 5 Hz).

¹³C NMR (CDCl₃): 115.1, 115.4, 115.6, 115.9, 120.2, 122.7, 124.0, 124.1, 124.6, 129.0, 129.1, 130.6, 131.6, 131.7, 132.2, 134.1, 138.5, 145.7, 149.6, 160.4, 161.0163.7, 164.3.

IR (KBr): 3075, 1603, 1516, 1480, 1393, 1233, 1160, 1092, 956, 836, 815, 778, 735, 670, 578 cm^-1.

m/z: 349 (M+, 44%), 332 (22), 211 (28), 201 (12), 150 (10), 123 (20), 107 (48), 95 (28), 79 (100), 69 (22), 57 (58).

4,5-Dimethyl-2-(4-nitrophenyl)-1H-imidazole-1-ol⁶   (12):

The yellow solid was prepared in a similar way to (1) using p-nitrobenzaldehyde (1.0 g, 6.6 mmol) and diacetyl monoxime (1.0 g, 10 mmol). The solid was crystallised from acetonitrile/ethanol giving yellow crystals (1.2 g, 55%), mp 221 °C.

¹H NMR (CDCl₃): 2.25 (3H, s), 2.55 (3H, s), 8.05 (2H, d, J = 9.1 Hz), 8.27 (2H, d, J = 9.1Hz).

IR (KBr): 3325, 2420, 1633, 1600, 1544, 1355, 1310, 1231, 1154, 1115, 855 cm^-1.

3. RESULTS AND DISCUSSION:

The Akagane⁸ method was followed for the synthesis of new derivatives (10, 11) and other hydroxyimidazole compounds. A diacethyl monoxime or benzil monoxime was reacted with an appropriate aldehyde as shown in Scheme 1. The reaction was carried out in aqueous media using ammonia and water mixture (1:1) in a stoppard flask at room temperature. The products are formed in solid form with good yields. The reactions were monitored by TLC, using silica gel as an adsorbent and ethyl acetate-hexane in different ratios as eluent, and they were characterized by spectroscopic techniques (Table 1).

Scheme 1. General synthetic reaction for 1-hydroxyimidazole derivatives

Table 1. Products of 1-Hydroxyimidazole derivatives

Entry	R	R1	Entry	R	R1
5	CH3		9	CH3
6	Ph		10	CH3
7	CH3		11
8	Ph		12	CH3

3.1. Biological Evaluation:

The antimicrobial activities were determined using agar–cup method by measuring the zone of inhibition in mm. All newly synthesized compounds were screened in vitro for their antibacterial activity against gram positive bacteria such as B.sub:bacillus subtilis, St.aur: Staphylococcus aureus, MRSA:Metacillin-Resistant Staphylococcus Aureus and gram negative bacteria such as K.P:Klebsiella pneumoniae, E.Coli:Escherichia coli, P.aeru:Pseudomonas aeruginosa by agar plate method. Nitrofurantoin (F, 300 µg) is a standard reference antibiotic used for antibacterial comparison activity with tested synthesized compounds (5-12, Table 1). DMSO 5% was used as solvent to enhance the solubility of the compounds. The zone of inhibition was recorded in mm after incubation of plates of agar medium for 24 hrs at 37 ºC. The results of antibacterial activity indicated that compounds 10,12 have a good antibacterial activity compared to the standard drug as shown in Table 2. Compound 10 has moderate activity on gram-positive bacteria and have similar activity with same concentration on P. aeru and B. sub compared to nitrofurantoin, while compound 12 has exhibited good activity on St.aur and MRSA and showed no effect on the other species. The results did not show any antibacterial activity of the other prepared compounds (Table 2). Structurally the imidazole ring of the prepared compounds is multi-substituted, these substituents make the ring unable to move freely and bind with function groups of bacterial proteins. The activity of compound 10 on some species of gram positive and gram negative may due to the double bond and phenyl group at position two. Substitution of phenyl group at para- position with nitro group provides compound 12 some moderate activity compared with compound 9. In general most of 1-hydroxyimidazole compounds have low or no activity against different bacterial species, therefore, some structural modifications are necessary to improve their activity.

Table 2. Antibacterial activity of tested compounds 5-12

	Zone of inhibition (mm)
	Gram negative bacteria			Gram positive  bacteria
Compound	K. p	E. coli	P. aeru	B. sub	St. aur	MRSA
5	6	6	6	6	9	6
6	6	6	6	6	6	6
7	6	6	6	6	6	6
8	6	6	6	6	6	6
9	6	6	6	6	6	6
10	6	6	11	12	14	14
11	6	6	6	6	6	6
12	6	6	6	6	12	13
DMSO	6	6	6	6	6	6
F	18	18	11	11	20	21

The concentration of each tested compounds and nitrofurantoin F is 300 µg

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Received on 25.12.2019 Modified on 18.01.2020

Accepted on 21.02.2020      ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2020; 10(1):07-10.

DOI: 10.5958/2231-5713.2020.00002.1