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Molecules 2017, 22(11), 1895; doi:10.3390/molecules22111895

Article
Synthesis, Single Crystal X-ray Analysis, and Antifungal Profiling of Certain New Oximino Ethers Bearing Imidazole Nuclei
Reem I. Al-Wabli 1,*, Alwah R. Al-Ghamdi 1, Hazem A. Ghabbour 1,2Orcid, Mohamed H. Al-Agamy 3,4Orcid and Mohamed I. Attia 1,5,*Orcid
1
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
2
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
3
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
4
Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
5
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza 12622, Egypt
*
Correspondence:
Received: 4 October 2017 / Accepted: 31 October 2017 / Published: 3 November 2017

Abstract

:
Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers Van bearing imidazole nuclei are reported. The (E)-configuration of the imine double bond of the synthesized compounds Van has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic, P21/c, a = 18.7879(14) Å, b = 5.8944(4) Å, c = 16.7621(12) Å, β = 93.063(3)°, V = 1855.5(2) Å3, Z = 4. The in vitro antifungal activity of the synthesized compounds Van were evaluated using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against different fungal strains. Compound Ve manifested anti-Candida albicans activity with an MIC value of 0.050 µmol/mL, being almost equipotent with the reference antifungal drug fluconazole (FLC),while compounds Vi and Vn are the most active congeners against Candida parapsilosis, being equipotent and about twenty-three times more potent than FLC with an MIC value of 0.002 µmol/mL. The results of the current report might support the development of new potent and safer antifungal azoles.
Keywords:
imidazole; Mannich reaction; X-ray; antifungal agents; anti-Candida

1. Introduction

Fungal infections are an ever-growing burden on the health of mankind. They sometimes cause significant morbidity and mortality particularly in immune-compromised individuals, like those taking anticancer chemotherapy, patients with AIDS, or those receiving organ transplants [1,2]. Invasive fungal infections, like invasive aspergillosis and candidiasis, threaten the human health of millions of patients annually worldwide [3]. The available antifungal drugs can be classified into five main categories according to their mode of action: antimetabolites (e.g., 5-fluorocytosine) [4], polyenes (e.g., nystatin and amphotericin B) [5], azoles (e.g., itraconazole, voriconazole and fluconazole) [5], allylamines (e.g., naftifine and terbinafine) [6], and echinocandins (e.g., micafungin and caspofungin) [7].
Azoles bearing either imidazole or triazole moiety as a pharmacophoric portion constitute the mainstay antifungal therapy due to their good safety profile and favorable bioavailability [6]. They target lanosterol 14α-demethylase (CYP51) enzyme, a member of the CYP51 class of cytochrome P450 enzymes, leading to inhibition of the biosynthesis of ergosterol and accumulation of the toxic methylated sterol, which ultimately results in fungi cell death [8]. Even though azoles are currently the most clinically prescribed antifungal agents, they suffer from some limitations. Inhibition of cytochrome P450 enzymes by azoles leads to interference with the metabolism of other co-administered medications [9]. Moreover, azoles lack fungicidal activity against many fungi, which leads to the development of resistance toward fungal therapy [3]. Therefore, there is considerable interest in developing new azole-bearing antifungal agents endowed with a wide antifungal spectrum, high potency, diminished undesired drug–drug interactions, and reduced adverse effects.
Screening the literature revealed that oxiconazole (1, Figure 1) and its inverted oxime analog 2 (Figure 1) are well known antifungal agents bearing both imidazole and oxime functionalities [10,11]. Moreover, most of the currently available azole-bearing antifungal agents feature a spacer of two carbon atoms between the azole pharmacophore moiety and an aromatic nucleus, while insufficient information is available about azole antifungals bearing a three-carbon bridge connecting azole and aromatic moieties [12,13,14]. Accordingly, it was of our interest to synthesize the oximino ethers Vag to be evaluated as new antifungal agents bearing oxime and imidazole fragments with a three-carbon atom bridge between the imidazole pharmacophore and the aromatic moiety. In addition, a 1,3-benzodioxole scaffold was incorporated into a plethora of bioactive molecules including antimicrobials [15,16,17]. Therefore, the phenyl ring in compounds Vag was replaced by 1,3-benzodioxole moiety to afford the respective compounds Vhn to be assessed as new antifungal candidates. Moreover, the configuration around the imine double bond of the title compounds Van was explored via single crystal X-ray analysis of compound Vi as a representative example of this type of compounds.

2. Results and Discussion

2.1. Chemistry

The target compounds Van and their intermediates were successfully achieved as illustrated in Scheme 1. The synthesis was commenced by utilizing the commercially available acetophenones Ia,b to perform Mannich reactions to give the respective Mannich bases IIa,b. Compounds IIa,b were elaborated to the corresponding ketones IIIa,b which were subsequently transformed to the oximes IVa,b. The target oximino ethers Van were obtained in 24–63.4% yields via etherification of the pivotal oximes IVa,b using the appropriate benzyl bromide/chloride in the presence of sodium hydride. The assigned chemical structures of the title compounds Van were confirmed via different spectroscopic techniques (IR, 1H-NMR, 13C-NMR and mass spectrometry). The aromatic protons of compounds Van appeared along with imidazole protons in the range of 6.75–8.39 ppm, while the benzylic protons occurred in the range of 5.13–5.29 ppm. The benzodiaxole methylene protons of compounds Vhn manifested around 5.9 ppm. The aliphatic ethylene protons of compounds Van were observed in the expected upfield region of 3.14–4.29 ppm. The 13C spectra of compounds Van showed aromatic as well as imidazole carbons in the range of 106.2–162.6 ppm. Their benzylic carbons occurred at 74.8–76.7 ppm, while the benzoldiaxole methylene carbons of compounds Vhn were observed around 101 ppm. Moreover, the aliphatic ethylene carbons of compounds Van exhibited signals in the expected region of 28.9–44.3 ppm while the oximino carbons manifested signals around 155 ppm. The mass spectral data of the target compounds Van are consistent with their assigned chemical structures. The (E)-configuration of the oximino double bond of the title compounds Van has been proved using single crystal X-ray analysis of compound Vi as a representative example of the prepared compounds Van.

2.2. Crystal Structure of Compound Vi

The selected bond lengths and bond angles of compound Vi are listed in Table 1. The asymmetric unit contains one independent molecule as shown in Figure 2. All the bond lengths and angles are within normal ranges [18]. In the crystal packing, Figure 3, molecules are linked via one intermolecular hydrogen bond (Table 2).

2.3. Antifungal Evaluation

The antifungal activity of the synthesized compounds Van was determined against three Candida species and Asperagillus niger using in vitro diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays; the results are presented in Table 3.

2.4. Structure–Activity Relationships

The current study reports the antifungal potential of certain imidazole-bearing compounds having either an unsubstituted phenyl ring (compounds Vag) or a benzodioxole fragment (compounds Vhn) representing the aromatic pharmacophore moieties. The title compounds Van feature 3-aryl-3-iminopropyl moiety attached at N1 of the imidazole ring. It has been previously reported that the presence of chlorine atoms in the aromatic moiety of the antifungal agents contributes to the enhancement of their antifungal activity [19]. Substitution of the phenyl moiety of the benzyl fragment with halogen, methyl, or 3,5-bis-trifluoromethyl groups of compounds Vag enhanced their antifungal activity against the tested Candida species. Compound Ve bearing 4-methylbenzyl moiety exhibited the best MIC value of 0.050 µmol/mL, being nearly equipotent with the reference fluconazole (FLC) towards Candida albicans, while compounds Vb (4-bromobenzyl derivative) and Vg (3,5-bis-trifluoromethyl benzyl derivative) manifested the best MIC values of 0.083 and 0.36 µmol/mL towards Candida tropicalis and Candida parapsilosis, respectively. The same anti-Candida profile was mostly observed in the respective analogs Vhn except towards Candida parapsilosis in which substitution with halogen or methyl did not improve the activity as compared with the unsubstituted analog, compound Vh. Substitution with the trifluoromethyl group gave compound Vm improved activity towards Candida albicans and Candida tropicalis with, an MIC value of 0.153 µmol/mL. The highest sensitivity of Asperagillus niger was observed towards the 4-chlorobenzyl derivative analog, compound Vc, with an MIC value of 0.047 µmol/mL. In summary, compounds Vb, Vc, Ve and Vi, or Vn are the most active congeners towards Candida tropicalis, Asperagillus niger, Candida albicans, and Candida parapsilosis, respectively. It seems that the antifungal profile of compounds Vag is better than that of their respective benzodioxole analogs, compounds Vhn. Therefore, it is believed that the replacement of an unsubstituted phenyl pharmacophore with benzodioxole moiety is not favorable towards the tested fungal strains.

3. Experimental

3.1. General

The melting points were measured using a Gallenkamp melting point device and are uncorrected. The NMR samples of the synthesized compounds Van were dissolved in DMSO-d6 and the NMR spectra were recorded using a Bruker NMR spectrometer (Bruker, Reinstetten, Germany) at 500 MHz for 1H and 125.76 MHz for 13C at the Research Center, College of Pharmacy, King Saud University, Saudi Arabia. Chemical shifts are expressed in δ-values (ppm) relative to TMS as an internal standard. Elemental analyses were carried out at Microanalysis Laboratory, Cairo University, Cairo, Egypt and the results agreed favorably with the proposed structures within ±0.4% of the theoretical values. Mass spectra were recorded using Agilent Quadrupole 6120 LC/MS with ESI (Electrospray ionization) source (Agilent Technologies, Palo Alto, CA, USA).

3.2. Chemistry

3.2.1. Synthesis of (1E)-1-(2H-1,3-benzodioxol-5-yl)-N-hydroxy-3-(1H-imidazol-1-yl)propan-1-imine (IV)

Compound IV and its intermediates were prepared as previously reported [20,21]. Their spectral data are consistent with the reported ones.

3.2.2. Synthesis of the Oximino Ethers Van

Sodium hydride (1.5 mmol) was added to a solution of the oxime (IV, 1.0 mmol) in DMF (5 mL) and the reaction mixture was stirred at room temperature for 10 min. Then, the appropriate benzyl bromide/chloride (1.1 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min. then heated at 80 °C for two hours. The reaction mixture was concentrated under vacuum and the residue was poured into ice cold water and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and washed with water (2 × 15 mL), dried (Na2SO4), and evaporated under reduced pressure. The crude oximino ethers Van were purified using column chromatography, and chloroform/methanol (18:1) was used as the solvent system.
(1E)-N-(Benzyloxy)-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Va). Yield 52.9%; light brown viscous oil; IR (KBr): ν (cm−1) 3003, 2964, 1724 1673 (C=N), 1506, 1437, 1286, 700; 1H-NMR (CDCl3): δ (ppm) 3.16 (br. s., 2H, –CH2–CH2–N), 4.12 (br. s., 2H, –CH2–CH2–N), 5.25 (s, 2H, –CH2–C6H5), 6.77 (s, 1H, –N–CH=CH–N=), 6.94 (s, 1H, –N–CH=CH–N=), 7.27–7.31 (m, 5H, Ar–H), 7.33–7.38 (m, 5H, Ar–H), 7.41 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.4 (–CH2–CH2–N), 43.4 (–CH2CH2–N), 76.7 (–CH2–C6H4), 118.8 (–N–CH=CH–N=), 125.9, 128.1, 128.3, 128.4, 128.5, 128.6, 129.1, 129.5, 134.8 (Ar–CH, Ar–C, –N–CH=CH–N=), 137.3 (–N–CH=N–), 154.9 (C=N); MS m/z (ESI): 306.2 [M + H]+, 307.1 [(M + 1) + H]+.
(1E)-N-[(4-Bromobenzyl)oxy]-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vb). Yield 43.4%; pale yellow viscous oil; IR (KBr): ν (cm−1) 3003, 2924, 1720, 1672 (C=N), 1510, 1436, 1220, 785; 1H-NMR (CDCl3): δ (ppm) 3.34 (br. s., 2H, –CH2–CH2–N), 4.29 (br. s., 2H, –CH2–CH2–N), 5.24 (s, 2H, –CH2–C6H4), 6.94 (s, 1H, –N–CH=CH–N=), 7.11 (s, 1H, –N–CH=CH–N=), 7.37 (d, J = 7.5 Hz, 2H, Ar–H), 7.47–7.57 (m, 5H, Ar–H), 7.62 (d, J = 7.4 Hz, 2H, Ar–H), 7.66 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.2 (–CH2–CH2–N), 43.7 (–CH2CH2–N), 75.8 (–CH2–C6H4), 119.0 (–N–CH=CH–N=), 122.1, 126.1, 127.7, 128.5, 128.7, 129.7, 130.1, 131.6, 134.5 (Ar–CH, Ar–C, –N–CH=CH–N=), 136.4 (–N–CH=N–), 155.0 (C=N); MS m/z (ESI): 384.1 [M + H]+, 386.1 [(M + 2) + H]+, 387.1 [(M + 3) + H]+.
(1E)-N-[(4-Chlorobenzyl)oxy]-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vc). Yield 63.4%; light brown viscous oil; IR (KBr): ν (cm−1) 3003, 2928, 1722, 1671 (C=N), 1511, 1437, 1224, 696; 1H-NMR (CDCl3): δ (ppm) 3.30 (br. s., 2H, –CH2–CH2–N), 4.25 (br. s., 2H, –CH2–CH2–N), 5.26 (s, 2H, –CH2–C6H4), 6.92 (s, 1H, –N–CH=CH–N=), 7.08 (s, 1H, –N–CH=CH–N=), 7.44–7.52 (m, 9H, Ar–H), 7.55 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.2 (–CH2–CH2–N), 43.4 (–CH2CH2–N), 75.7 (–CH2–C6H4), 118.8 (–N–CH=CH–N=), 125.9, 128.5, 128.6, 129.1, 129.6, 129.7, 133.8, 134.5, 135.9 (Ar–CH, Ar–C, –N–CH=CH–N=), 136.8 (–N–CH=N–), 155.0 (C=N); MS m/z (ESI): 340.1 [M + H]+, 341.1 [(M + 1) + H]+, 342.1 [(M + 2) + H]+.
(1E)-N-[(4-Fluorobenzyl)oxy]-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vd). Yield 59.9%; light brown viscous oil; IR (KBr): ν (cm−1) 3003, 2924, 1720, 1670 (C=N), 1510, 1435, 1217, 765; 1H-NMR (CDCl3): δ (ppm) 3.29 (t, J = 6.6 Hz, 2H, –CH2–CH2–N), 4.25 (t, J = 6.5 Hz, 2H, –CH2–CH2–N), 5.27 (s, 2H, –CH2–C6H4), 6.90 (s, 1H, –N–CH=CH–N=), 7.08 (s, 1H, –N–CH=CH–N=), 7.15–7.22 (m, 2H, Ar–H), 7.45–7.56 (m, 8H, Ar–H, –N–CH=N–), 13C-NMR (CDCl3): δ (ppm) 29.2 (–CH2–CH2–N), 43.5 (–CH2CH2–N), 75.9 (–CH2–C6H4), 115.3 (d, JC–3′, F&C–5′, F = 21.1 Hz, C–3′ and C–5′), 118.9 (–N–CH=CH–N=), 125.9, 128.7, 128.8, 129.6, 134.6 (Ar–CH, Ar–C, –N–CH=CH–N=), 130.3 (d, JC–2′, F&C–6′, F = 8.3 Hz, C–2′ and C–6′), 133.2 (d, JC–1′, F = 2.8 Hz, C–1′), 136.8 (–N–CH=N–), 154.9 (C=N), 162.5 (d, JC–4′, F = 246.9 Hz, C–4′); MS m/z (ESI): 324.2 [M + H]+, 325.2 [(M + 1) + H]+.
(1E)-3-(1H-Imidazol-1-yl)-N-[(4-methylbenzyl)oxy]-1-phenylpropan-1-imine (Ve). Yield 52.2%; light brown viscous oil; IR (KBr): ν (cm−1) 3003, 2781, 1714, 1676 (C=N), 1512, 1220, 790; 1H-NMR (CDCl3): δ (ppm) 2.41 (s, 3H, CH3), 3.25 (br. s., 2H, –CH2–CH2–N), 4.22 (br. s., 2H, –CH2–CH2–N), 5.26 (s, 1H, –CH2–C6H4), 6.95 (s, 1H, –N–CH=CH–N=), 7.04 (s, 1H, –N–CH=CH–N=), 7.26 (d, J = 6.3 Hz, 2H, Ar–H), 7.37 (d, J = 6.5 Hz, 2H, Ar–H), 7.41–7.51 (m, 5H, Ar–H), 7.64 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 21.2 (CH3), 29.4 (–CH2–CH2–N), 43.4 (–CH2CH2–N), 76.6 (–CH2–C6H4), 118.9 (–N–CH=CH–N=), 125.9, 127.3, 128.5, 128.6, 129.1, 129.5, 129.6, 134.3, 134.9 (Ar–CH, Ar–C, –N–CH=CH–N=), 137.9 (–N–CH=N–), 154.7 (C=N); MS m/z (ESI): 320.2 [M + H]+, 321.2 [(M + 1) + H]+.
(1E)-3-(1H-Imidazol-1-yl)-1-phenyl-N-{[4-(trifluoromethyl)benzyl]oxy}propan-1-imine (Vf). Yield 43.3%; light brown viscous oil; IR (KBr): ν(cm−1) 3003, 2975, 1717, 1676 (C=N), 1502, 1437, 1219, 790; 1H-NMR (CDCl3): δ (ppm) 3.27 (br. s., 2H, –CH2–CH2–N), 4.21 (br. s., 2H, –CH2–CH2–N), 5.27 (s, 1H, –CH2–C6H4), 6.86 (s, 1H, –N–CH=CH–N=), 7.01 (s, 1H, –N–CH=CH–N=), 7.39–7.51 (m, 9H, Ar–H), 7.65 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.2 (–CH2–CH2–N), 43.6 (–CH2CH2–N), 75.7 (–CH2–C6H4), 119.0 (–N–CH=CH–N=), 125.4, 125.5, 126.1, 127.4, 128.3, 128.8, 129.0, 129.8, 134.4, 136.9, 141.6 (Ar–CH, Ar–C, –N–CH=CH–N=, –N–CH=N–), 155.4 (C=N); MS m/z (ESI): 374.2 [M + H]+, 375.1 [(M + 1) + H]+.
(1E)-N-{[3,5-Bis(trifluoromethyl)benzyl]oxy}-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (Vg). Yield 28%; light brown viscous oil; IR (KBr): ν (cm−1) 3003, 2970, 1717,1673 (C=N), 1502, 1420, 1223, 702; 1H-NMR (CDCl3): δ (ppm) 3.31 (br. s., 2H, –CH2–CH2–N), 4.25 (br. s., 2H, –CH2–CH2–N), 5.29 (s, 1H, –CH2–C6H4), 6.89 (s, 1H, –N–CH=CH–N=), 7.05 (s, 1H, –N–CH=CH–N=), 7.39–7.52 (m, 6H, Ar–H, –N–CH=N–), 7.75–7.86 (m, 2H, Ar–H), 8.39 (s, 1H, Ar–H); 13C-NMR (CDCl3): δ (ppm) 28.9 (–CH2–CH2–N), 44.3 (–CH2CH2–N), 74.9 (–CH2–C6H4), 119.4 (–N–CH=CH–N=), 121.9, 122.5, 124.0, 126.2, 128.3, 128.9, 130.2, 131.7, 131.9, 136.6, 140.1 (Ar–CH, Ar–C, –N–CH=CH–N=, –N–CH=N–), 155.8 (C=N); MS m/z (ESI): 442.1 [M + H]+, 443.1 [(M + 1) + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-(benzyloxy)propan-1-imine (Vh). Yield 61%; light brownviscousoil; IR (KBr): ν (cm−1) 3030, 2927, 1670 (C=N), 1606, 1489, 1284, 700; 1H-NMR (CDCl3): δ (ppm) 3.17 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 4.18 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 5.22 (s, 2H, –CH2–C6H5), 5.99 (s, 2H, –O–CH2–O–), 6.76 (d, J = 8.0 Hz, 1H, Ar–H), 6.82 (s, 1H, –N–CH=CH–N=), 6.86 (dd, J = 1.5, 8.5 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=CH–N=), 7.09 (d, J = 1.0 Hz, 1H, Ar–H), 7.33–7.37 (m, 5H, Ar–H), 7.50 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.4 (–CH2–CH2–N), 43.7 (–CH2CH2–N), 76.2 (–CH2–C6H4), 101.4 (–O–CH2–O–), 106.2, 108.2 (Ar–CH), 119.0 (–N–CH=CH–N=), 120.3, 128.2, 128.4, 128.5,128.7, 129.0, 136.9 (Ar–CH, Ar–C, –N–CH=CH–N=), 137.5 (–N–CH=N–), 148.2, 148.3 (Ar–C), 154.3 (C=N); MS m/z (ESI): 350.1 [M + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-bromobenzyl)oxy]propan-1-imine (Vi). Yield 55%; pale yellow solid, m.p. 80–82 °C; IR (KBr): ν (cm−1) 3115, 2934, 1670 (C=N), 1506, 1489, 1232, 756; 1H-NMR (CDCl3): δ (ppm) 3.17 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 4.17 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 5.13 (s, 2H, –CH2–C6H4), 5.98 (s, 2H, –O–CH2–O–), 6.76 (d, J = 8.0 Hz, 1H, Ar–H), 6.84 (s, 1H, –N–CH=CH–N=), 6.88 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=CH–N=), 7.07 (d, J = 1.0 Hz, 1H, Ar–H), 7.25 (d, J = 8.0 Hz, 2H, Ar–H), 7.50 (d, J = 8.5 Hz, 2H, Ar–H), 7.52 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.2 (–CH2–CH2–N), 43.7 (–CH2CH2–N), 75.8 (–CH2–C6H4), 101.5 (–O–CH2–O–), 106.2, 108.2 (Ar–CH), 119.0 (–N–CH=CH–N=), 120.4, 122.1, 128.7, 128.9, 130.1, 131.5, 136.5 (Ar–CH, Ar–C, –N–CH=CH–N=), 136.9 (–N–CH=N–), 148.2, 149.0 (Ar–C), 154.6 (C=N); MS m/z (ESI): 428.1 [M + H]+, 430.0 [(M + 2) + H]+, 431.0[(M + 3) + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-chlorobenzyl)oxy]propan-1-imine (Vj). Yield 40%; light brown viscous oil; IR (KBr): ν (cm−1) 3017, 2932, 1670 (C=N), 1506, 1491, 1280, 756; 1H-NMR (CDCl3): δ (ppm) 3.16 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 4.15 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 5.15 (s, 2H, –CH2–C6H4), 5.98 (s, 2H, –O–CH2–O–), 6.76 (d, J = 8.0 Hz, 1H, Ar–H), 6.84 (s, 1H, –N–CH=CH–N=), 6.86 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=CH–N=), 7.07 (d, J = 1.0 Hz, 1H, Ar–H), 7.31–7.33 (m, 2H, Ar–H), 7.35 (d, J = 8.5 Hz, 2H, Ar–H), 7.43 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.3 (–CH2–CH2–N), 43.6 (–CH2CH2–N), 76.7 (–CH2–C6H4), 101.5 (–O–CH2–O–), 106.2, 108.2 (Ar–CH), 118.9 (–N–CH=CH–N=), 120.4, 121.9, 128.7, 129.3, 129.7, 133.9, 136.5 (Ar–CH, Ar–C, –N–CH=CH–N=), 136.9 (–N–CH=N–), 148.2, 149.0 (Ar–C), 154.6 (C=N); MS m/z (ESI): 384.1 [M + H]+, 385.1 [(M + 1) + H]+, 386.1 [(M + 2) + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-fluorobenzyl)oxy]propan-1-imine (Vk). Yield 32%; light brown viscous oil; IR (KBr): ν (cm−1) 3018, 2962, 1604 (C=N), 1510, 1490, 1215, 759; 1H-NMR (CDCl3): δ (ppm) 3.14 (t, J = 7.1 Hz, 2H, –CH2–CH2–N), 4.14 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 5.14 (s, 2H, –CH2–C6H4), 5.96 (s, 2H, –O–CH2–O–), 6.75 (d, J = 8.1 Hz, 1H, Ar–H), 6.82 (s, 1H, –N–CH=CH–N=), 6.86 (dd, J = 2.0, 8.5 Hz, 1H, Ar–H), 6.99 (s, 1H, –N–CH=CH–N=), 7.04–7.07 (m, 3H, Ar–H), 7.35–7.38 (m, 2H, Ar–H), 7.41 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.3 (–CH2–CH2–N), 43.6 (–CH2CH2–N), 75.9 (–CH2–C6H4), 101.5 (–O–CH2–O–), 106.2, 108.2 (Ar–CH), 115.4 (d, JC–3′, F&C–5′, F= 21.4 Hz, C–3′ and C–5′), 119.0 (–N–CH=CH–N=), 120.3, 128.9, 129.3, (Ar–CH, Ar–C, –N–CH=CH–N=), 130.3 (d, JC–2′, F&C–6′, F= 8.2 Hz, C–2′ and C–6′), 133.3 (d, JC–1′, F = 3.2 Hz, C–1′), 136.9 (–N–CH=N–), 148.2, 149.0 (Ar–C), 154.5 (C=N), 162.6 (d, JC–4′, F= 246.4 Hz, C–4′); MS m/z (ESI): 368.1 [M + H]+, 369.1 [(M + 1) + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-[(4-methylbenzyl)oxy]propan-1-imine (Vl). Yield 24%; light brown viscous oil; IR (KBr): ν (cm−1) 3669, 3115, 2953, 1614 (C=N), 1585, 1510, 1248, 754; 1H-NMR (CDCl3): δ (ppm) 2.39 (s, 3H, CH3), 3.15 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 4.17 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 5.18 (s, 2H, –CH2–C6H4), 5.99 (s, 2H, –O–CH2–O–), 6.77 (d, J = 8.0 Hz, 1H, Ar–H), 6.83 (s, 1H, –N–CH=CH–N=), 6.88 (dd, J = 1.5, 8.0 Hz, 1H, Ar–H), 7.01 (s, 1H, –N–CH=CH–N=), 7.09 (d, J = 1.5 Hz, 1H, Ar–H), 7.22 (d, J = 7.5 Hz, 2H, Ar–H), 7.32 (d, J = 8.0 Hz, 2H, Ar–H), 7.46 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 21.2 (CH3), 29.4 (–CH2–CH2–N), 43.7 (–CH2CH2–N), 76.6 (–CH2–C6H4), 101.4 (–O–CH2–O–), 106.2, 108.2 (Ar–CH), 118.9 (–N–CH=CH–N=), 120.4, 128.6, 128.9, 129.1, 129.2, 134.4, 136.9 (Ar–CH, Ar–C, –N–CH=CH–N=), 137.9 (–N–CH=N–), 148.1, 148.9 (Ar–C), 154.2 (C=N); MS m/z (ESI): 364.1 [M + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-{[4-(trifluromethyl)benzyl]oxy}propan-1-imine (Vm). Yield 25%; light brown solid, m.p. 81–83 °C; IR (KBr): ν (cm−1) 3016, 2941, 1670 (C=N), 1506, 1448, 1232, 756; 1H-NMR (CDCl3): δ (ppm) 3.23 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 4.23 (t, J = 7.0 Hz, 2H, –CH2–CH2–N), 5.24 (s, 2H, –CH2–C6H4), 5.99 (s, 2H, –O–CH2–O–), 6.78 (d, J = 8.1 Hz, 1H, Ar–H), 6.86 (s, 1H, –N–CH=CH–N=), 6.91 (dd, J = 1.6, 8.1 Hz, 1H, Ar–H), 7.04 (s, 1H, –N–CH=CH–N=), 7.09 (d, J = 1.4 Hz, 1H, Ar–H), 7.49 (d, J = 7.7 Hz, 2H, Ar–H), 7.65 (d, J = 7.9 Hz, 2H, Ar–H), 7.68 (s, 1H, –N–CH=N–); 13C-NMR (CDCl3): δ (ppm) 29.1 (–CH2–CH2–N), 43.9 (–CH2CH2–N), 75.6 (–CH2–C6H4), 101.5 (–O–CH2–O–), 106.2, 108.3 (Ar–CH), 119.1 (–N–CH=CH–N=), 120.5, 123.0, 125.4, 125.5, 128.4, 128.5, 130.1, 136.8, 141.6 (Ar–CH, Ar–C, –N–CH=CH–N=, –N–CH=N–), 148.3, 149.2 (Ar–C), 154.8 (C=N); MS m/z (ESI): 418.1 [M + H]+, 419.1 [(M + 1) + H]+.
(1E)-1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)-N-{[3,5-bis(trifluromethyl)benzyl]oxy} propan-1-imine (Vn). Yield 55%; light brown viscous oil; IR (KBr): ν (cm−1) 3014, 2900, 1670 (C=N), 1504, 1446, 1232, 754; 1H-NMR (CDCl3): δ (ppm) 3.24 (t, J = 6.9 Hz, 2H, –CH2–CH2–N), 4.22 (t, J = 6.9 Hz, 2H, –CH2–CH2–N), 5.26 (s, 2H, –CH2–C6H4), 5.99 (s, 2H, –O–CH2–O–), 6.78 (d, J = 8.1 Hz, 1H, Ar–H), 6.89 (s, 1H, –N–CH=CH–N=), 6.92 (dd, J = 1.5, 8.1 Hz, 1H, Ar–H), 7.03 (s, 1H, –N–CH=CH–N=), 7.06 (d, J = 1.3 Hz, 1H, Ar–H), 7.65 (s, 1H, –N–CH=N–), 7.84–7.86 (m, 3H, Ar–H); 13C-NMR (CDCl3): δ (ppm) 29.1 (–CH2–CH2–N), 43.9 (–CH2CH2–N), 74.8 (–CH2–C6H4), 101.6 (–O–CH2–O–), 106.2, 108.3 (Ar–CH), 119.1 (–N–CH=CH–N=), 120.6, 121.9, 124.4, 128.1, 128.2, 131.7, 131.9, 136.8, 140.3 (Ar–CH, Ar–C, –N–CH=CH–N=, –N–CH=N–), 148.3, 149.4 (Ar–C), 155.4 (C=N); MS m/z (ESI): 486.1 [M + H]+, 487.1 [(M + 1) + H]+.

3.3. Crystal Structure Determination

Compound Vi was obtained as single crystals by slow evaporation from ethanolic solution of the pure compound at room temperature. Data were collected on a Bruker APEX-II D8 Venture area diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å at 293 (2) K. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT [22,23] was used to solve the structure. The final refinement was performed by full-matrix least-squares techniques with anisotropic thermal data for non-hydrogen atoms. In compound Vi, C20H18BrN3O3, the crystallographic data and refinement information are summarized in Table S1. The crystallographic data of compound Vi have been deposited with the Cambridge Crystallographic Data Center (CCDC-1577844) and can be found in Supplementary Materials. Copies of the data may be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (deposit@ccdc.cam.ac.uk).

3.4. Antifungal Activity

3.4.1. Materials

The reference standard antifungal drugs, fluconazole and ketoconazole, were obtained from Shouguang-Fukang Pharmaceutical Ltd. (Weifang, China) and from Sigma-Aldrich Co. (St. Louis, MO, USA), respectively. Liquid RPMI 1640 medium supplemented with l-glutamine was purchased from Gibco-BRL, Life Technologies (Paisley, Scotland). Sabouraud Dextrose Agar (SDA) was obtained from Merck Co. (Darmstadt, Germany). Dimethyl sulfoxide (100%) was used to dissolve the reference standards and/or the tested compounds Van to afford an initial concentration of 2048 mg/L.

3.4.2. Organisms

Candida albicans (ATCC 90028), Candida tropicalis (ATCC 66029), Candida parapsilosis (ATCC 22019), and Aspergillus niger (ATCC 16404) were used to assess antifungal activity.

3.4.3. Preparation of Fungal Inocula

Fungal inocula were prepared as previously reported [21].

3.4.4. Preparation of the Tested Compound Solutions

Briefly, a twofold dilution series of the tested compounds Van was prepared in a double-strength RPMI 1640 culture medium. Ten serial dilutions were prepared to afford concentrations ranging from 1024 mg/L to 2 mg/L.

3.4.5. Antifungal Susceptibility Studies

The MIC values of the tested compounds Van were determined as previously reported [21].

4. Conclusions

The synthesis and spectroscopic characterization of certain new oximino ethers Van bearing imidazole pharmacophore moiety have been reported. Single crystal X-ray analysis of compound Vi confirmed the assigned (E)-configuration of the imine functionality of the target compounds Van. The in vitro antifungal potential of compounds Van was assessed using DIZ and MIC assays. Compound Ve emerged as the most active compound toward Candida albicans, being nearly equipotent with the reference antifungal drug FLC with an MIC value of 0.050 µmol/mL. On the other hand, compounds Vi and Vn exhibited the most potent activity towards Candida parapsilosis, with an MIC value of 0.002 µmol/mL—about twenty-three times more potent than FLC. It seems that the replacement of the phenyl ring in compounds Vag with the 1,3-benzodioxole scaffold, which gave their respective compounds Vhn, did not show superior antifungal activity against the tested fungal strains except towards Candida parapsilosis. The antifungal results of the current investigation might support the development of new potent and safer azole antifungal agents to be harnessed in the clinic.

Supplementary Materials

Supplementary Materials are available online.

Acknowledgments

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project No. RGP-196.

Author Contributions

R.I.A.-W. and A.R.A.-G. prepared and characterized the title compounds. H.A.G. performed the X-ray analysis. M.H.A.-A. carried out the in vitro antifungal assessment of the target compounds. M.I.A. proposed the work, prepared the single crystals of compound Vi and prepared the manuscript for publication. All authors discussed the contents of the manuscript.

Conflicts of Interest

The authors have declared no conflict of interest.

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  • Sample Availability: Samples of the synthesized compounds are available from the corresponding authors.
Figure 1. Chemical structures of the antifungal agents 1 and 2 as well as the target compounds Van.
Figure 1. Chemical structures of the antifungal agents 1 and 2 as well as the target compounds Van.
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Scheme 1. Synthesis of the target compounds Van. Reagents and conditions: (i) HN(CH3)2.HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) Imidazole, water, reflux, 5 h; (iii) H2NOH.HCl, KOH, ethanol, reflux, 18 h; (iv) Appropriate benzyl chloride/bromide derivative, NaH, DMF, 80 °C, 3 h.
Scheme 1. Synthesis of the target compounds Van. Reagents and conditions: (i) HN(CH3)2.HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) Imidazole, water, reflux, 5 h; (iii) H2NOH.HCl, KOH, ethanol, reflux, 18 h; (iv) Appropriate benzyl chloride/bromide derivative, NaH, DMF, 80 °C, 3 h.
Molecules 22 01895 sch001
Figure 2. ORTEP diagram of compound Vi. Displacement ellipsoids are plotted at the 40% probability level for non-H atoms.
Figure 2. ORTEP diagram of compound Vi. Displacement ellipsoids are plotted at the 40% probability level for non-H atoms.
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Figure 3. Molecular packing of compound Vi.
Figure 3. Molecular packing of compound Vi.
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Table 1. Selected geometric parameters (Å, °).
Table 1. Selected geometric parameters (Å, °).
Bond Lengths
Br1–C181.905(3)N1–C81.290(4)
O1–C11.432(5)N2–C101.462(5)
O1–C21.386(4)N2–C111.337(5)
O2–C11.428(5)N2–C131.347(6)
O2–C71.373(4)N3–C111.313(6)
O3–N11.410(4)N3–C121.343(6)
O3–C141.442(4)
Bond Angles
C1–O1–C2105.9(3)O2–C7–C2110.5(3)
C1–O2–C7105.9(3)O2–C7–C6128.4(3)
N1–O3–C14107.6(2)N1–C8–C4114.9(3)
O3–N1–C8111.8(3)N1–C8–C9123.1(3)
C10–N2–C11127.2(3)N2–C10–C9112.3(3)
C10–N2–C13126.8(3)N2–C11–N3112.3(4)
C11–N2–C13106.0(3)N3–C12–C13110.2(4)
C11–N3–C12104.8(4)N2–C13–C12106.7(4)
O1–C1–O2108.0(3)O3–C14–C15113.3(3)
O1–C2–C3127.9(3)Br1–C18–C17119.4(2)
O1–C2–C7109.3(3)Br1–C18–C19119.3(3)
Table 2. Hydrogen-bond geometry (Å, °).
Table 2. Hydrogen-bond geometry (Å, °).
D–H···AD–HH···AD···AD–H···A
C3–H3A···N30.93002.53003.453(5)169.00
Symmetry codes: (i) –x − 2, −y, −z + 1.
Table 3. Antifungal activity of the target oximino ethers Van against C. albicans, C. tropicalis, C. parapsilosis and A. niger.
Table 3. Antifungal activity of the target oximino ethers Van against C. albicans, C. tropicalis, C. parapsilosis and A. niger.
Compound No.Candida albicansCandida tropicalisCandida parapsilosisAsperagillus niger
DIZ ± SD (mm)MIC (µmol/mL)DIZ ± SD (mm)MIC (µmol/mL)DIZ ± SD (mm)MIC (µmol/mL)DIZ ± SD (mm)MIC (µmol/mL)
Va18 ± 1.000.20916 ± 1.160.41920 ± 0.680.10521 ± 1.140.105
Vb23 ± 0.630.08318 ± 0.970.08324 ± 0.450.04222 ± 0.940.083
Vc22 ± 0.520.09422 ± 0.630.09423 ± 0.610.04719 ± 0.750.047
Vd18 ± 1.120.19815 ± 1.210.19819 ± 0.850.04912 ± 0.300.198
Ve19 ± 1.100.05017 ± 1.140.10020 ± 1.000.05012 ± 0.410.201
Vf18 ± 0.950.68618 ± 1.130.34321 ± 0.430.04322 ± 0.990.172
Vg21 ± 1.130.07320 ± 0.910.14522 ± 0.580.03613 ± 0.640.290
Vh14 ± 0.500.18310 ± 0.580.18313 ± 0.600.00320 ± 0.500.733
Vi15 ± 1.200.14915 ± 0.300.14914 ± 0.500.00213 ± 1.530.299
Vj15 ± 0.300.16714 ± 0.600.16721 ± 1.000.01016 ± 1.310.667
Vk15 ± 0.580.17412 ± 0.580.17413 ± 0.580.04423 ± 0.500.697
Vl16 ± 1.000.17613 ± 0.600.17619 ± 1.000.00612 ± 0.580.705
Vm15 ± 0.580.15313 ± 0.400.15323 ± 0.600.01914 ± 1.000.307
Vn13 ± 0.400.52715 ± 1.200.52719 ± 0.580.00211 ± 0.20>1.05
Fluconazole18 ± 1.100.05119 ± 1.000.04519 ± 0.900.047NDND
KetokonazoleNDNDNDNDNDND29 ± 0.600.02
Arithmetic mean ± standard deviation; DIZ: diameter of the inhibition zone; SD: standard deviation; MIC: minimum inhibitory concentration; ND: not determined.
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