Scientific paper
The Design, Synthesis, and Antioxidant Activity of Amphophilic Oximes and Amidoximes
Mirjam Gosenca, Janez Mravljak, Mirjana Gasperlin and Ales Obreza*
University of Ljubljana, Faculty of Pharmacy, A{ker~eva 7, 1000 Ljubljana, Slovenia.
* Corresponding author: E-mail: ales.obreza@ffa.uni-lj.si; Tel.: (+386) 14769677; Fax: (+386) 14258031
Received: 13-12-2012
Abstract
New amphiphilic benzamidoxime, benzoxime, and aliphatic oxime derivatives of glycolipid mimetics were synthesized. The total antioxidant capacity of these amphiphilic derivatives was evaluated using DPPH assay. The observed antioxidant activity was the highest for benzamidoxime derivatives and glycolipid mimetics with two oxime functionalities, followed by benzoxime derivatives, glycolipid mimetics with one oxime group, and dimers of oxime. Due to their amphiphilic structure, which was a guidance for compound design and synthesis, these novel amphiphilic compounds can be proposed as potential antioxidants for tackling oxidative processes in two-phase systems, either biological (cell membranes) or artificial (emulsions).
Keywords: Amphiphilic molecules, amidoximes, oximes, glycolipid mimetics, antioxidant activity.
1. Introduction
The stability of an active pharmaceutical ingredient (API) and/or final formulation is of the primary concern in the field of pharmaceutical formulation, with oxidation processes being one of the common contributors to instability problems. Various approaches can be used to eliminate or diminish the extent of oxidative degradation, the addition of antioxidants being one of them.1 Antioxi-dants are molecules that prevent oxidation even in a low concentration and an antioxidant effect can be achieved through their ability to complex transition metal ions, catalyzing the breakdown of oxidizing species, or reacting directly with free radicals.2 Antioxidants are used not only as excipients, but can also be used as APIs themselves. Namely, all living organisms require molecular oxygen for energy production, but as triplet oxygen is a biradical it is impossible to avoid secondary oxidations not involved in physiological metabolism. Free radicals, reactive oxygen species, and reactive nitrogen species are formed. These mediate oxidative stress, defined as an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. They are involved in many pathologies such as cancer, ischemia-reperfusion disorders, cardiovascular di-
seases, and neurodegenerative disorders (Parkinson's disease and Alzheimer's disease). The role of antioxidants in prophylaxis of these conditions, as well as in the aging process, emphasizes the importance of developing antio-xidants as APIs.3-5
Antioxidant is any substance that delays, prevents or removes oxidative damage to a target molecule.6 Most of them are reactive and therefore highly unstable compounds. Their consumption and loss of efficacy can usually be attributed to oxidation processes (and hydrolysis in some cases). An acknowledged approach for increasing their stability is incorporation into a suitable delivery system because stability can be influenced by the structural properties of the formulation. However, this is often insufficient to achieve adequate long-term stability.7-8 Therefore a new approach for increasing the stability of ascorbyl palmitate (AP), an antioxidant, incorporated as API in mi-croemulsions for preventing skin aging, was reported by our research group. The oxime molecule, 4-(tridecy-loxy)benzaldehyde oxime (TDBO), was designed and synthesized based on structural similarity to AP, and its an-tioxidant activity was confirmed. Incorporation of the oxi-me molecule as a co-antioxidant resulted in increased AP stability in hydrophilic microemulsions and the effect was explained by higher local concentration of both molecules in the inner phase of the system and consequently better
protection of AP.9 This led us to further investigation oriented towards designing and synthesizing antioxidants with an amphiphilic structure for incorporation into two-phase delivery systems; that is, regular emulsions, microemul-sions, or lyotropic liquid crystals. The design strategy was oriented towards long linear molecules composed of lipop-hilic alkyl or acyl residue of varying length and polar moiety, bearing either the oxime or amidoxime group. The oxime group is often associated with its antioxidant activity, and therefore oxime compounds are of particular interest in a state of oxidative stress displaying free-radical scavenging and/or chelating properties. They have been used as cholinesterase reactivators following organophosp-hate-induced oxidative damage and have been studied as inhibitors of low-density lipoprotein oxidation and lipid peroxidation.10-12 Amidoximes have been proven to exhibit numerous biological activities (anti-inflammatory, antiviral, etc.). For nicotinic amidoxime derivative behavior similar to antioxidants was confirmed, as ischemia-reperfu-sion-induced mitochondrial reactive oxygen species formation and oxidative cell damage was decreased due to inhibition of specific nuclear polymerase.13
Amphiphilic molecules are distinctive for their surfactant properties. Surfactant molecules find a wide range of uses in pharmaceutical preparation, but can also contribute to adverse reactions, skin irritation following dermal application being one of them.14 Therefore the use of biocompatible and naturally occurring surfactants is a trend and a must in pharmacy, one important group of amphip-hilic biomolecules being glycolipids.15 Recently, we reported the synthesis of novel amphiphilic oximes of galactose and glucosamine.16
In this context, this work is a continuation of our previous study9 and reports the design, synthesis, and characterization of a new set of amphiphilic oxime and ami-doxime molecules and the evaluation for their antioxidant activity. The new group of compounds was designed to improve polarity by introducing a polar ethanolamine spacer between benzoxime or benzamidoxime functionality and the lipophilic hydrocarbon chain of TDBO. In the second part of our research we synthesized glycolipid mi-metics in which the aromatic ring was replaced by a biologically acceptable monosaccharide D-galactose or D-glu-cose with one or two oxime functionalities.16
Scheme 1. Synthesis of amphiphilic benzamidoxime and benzoxime derivatives: i. epichlorhydrine, NaOH/H2O, dioxane, r.t., 12 h ii. Ca(OTf)2, H2N(CH2)nCH3 (n = 5, 7, 9, 11, 13), anhydrous dioxane, reflux, 6 h, iii. NH2OH X HCl, K2CO3, anhydrous ethanol, reflux, 12 h.
2. Results and Discussion
2. 1. Chemistry
Based on our previous studies in the field of new antimicrobial drug design1718 and further docking studies, we came across several useful intermediates for the synthesis of amphiphilic compounds. The overall synthetic approach is outlined in Schemes 1, 2, and 3. The synthesis of benza-midoxime and benzoxime derivatives (Scheme 1) was started from 4-cyanophenol (1),19 which was reacted with epichlorhydrine to yield compound 2, followed by nuc-leophylic substitution at the less sterically hindered carbon with aliphatic amines with different length of alkyl chain to yield amphiphilic compounds 3a-e. In the last step, nitrile functionality was transformed to amidoxime 4a-e with hydroxylamine hydrochloride. Oximes 8a-e were prepared in an analogous way, starting from 4-hydroxybenzaldehyde (5). The reaction of epoxide with alkyl amines20 in the latter case resulted in the formation of about 10% of tertiary amines 9a-e that were also transformed to oximes 10a-e.
The synthesis of glycolipid derivatives21 is presented in Schemes 2 and 3 and described in detail in a recent paper.16
The HLB parameter is used to characterize the ratio between hydrophilic and lipophilic parts of the surfactant
molecule and was calculated for all synthesized compounds with the results depicted in Table 1. As expected, among individual groups of compounds HLB values vary by changing the length of the aliphatic tail: the HLB value and thereby the hydrophilic character decreases with increasing length of the alkyl or acyl residue. The data obtained show that benzamidoxime and benzoxime derivatives are more hydrophilic compared to previously synthesized highly lipophilic glycolipid mimetic TDBO; this effect is the most notable for dimers of oxime (10a-10e).
2. 2. Evaluation of Aantioxidant Capacity of Amphiphilic Amidoxime, Oxime, and Glycolipid Derivatives
Total antioxidant capacity assay was used to determine the hierarchy of radical-scavenging abilities of potential antioxidants that work either through electron- or H-donating mechanisms. Accordingly, DPPH assay was used to assess the radical-scavenging ability of synthesized derivatives that can be divided among different groups regarding their structure; that is, benzamidoxime (4a-e), benzoxime (8a-e), benzoxime dimers (10b, 10d), galactose derivatives (15a-e), and glucosamine derivati-
Scheme 2: Synthesis of amphiphilic derivatives of galactose: i. acetone, CuSO4 (2.4 equiv), H2SO4 (0.35 equiv), r. t., 24 h, then Ba(OH)2 (0.35 equiv); ii. CH3(CH2)nBr (n = 7, 9, 11, 13, 15; 1.5 equiv), NaH (1.5 equiv), 15-Crown-5 (0.02 equiv), imidazole (0.01 equiv), 1,4-dioxane; iii. 75% TFA, H2O, 0 °C ^ r t., 1.5 h; iv. NH2OH (5 equiv), pyridine, 40 °C, 48 h.
Table 1. HLB values of synthesized amphiphilic derivatives
HLB values
benzamidoxime & benzoxime derivatives
4a 4b 4c 4d 4e 8a 8b 8c 8d 8e 10a 10b 10c 10d 10e
14.50 13.29 12.27 11.39 10.64 14.21 12.98 11.94 11.05 10.29 16.51 15.61 14.80 14.08 13.42
derivatives of galactose & glucose
15a 15b 15c 15d 15e 22a 22b 22c 22d 23a 23b 23c 23d
12.63 11.58 10.68 9.92 9.26 12.96 12.03 11.22 10.51 12.68 11.73 10.91 10.20
Scheme 3: Synthesis of amphiphilic derivatives of glucose: i. CH3(CH2)nCOCl (n = 8, 10, 12, 14; 1.1 equiv), NaHCO3 (2 equiv), H2O, 1,4-dioxa-ne, r. t., 24 h; ii. Ph3CCl (1.7 equiv), DMAP (0.05 equiv), pyridine;, 75 °C, 2 h; iii. Ac2O (6 equiv), pyridine, 0 °C ^ r. t., 12 h; iv. FeCl3 (2 equiv), H2O, CH2Cl2, r. t., 2 h; v. DMP (1.2 equiv), CH2Cl2, r. t., 1.5 h, then work-up with Na2S2O3; vi NH2OH (7 equiv), EtOH, 40 °C, 48 h.
ves with two (22a-d) or one (23a-d) oxime functionality.
It is evident for all tested benzamidoxime and ben-zoxime derivatives that their antioxidant activity correlates with concentration: the higher the concentration, the lower the amount of remaining DPPH' (DPPH' rem) and the higher the free radical-scavenging activity (Figure 1). The molecular structure of tested molecule had a great impact on its radical-scavenging ability against DPPH. Benzamidoxime derivatives (4a-e) demonstrate the highest antioxidant potential, followed by benzoxime derivatives (8a-e), and being the lowest for compounds with two oxime moieties (10b, 10d). Comparison of amidoxime with oxime group emphasizes additional amino group as an important factor that enhances antioxidant activity. In the same series, benzamidoxime derivatives 4a-e exhibit similar antioxidant performance; 4b being the most pronounced (it reacted rapidly with the DDPH radical, which was completely reduced in a reaction time of 4 minutes) with a chain of eight carbon atoms. Antioxidant activity decreases with either shortening or prolongation of the
alkyl chain within this series. The same tendency was also observed for benzoxime derivatives 8a-e. A proportional relationship of antioxidant properties and concentration was also noted for glycolipid mimetics, except for derivatives of galactose 15a-e, which expressed no antioxidant activity. It should be mentioned that galactose derivatives 15a-e were tested only at the lowest concentration, due to solubility limitations (Figure 2). Amphiphilic derivatives of glucose express significant differences in antioxidant properties, depending on whether they consist of two (22a-d) or only one oxime functionality (23a-d). The results agreed well with the expected activities because the compounds with two oxime groups (22b-d) showed higher antioxidant activity compared to compounds with only one oxime group (23a-d). Among compounds with two oxime groups, the highest scavenging activity was observed for 22c with a long length of the aliphatic tail.
In addition, compared to TDBO, which was confirmed as an effective co-antioxidant in microemulsion systems in our previous published work, benzamidoximes and derivatives of glucose with two oxime functionalities
Figure 1. Free radical scavenging activity expressed as DPPH' rem of tested benzamidoxime and benzoxime derivatives at concentrations of 5 mM (O) and 10 mM (□) after 30 min.
a s	m		m	§ g
		□ ©	CD	§ o
	E			
	©	§	$	
		I		
15a 15b 15c 22b 22c 22 (J 23a 23b 23c 23d
Figure 2. Free radical scavenging activity expressed as DPPH' rem of tested glycolipid derivatives at concentrations of 0.5 mM (□), 1 mM (O) and 5 mM (O) after 30 min.
demonstrated superior antioxidant activity in the same concentration range.
3. Experimental
3. 1. General
Chemicals from Fluka and Sigma-Aldrich Chemical Co. were used without further purification. Anhydrous dio-xane, dichloromethane and Et3N were dried and purified by distillation over Na, K2CO3 and KOH, respectively. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel (60F254) plates (0.25 mm). Co-
lumn chromatography was performed on silica gel 60 (Merck, particle size 240-400 mesh). Melting points were determined on a Reichert hot stage microscope and are uncorrected. 1H NMR spectra were recorded on a Bruker AVANCE DPX300 spectrometer in CDCl3 or DMSO-d6 solution with TMS as internal standard. Chemical shifts were reported in ppm (5) downfield from TMS. All the coupling constants J) are in hertz. IR spectra were recorded on a Perkin-Elmer FTIR 1600 spectrometer. Mass spectra were obtained with a VG-Analytical Autospec Q mass spectrometer with EI or FAB ionization (MS Centre, Jožef Stefan Institute, Ljubljana). All reported yields are yields of purified products.
3. 2. Synthesis of 4-(oxiran-2-ylmethoxy) benzonitrile (2)
To a solution of 4-hydroxybenzonitrile (6.00 g; 50.4 mmol) in 30 mL 2M NaOH, epichlorhydrin (4.68 g; 50.0 mmol) was added dropwise on ice-bath. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. After the addition of dichloromethane (100 mL) the phases were separated. The organic phase was washed with 1M HCl (3 x 40 mL), water (40 mL) and brine (40mL), dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was further purified by column chromatography to yield white solid (MF: petrolet-her/ethyl acetate = 2:1). Yield 84%. 1H NMR (300 MHz, DMSO-d6): 5 2.72 (m, 1H, CH2), 2.85 (m, 1H, CH2), 3.35 (m, 1H, CH), 3.93 (m, 1H, CH2), 4.45 (m, 1H, CH2), 7.12 (A2X2, J = 8.6 Hz, Av = 201 Hz, 2H, Ar-H), 7.79 (A2X2, J = 82.6 Hz, Av = 201 Hz, 2H, Ar-H)ppm. MS m/z (relative intensity): 175(M+, 100). IR (KBr) v 3609, 3006, 2224, 1605, 1509, 1300, 1259, 1175, 1026, 919, 841, 766 cm-1. Anal. Calcd for C9H10NO2: C 68.56, H 5.18, N 8.00. Found: C 68.61, H 5.23, N 77.79, mp 37-38 °C.
3. 3. Synthesis of 4-(oxiran-2-ylmethoxy) benzaldehyde (6)19
To a solution of 4-hydroxybenzaldehyde (6.10 g; 50.0 mmol) in 30 mL 2M NaOH, epichlorhydrin (4.68 g; 50.0 mmol) was added dropwise on ice-bath. The reaction mixture was allowed to warm to room temperature and stirred for 24 hours. After the addition of dichloromethane (100 mL) the phases were separated. The organic phase was washed with 1M HCl (3 x 40 mL), water (40 mL) and brine (40mL), dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was further purified by column chromatography to yield white solid (MF: petro-lether/ethyl acetate = 2:1). Yield 79%. 1H NMR (300 MHz, DMSO-d6): 5 2.73 (m, 1H, CH2), 2.87 (m, 1H, CH2), 3.37 (m, 1H, CH), 3.96 (m, 1H, CH2), 4.47 (m, 1H, CH2), 7.16 (A2X2, J = 8.7 Hz, Av = 214 Hz, 2H, Ar-H), 7.81 (A2X2, J = 8.7 Hz, Av = 214 Hz, 2H, Ar-H), 9.88 (s, 1H, CHO) ppm. 13C NMR (300 MHz, DMSO-d6): 44.6, 50.3, 70.3, 115.9, 130.8, 132.7, 164.0, 192.2 ppm. MS m/z (relative intensity): 178(M+, 100). IR (KBr) v 3675, 3069, 1681, 1600, 1576, 1424, 1303, 1246, 1163, 1024, 911, 837 cm-1, Anal. Calcd for C10H10O3: C 67.41, H 5.66, N 0. Found: C 67.77, H 5.78, N 0; mp 32-34 °C.
3. 4. General procedure for the synthesis of 1-(alkylamino)-3-phenoxypropan-2-ols (3a-e, 7a-e)
The corresponding oxiran 4-(oxiran-2-ylmet-hoxy)benzonitrile (2) or 4-(oxiran-2-ylmethoxy)benzal-dehyde (6) (8.50 mmol), Ca(OTf)2 (1.45 g; 4.28 mmol) and alkylamine (13.0 mmol) were dissolved in anhydrous
dioxane (50 mL). The reaction mixture was stirred at reflux for 6 hours, allowed to cool to room temperature and stirred overnight under argon atmosphere. The precipitate was filtered off and the filtrate was concentrated in vacuo. The crude product was further purified by column chromatography to yield white solid (MF: dichlorometha-ne/methanol = 20:1). In case of aldehydes a small amount of tertiary amines as yellow viscous liquids (9a-e) were also isolated.
4-(2-hydroxy-3-(hexylamino)propoxy)benzonitrile (3a)
Yield 86%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J = 6.6 Hz, CH3), 1.28 (m, 6H, CH2), 1.52 (m, 2H, CH2), 2.85 (m, 4H, CH2), 3.57 (s, 1H, OH), 4.05 (m, 3H, CH, CH2), 5.71 (s, 1H, NH), 7.14 (A2X2, J = 9.0 Hz, Av = 180 Hz, 2H, Ar-H), 7.74 (A2X2, J = 9.0 Hz, Av = 180 Hz, 2H, Ar-H) ppm. MS m/z (relative intensity): 277(M+H, 19), 114(100). IR (KBr) v 3435, 3283, 2928, 2855, 2227, 1606, 1510, 1258, 1162, 1028, 943, 833 cm1, mp 65-68 °C.
4-(2-hydroxy-3-(octylamino)propoxy)benzonitrile (3b)
Yield 73%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J = 6.3 Hz, CH3), 1.24 (m, 10H, CH2), 1.51 (m, 2H, CH2), 2.64 (m, 4H, CH2), 3.39 (s, 1H, OH), 3.90 (m, 2H, CH2), 4.07 (m, 1H, CH), 4.86 (s, 1H, NH), 7.09 (A2X2, J = 9.0 Hz, Av = 204 Hz, 2H, Ar-H), 7.77 (A2X2, J = 9.0 Hz, Av = 204 Hz, 2H, Ar-H) ppm. MS m/z (relative intensity): 305(M+H, 24), 142 (100). IR (KBr) v 3484, 3288, 2927, 2855, 2227, 1606, 1511, 1258, 1162, 1026, 951, 833 cm-1, mp 63-66 °C.
4-(2-hydroxy-3-(decylamino)propoxy)benzonitrile (3c)
Yield 77%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J=6.3 Hz, CH3), 1.24 (m, 14H, CH2), 1.47 (m, 2H, CH2), 2.77 (m, 4H, CH2), 3.48 (s, 1H, OH), 4.04 (m, 3H, CH2 CH2), 5.19 (s, 1H, NH), 7.12 (A2X2, J = 9.0 Hz, Av = 204 Hz, 2H, Ar-H), 7.78 (A2X2, J = 9.0 Hz, Av = 204 Hz, 2H, Ar-H) ppm. MS m/z (relative intensity): 333(M+H, 100). IR (KBr) v 3482, 3159, 2922, 2852, 2226, 1606,
1510,	1258, 1162, 1117, 1038, 834 cm-1, mp 63-66 °C.
4-(2-hydroxy-3-(dodecylamino)propoxy)benzonitrile (3d)
Yield 79%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J = 6.6 Hz, CH3), 1.24 (m, 18H, CH2), 1.48 (m, 2H, CH2), 2.78 (m, 4H, CH2), 3.50 (s, 1H, OH), 4.04 (m, 3H, CH2 CH2), 5.53 (s, 1H, NH), 7.12 (A2X2, J = 8.7 Hz, Av = 192 Hz, 2H, Ar-H), 7.76 (A2X2, J = 8.7 Hz, Av = 192 Hz, 2H, Ar-H) ppm. MS m/z (relative intensity): 361(M+H, 100). IR (KBr) v 3445, 3288, 2920, 2852, 2227, 1606,
1511,	1258, 1161, 1026, 950, 834 cm-1, mp 76-78 °C.
4-(2-hydroxy-3-(tetradecylamino)propoxy)benzonitri-
le (3e)
Yield 81%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J = 6.6 Hz, CH3), 1.24 (m, 22H, CH2), 1.50 (m, 2H,
CH2), 2.82 (m, 4H, CH2), 3.55 (s, 1H, OH), 4.04 (m, 3H, CH, CH2), 5.73 (s, 1H, NH), 7.12 (A2X2, J = 8.7 Hz, Av = 197 Hz, 2H, Ar-H), 7.77 (A2X2, J = 8.7 Hz, Av = 197 Hz, 2H, Ar-H) ppm. MS m/z (relative intensity): 389(M+H, 100), HRMS: calcd for C24H41 N2O2, 389.3168; found, 389.3170. IR (KBr) v 3445, 3287, 2920, 2851, 2225, 1605, 1510, 1467, 1257, 1161, 1038, 833 cm-1, mp 77-78 °C.
4-(3-(hexylamino)-2-hydroxypropoxy)benzaldehyde (7a)
Yield 43%. 1H NMR (300 MHz, DMSO-d6): 5 0.88 (t, 3H, J = 6.6 Hz, CH3), 1.29 (m, 6H, CH2), 1.62 (m, 2H, CH2), 2.97 (m, 2H, CH2), 3.15 (m, 2H, CH2), 4.10 (d, 2H, J = 5.1 Hz, CH2), 4.20 (m, 1H, CH), 5.91 (s, 1H, OH), 7.15 (A2X2, J = 9.0 Hz, Av = 221 Hz, 2H, Ar-H), 7.89 (A2X2, J = 9.0 Hz, Av = 221 Hz, 2H, Ar-H), 8.57 (s (broad), 1H, NH), 9.89 (s, 1H, CHO)ppm. MS m/z (relative intensity): 280(M+H, 21), 141(100). IR (KBr) v 3479, 2957, 2860, 1685, 1606, 1582, 1509, 1249, 1161, 1039,
828	cm-1, mp 78-82 °C.
4-(3-(octylamino)-2-hydroxypropoxy)benzaldehyde (7b)
Yield 34%. 1H NMR (300 MHz, DMSO-d6): 5 0.87 (t, 3H, J = 6.3 Hz, CH3), 1.27 (m, 10H, CH2), 1.64 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.16 (m, 2H, CH2), 4.10 (d, 2H, J = 5.1 Hz, CH2), 4.22 (m, 1H, CH), 5.92 (s, 1H, OH),
7.15	(A2X2, J = 9.0 Hz, Av = 226 Hz, 2H, Ar-H), 7.90 (A2X2, J = 9.0 Hz, Av = 226 Hz, 2H, Ar-H), 8.67 (s (broad), 1H, NH), 9.89 (s, 1H, CHO)ppm. MS m/z (relative intensity): 308(M+H, 100). HRMS: calcd for C18H30NO3, 308.2226; found, 308.2226. IR (KBr) v 3468, 29)24, 2855, 1681, 1600, 1581, 1508, 1242, 1160, 1031,
829	cm-1, mp 93-94 °C.
4-(3-(decylamino)-2-hydroxypropoxy)benzaldehyde (7c)
Yield 51%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.3 Hz, CH3), 1.26 (m, 14H, CH2), 1.64 (m, 2H, CH2), 2.96 (m, 2H, CH2), 3.14 (m, 2H, CH2), 4.11 (d, 2H, J =5.1 Hz, CH2), 4.242 (m, 1H, CH), 5.93 (s, 1H, OH),
7.16	(A2X2, J = 8.7 Hz, Av = 217 Hz, 2H, Ar-H), 7.88 (A2X2, J = 8.7 Hz, Av = 217 Hz, 2H, Ar-H), 8.57 (s (broad), 1H, NH), 9.89 (s, 1H, CHO)ppm. MS m/z (relative intensity): 336(M+H, 100). HRMS: calcd for C20H34NO3, 336.2539; found, 336.2528. IR (KBr) v 3413, 2921 2852, 1681, 1601, 1582, 1508, 1245, 1159, 1038,
830	cm-1, mp 100-103 °C.
4-(3-(dodecylamino)-2-hydroxypropoxy)benzaldehyde (7d)
Yield 62%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.6 Hz, CH3), 1.25 (m, 18H, CH2), 1.63 (m, 2H, CH2), 2.94 (m, 2H, CH2), 3.15 (m, 2H, CH2), 4.11 (d, 2H, J =5.1 Hz, CH2), 4.23 (m, 1H, CH), 5.92 (s, 1H, OH), 7.16 (A2X2, J = 9.0 Hz, Av = 221 Hz, 2H, Ar-H), 7.88 (A2X2, J = 9.0 Hz, Av = 221 Hz, 2H, Ar-H), 8.76 (s (broad), 1H, NH), 9.89 (s, 1H, CHO)ppm. MS m/z (relative intensity): 364(M+H, 100). HRMS: calcd for
C22H38NO3, 364.2852; found, 364.2845. IR (KBr) v 3413, 29203 2850, 1681, 1601, 1583, 1508, 1244, 1158, 1038, 832 cm-1, mp 120-125 °C.
4-(3-(tetradecylamino)-2-hydroxypropoxy)benzaldehy-de (7e)
Yield 17%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.3 Hz, CH3), 1.25 (m, 22H, CH2), 1.62 (m, 2H, CH2), 2.93 (m, 2H, CH2), 3.14 (m, 2H, CH2), 4.11 (d, 2H, J = 5.1 Hz, CH2), 4.17 (m, 1H, CH), 5.93 (s, 1H, OH), 7.16 (A2X2, J = 8.7 Hz, Av = 221 Hz, 2H, Ar-H), 7.90 (A2X2, J = 8.7 Hz, Av = 221 Hz, 2H, Ar-H), 8.74 (s (broad), 1H, NH), 9.89 (s, 1H, CHO)ppm. MS m/z (relative intensity): 392(M+H, 100). HRMS: calcd for C24H42NO3, 392.3165; found, 392.3163. IR (KBr) v 3468, 29220, 2851, 1684, 1603, 1578, 1508, 1468, 1252, 1164, 1030, 832 cm-1, mp 69-74 °C.
4,4'-(((hexylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (9a)
Yield 8%. 1H NMR (300 MHz, DMSO-d6): 5 0.77 (m, 3H, CH3), 1.14 (m, 6H, CH2), 1.32 (m, 2H, CH2), 2.44 (m, 6H, CH^, 4.00 (m, 6H, CH, CH2), 4.93 (s, 2H, OH), 7.03 (A2X2,2J = 8.7 Hz, Av = 228 H2 z, 2H, Ar-H), 7.08 (A2X2, J= 8.7 Hz, Av = 223 Hz, 2H, Ar-H), ), 7.79 (A2X2, J = 827 Hz, Av = 228 Hz, 2H, Ar-H), 7.82 (A2X2, J = 8.7 Hz, Av = 223 Hz, 2H, Ar-H), 9.85 (s, 2H, CHO)ppm. MS m/z (relative intensity): 458(M+H, 100). HRMS: calcd for C26H36NO6, 458.2453; found 458.2448. IR (KBr) v 3404, 29293 2856, 1689, 1601, 1510, 1310, 1257, 1161, 1029,
832 cm-1.
4,4'-(((octylazanediyl)bis(2-hydroxypropane-3,1-diyl)) bis(oxy))dibenzaldehyde (9b)
Yield 16%. 1H NMR (300 MHz, DMSO-d6): 5 0.80 (m, 3H, CH3), 1.11 (m, 10H, CH2), 1.34 (m, 2H, CH2), 2.43 (m, 6H, CH2), 4.00 (m, 6H, CH, CH2), 4.92 (s, 1H, OH), 4.94 (s, 1H, OH), 7.03 (A2X2, J = 8.72 Hz, Av = 228 Hz, 2H, Ar-H), 7.06 (A2X2, J = 8.72 Hz, Av = 229 Hz, 2H, Ar-H), ), 7.79 (A2X2, J = 8.7 Hz, Av = 228 Hz, 2H, Ar-H), 7.82 (A2X2, J = 82.7 Hz, Av = 229 Hz, 2H, Ar-H), 9.83 (s, 2H, CHO), 9.85 (s, 2H, CHO) ppm. MS m/z (relative intensity) : 486(M+H, 100). HRMS: calcd for C28H40NO6, 486.2856; found 486.2858. IR (KBr) v 3410, 2926, 28546, 1686, 1601, 1509, 1312, 1259, 1161, 1029, 832 cm-1.
4,4'-(((decylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (9c)
Yield 10%. 1H NMR (300 MHz, DMSO-d6): 5 0.83 (m, 3H, CH3), 1.14 (m, 14H, CH2), 1.31 (m, 2H, CH2), 2.48 (m, 6H, CH2), 4.02 (m, 6H, CH, CH2), 4.93 (s, 2H, OH), 7.02 (A^ J = 8.7 Hz, Av = 231 Hz, 2H, Ar-H), 7.08 (A2X2, J = 8.7 Hz, Av = 223 Hz, 2H, Ar-H), ), 7.79 (A2X2, J = 8.7 Hz, Av = 231 Hz, 2H, Ar-H), 7.82 (A2X2, J = 8.7 Hz, Av = 223 Hz, 2H, Ar-H), 9.83 (s, 2H, CHO), 9.85 (s, 2H, CHO) ppm. MS m/z (relative intensity):
514(M+H, 38), 77 (100). HRMS: calcd for C30H44NO6, 514.3169; found, 514.3163. IR (KBr) v 3412, 2S>25, 2853, 1690, 1601, 1510, 1311, 1257, 1161, 1030, 832 cm1.
4,4'-(((dodecylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (9d)
Yield 5%. 1H NMR (300 MHz, DMSO-d6): 5 0.84 (t, 3H, J = 6.3 Hz, CH3), 1.16 (m, 18H, CH2), 1.34 (m, 2H, CH2), 2.43 (m, 6H, CH2), 4.02 (m, 6H, CH, CH2); 4.93 (s, 2H, OH), 7.03 (A2X2, J = 8.7 Hz, Av = 205 Hz, 2H, Ar-H), 7.08 (A2X2, J = 8.7 Hz, Av = 223 Hz, 2H, Ar-H), 7.76 (A2X2, J = 8.7 Hz, Av = 205 Hz, 2H, Ar-H), 7.82 (A2X2, J = 8.77 Hz, Av = 223 Hz, 2H, Ar-H), 9.85 (s, 2H, CHO)ppm. MS m/z (relative intensity): 542(M+H, 100). HRMS: calcd for C32H48NO6, 542.3482; found, 542.3485. IR (KBr) v 3409, 2925, 2853, 1689, 1601, 1509, 1311, 1259, 1161, 1030, 832 cm1.
4,4'-(((tetradecylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (9e)
Yield 10%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J = 6.3 Hz, CH3), 1.19 (m, 22H, CH2), 1.34 (m, 2H, CH2), 2.48 (m, 6H, CH2), 4.02 (m, 6H, CH, CH2), 4.94 (s, 2H, OH), 7.03 (A2X2, J = 8.7 Hz, Av = 228 Hz, 2H, Ar-H), 7.07 (A2X2, J = 8.7 Hz, Av = 225 Hz, 2H, Ar-H), ), 7.79 (A2X2, J = 8.7 Hz, Av = 228 Hz, 2H, Ar-H), 7.82 (A2X2, J = 8.7 Hz, Av = 225 Hz, 2H, Ar-H), 9.83 (s, 1H, CHO), 9.85 (s, 1H, CHO) ppm. MS m/z (relative intensity): 570(M+H, 100). HRMS: calcd for C34H52NO6, 570.3795; found, 570.3807. IR (KBr) v 3382, 2924, 2853, 1689, 1601, 1509, 1311, 1259, 1160, 1030, 832 cm1.
3. 5. General Procedure for the Synthesis of Amidoximes (4a-e)
The corresponding 4-(3-(alkylamino)-2-hydroxypro-poxy)benzonitrile (3a-e) (3.60 mmol), hydroxylamine hydrochloride (500 mg; 7.20 mmol) and potassium carbonate (1.00 g; 7.25 mmol) were suspended in anhydrous et-hanol (50 mL). The reaction mixture was stirred at reflux for 12 hours. The precipitate was rapidly filtered off before cooling and the solvent was removed in vacuum. The crude product was recrystallized from ethanol to yield white solid.
4-(3-(hexylamino)-2-hydroxypropoxy)-N'-hydroxyben-zimidamide (4a)
Yield 40%. 1H NMR (300 MHz, DMSO-d6): 5 0.87 (t, 3H, J = 6.3 Hz, CH3), 1.30 (m, 6H, CH2), 1.64 (m, 2H, CH2), 2.93 (m, 2H, CH2), 3.01 (m, 2H, CH2), 3.99 (m, 2H, CH2), 4.55 (m, 1H, CH), 5.72 (s, 1H, NH), 5.85 (s, 1H, OH), 6.95 (A2X2, J = 8.7 Hz, Av = 198 Hz, 2H, Ar-H), 7.61 (A2X2, J = 8.7 Hz, Av = 198 Hz, 2H, Ar-H), 8.68 (s, 2H, NH2), 9.44 (s, 1H, NOH) ppm. MS m/z (relative intensity): 310(M+H, 17), 77 (100). HRMS: calcd for C16H28N3O3, 301.2131; found, 310.2130. IR (KBr) v
3295, 2929, 2854, 1641, 1519, 1381, 1251, 1180, 1113, 1034, 916, 832 cm-1, mp 173-178 °C.
4-(3-(octylamino)-2-hydroxypropoxy)-N'-hydroxyben-zimidamide (4b)
Yield 57%. 1H NMR (300 MHz, DMSO-d6): 5 0.87 (t, 3H, J = 6.6 Hz, CH3), 1.27 (m, 10H, CH2), 1.64 (m, 2H, CH2), 3.03 (m, 4H, CH2), 3.99 (m, 2H, CH2), 4.21 (m, 1H, CH), 5.73 (s, 1H, NH), 5.86 (s, 1H, OH), 6.95 (A2X2, J = 9.0 Hz, Av = 198 Hz, 2H, Ar-H), 7.61 (A2X2, J = 9.0 Hz, Av = 198 Hz, 2H, Ar-H), 8.75 (s, 2H, NH2), 9.45 (s, 1H, NOH) ppm. MS m/z (relative intensity): 338(M+H, 24), 77 (100). HRMS: calcd for C18H32N3O3, 338.2444; found, 338.2436. IR (KBr) v 3264, 2924, 2855, 1642, 1522, 1368, 1256, 1184, 1120, 940, 832 cm-1, mp 176-180 °C.
4-(3-(decylamino)-2-hydroxypropoxy)-N'-hydroxy-benzimidamide (4c)
Yield 40%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.3 Hz, CH3), 1.25 (m, 14H, CH2), 1.64 (m, 2H, CH2), 3.02 (m, 4H, CH2), 3.99 (m, 2H, CH2), 4.22 (m, 1H, CH2, 5.72 (s, 1H, NH), 5.87 (s, 1H, OH), 6.94 (A2X2, J = 8.7 Hz, Av = 201 Hz, 2H, Ar-H), 7.61 (A2X2, J = 8.7 Hz, Av = 201 Hz, 2H, Ar-H), 8.84 (s, 2H, NH2), 9.45 (s, 1H, NOH) ppm. MS m/z (relative intensity): 366(M+H, 11), 77 (100). IR (KBr) v 3263, 2920, 2855, 1634, 1521, 1368, 1259, 1176, 1121, 1046, 926, 831 cm-1. Anal. Calcd for C20H35N3O3: C 65.72, H 9.65, N 11.50. Found: C 65.91, H 9.608, N 11.21. mp 183-186 °C.
4-(3-(dodecylamino)-2-hydroxypropoxy)-N'-hydroxy-
benzimidamide (4d)
Yield 54%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.6 Hz, CH3), 1.25 (m, 18H, CH2), 1.61 (m, 2H, CH2), 3.02 (m, 4H, CH2), 3.99 (m, 2H, CH2), 4.18 (m, 1H, CH2, 5.71 (s, 1H, NH), 5.82 (s, 1H, OH), 6.94 (A2X2, J = 8.7 Hz, Av = 195 Hz, 2H, Ar-H), 7.59 (A2X2, J = 8.7 Hz, Av = 195 Hz, 2H, Ar-H), 8.56 (s, 2H, NH2), 9.44 (s, 1H, NOH) ppm. MS m/z (relative intensity): 394(M+H, 17), 77 (100). HRMS: calcd for C22H40N3O3, 394.3070; found, 394.3058. IR (KBr) v 3343, 2922, 2850, 1651, 1522, 1378, 1255, 1181, 1121, 1043, 923, 830 cm-1, mp 183-185 °C.
4-(3-(tetradecylamino)-2-hydroxypropoxy)-N'-hydroxybenzimidamide (4e)
Yield 67%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (t, 3H, J = 6.6 Hz, CH3), 1.24 (m, 22H, CH2), 1.64 (m, 2H, CH2), 3.02 (m, 2H, CH2), 3.99 (m, 2H, CH2), 4.21 (m, 1H, CH2, 5.72 (s, 1H, NH), 5.87 (s, 1H, OH), 6.96 (A2X2, J = 8.7 Hz, Av = 196 Hz, 2H, Ar-H), 7.61 (A2X2, J = 8.7 Hz, Av = 196 Hz, 2H, Ar-H), 8.81 (s, 2H, NH2), 9.44 (s, 1H, NOH) ppm. MS m/z (relative intensity): 3924(M+H, 3), 77 (100). IR (KBr) v 3341, 2921, 2849, 1651, 1522, 1376, 1255, 1180, 1119, 1044, 830 cm-1, Anal. Calcd for C24H43N3O3: C 68.73, H 10.28, N 9.97. Found: C 68.98, H 10.53, N 9.64, mp 186-189 °C.
3. 6. General Procedure for the Synthesis of Oximes (8a-e, 10a-e)
The corresponding aldehydes (7a-e, 9a-e) (1.15 mmol), hydroxylamine hydrochloride (100 mg; 1.44 mmol) and potassium carbonate (200 mg; 1.45 mmol) were suspended in anhydrous ethanol (10 mL). The reaction mixture was stirred at reflux for 12 hours. The precipitate was rapidly filtered off before cooling and the solvent was removed in vacuo. The crude product was further purified by column chromatography (MF: dichloromethane/methanol = 20 : 1).
4-(2-hydroxy-3-(hexylamino)propoxy)benzaldehyde oxime (8a)
Yield 56%. 1H NMR (300 MHz, DMSO-d6): 5 0.88 (t, 3H, J = 6.6 Hz, CH3), 1.28 (m, 6H, CH2), 1.58 (m, 2H, CH2), 2.93 (m, 2H, CH2), 3.12 (m, 2H, CH2), 3.99 (d, 2H, J = 5.4 Hz, CH2), 4.12 (m, 1H, CH), 5.75 (s, 1H, OH), 6.99 (A2X2, J = 8.7 Hz, Av = 162 Hz, 2H, Ar-H), 7.53 (A2X2, J = 8.7 Hz, Av = 162 Hz, 2H, Ar-H), 8.07 (m, 1H, CH), 8.61 (s (broad), 1H, NH), 10.96 (s, 1H, CHO)ppm. MS m/z (relative intensity): 295(M+H, 70), 77 (100). HRMS: calcd for C16H27N2O3, 295.2022; found, 295.2030. IR (KBr) v 3447, 2931, 2858, 1611, 1516, 1457, 1240, 1168, 1107, 1036, 965, 832 cm-1, mp 79-83 °C.
4-(2-hydroxy-3-(octylamino)propoxy)benzaldehyde oxime (8b)
Yield 62%. 1H NMR (300 MHz, DMSO-d6): 5 0.87 (t, 3H, J = 6.3 Hz, CH3), 1.27 (m, 10H, CH2), 1.59 (m, 2H, CH2), 2.78 (m, 2H, CH2), 3.10 (m, 2H, CH2), 3.99 (d, 2H, J = 5.1 Hz, CH2), 4.122 (m, 1H, CH), 5.76 (s, 1H, OH), 6.99 (A2X2, J = 9.0 Hz, Av = 163 Hz, 2H, Ar-H), 7.53 (A2X2, J = 9.0 Hz, Av = 163 Hz, 2H, Ar-H), 8.07 (m, 1H, CH), 8.61 (s (broad), 1H, NH), 10.96 (s, 1H, CHO)ppm. MS m/z (relative intensity): 323(M+H, 100). HRMS: calcd for C18H31N2O3, 323.2335; found, 323.2328. IR (KBr) v 3446, 292(5, 2856, 1610, 1516, 1457, 1238, 1171, 1113, 1035, 965, 832 cm-1, mp 81-84 °C.
4-(2-hydroxy-3-(decylamino)propoxy)benzaldehyde oxime (8c)
Yield 46%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.3 Hz, CH3), 1.28 (m, 14H, CH2), 1.63 (m, 2H, CH2), 2.95 (m, 2H, CH2), 3.14 (m, 2H, CH2), 4.00 (d, 2H, J =5.1 Hz, CH2), 4.21 (m, 1H, CH), 5.88 (s, 1H, OH), 6.99 (A2X2, J = 8.7 Hz, Av = 165 Hz, 2H, Ar-H), 7.53 (A2X2, J = 8.7 Hz, Av = 165 Hz, 2H, Ar-H), 8.07 (m, 1H, CH), 8.76 (s (broad), 1H, NH), 10.96 (s, 1H, CHO)ppm. MS m/z (relative intensity): 351(M+H, 100). HRMS: calcd for C20H35N2O3, 351.2648; found, 351.1647. IR (KBr) v 3394, 29244, 2852, 1609, 1518, 1466, 1250, 1176, 1119, 1046, 939, 816 cm-1, mp 83-86 °C.
4-(2-hydroxy-3-(dodecylamino)propoxy)benzaldehyde oxime (8d)
Yield 62%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.6 Hz, CH3), 1.25 (m, 18H, CH2), 1.63 (m, 2H, CH2), 2.95 (m, 2H, CH2), 3.15 (m, 2H, CH2), 4.00 (d, 2H, J = 5.4 Hz, CH2), 4.199 (m, 1H, CH), 5.86 (s, 1H, OH), 6.99 (A2X2, J = 8.7 Hz, Av = 162 Hz, 2H, Ar-H), 7.53 (A2X2, J = 8.7 Hz, Av = 162 Hz, 2H, Ar-H), 8.07 (m, 1H, CH), 8.63 (s (broad), 1H, NH), 10.96 (s, 1H, CHO)ppm. MS m/z (relative intensity): 379(M+H, 100). HRMS: calcd for C22H39N2O3, 379.2961; found, 379.2956. IR (KBr) v 3410, 2923, 2850, 1609, 1517, 1465, 1249, 1175, 1115, 1045, 939, 815 cm-1, mp 84-88 °C.
4-(2-hydroxy-3-(tetradecylamino)propoxy)benzal-dehyde oxime (8e)
Yield 55%. 1H NMR (300 MHz, DMSO-d6): 5 0.86 (t, 3H, J = 6.3 Hz, CH3), 1.24 (m, 22H, CH2), 1.56 (m, 2H, CH2), 2.89 (m, 2H, CH2), 3.07 (m, 2H, CH2), 3.98 (d, 2H, J = 4.8 Hz, CH2), 4.082 (m, 1H, CH), 5.75 (s, 1H, OH), 6.98 (A2X2, J = 8.7 Hz, Av = 165 Hz, 2H, Ar-H), 7.53 (A2X2, J = 8.7 Hz, Av = 165 Hz, 2H, Ar-H), 8.07 (m, 1H, CH), 8.61 (s (broad), 1H, NH), 10.96 (s, 1H, CHO)ppm. MS m/z (relative intensity): 323(M+H, 100). HRMS: calcd for C24H43N2O3, 407.3274; found, 407.3264. IR (KBr) v 3436, 219199, 2850, 1610, 1516, 1469, 1240, 1167, 1037, 966, 833 cm-1, mp 83-87 °C.
4,4'-(((hexylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (10a)
Yield 48%. 1H NMR (300 MHz, DMSO-d6): 5 0.78 (m, 3H, CH3), 1.14 (m, 6H, CH2), 1.34 (m, 2H, CH2), 2.45 (m, 4H, CH2), 2.63 (m, 2H, CH2), 3.97 (m, 6H, CH, CH2), 4.86 (s, 2H, OH), 6.89 (A2X2, J = 8.7 Hz, Av = 177 Hz, 2H, Ar-H), 6.92 (A2X2, J = 8.7 Hz, Av = 172 Hz, 2H, Ar-H), ), 7.47 (A2X2, J = 8.7 Hz, Av = 177 Hz, 2H, Ar-H), 7.49 (A2X2, J = 82.7 Hz, Av = 172 Hz, 2H, Ar-H), 8.04 (s, 1H, CH), 8.05 (s, 1H, CH), 10.92 (s, 2H, NOH)ppm. MS m/z (relative intensity): 488(M+H, 100). HRMS: calcdfor C26H38N3O6, 488.2682; found, 488.2714. IR(KBr) v 3307, 29228, 1606, 1514, 1458, 1302, 1249, 1173, 1035, 953, 830 cm-1.
4,4'-(((octylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (10b)
Yield 53%. 1H NMR (300 MHz, DMSO-d6): 5 0.81 (m, 3H, CH3), 1.18 (m, 10H, CH2), 1.33 (m, 2H, CH2), 2.45 (m, 4H CH2), 2.64 (m, 2H, CH2), 3.94 (m, 6H, CH, CH2), 4.85 (s, 2H, OH), 6.89 (A2X2, J= 8.7 Hz, Av = 177 Hz, 4H, Ar-H), 7.47 (A2X2, J = 8.7 Hz, Av = 177 Hz, 4H, Ar-H), 8.04 (s, 1H, CH), 8.05 (s, 1H, CH), 10.92 (s, 2H, NOH)ppm. MS m/z (relative intensity): 516(M+H, 60), 77(100). HRMS: calcd for C28H42N3O6, 516.3074; found, 516.3074. IR (KBr) v 3308, 2926, 2854, 1607, 1514, 1458, 1303, 1250, 1173, 1037, 955, 830 cm-1.
4,4'-(((decylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (10c)
Yield 47%. 1H NMR (300 MHz, DMSO-d6): 5 0.83 (t, 3H, J = 6.6 Hz, CH3), 1.14 (m, 14H, CH2), 1.33 (m, 2H, CH2), 2.42 (m, 4H, CH2), 2.65 (m, 2H, CH2), 3.94 (m, 6H, CH, CH2), 4.85 (s, 2H, OH), 6.89 (A2X2, J= 8.7 Hz, Av = 177 Hz, 2H, Ar-H), 6.91 (A2X2, J = 8.7 Hz, Av = 172 Hz, 2H, Ar-H), ), 7.48 (A2X2, J = 8.7 Hz, Av = 177 Hz, 2H, Ar-H), 7.48 (A2X2, J = 8.7 Hz, Av = 172 Hz, 2H, Ar-H), 8.04 (s, 1H, CH), 8.05 (s, 1H, CH), 10.92 (s, 2H, NOH)ppm. MS m/z (relative intensity): 544(M+H, 15), 77 (100). HRMS: calcd for C30H46N3O6, 544.3389; found, 544.3387. IR(KBr) v 3308, 2924, 2853, 1606, 1514, 1458, 1302, 1250, 1173, 1036, 830 cm-1.
(m, 2H, -O-CH2CH(OH)-), 4.64-4.71 (m, 2H, 2 x CH-OH), 4.95-5.01 (m, 1H, CH-OH), 5.55 (dd, 1H, J = 1.6, 6.94 Hz, -CH(OH)-CH=N-), 8.47 (d, 1H, J = 6.93, -CH=N-), 12.88 (s, 1H, =N-OH) ppm. The hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~6.36, ~7.71 and ~13.07 ppm (corresponding to the (Z)-oxime) are visible. MS m/z (relative intensity): 358 (MNa+, 75), 336 (M+H, 100). IR (KBr) v 3393, 3268, 2954, 2922, 2851, 2805, 2374, 2345, 1671, 1466, 1439, 1379, 1318, 1304, 1262, 1228, 1126, 1102, 1070, 1036, 1016, 996, 723 cm-1, mp 171-173 °C.
4,4'-(((dodecylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (10d)
Yield 68%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (m, 3H, CH3), 1.17 (m, 18H, CH2), 1.34 (m, 2H, CH2), 2.38 (m, 4H, CH2), 2.65 (m, 2H, CH2), 3.93 (m, 6H, CH, CH2), 4.86 (s, 2H, OH), 6.89 (A2X2, J= 8.7 Hz, Av = 177 Hz, 2H, Ar-H), 6.92 (A2X2, J = 8.7 Hz, Av = 170 Hz, 2H, Ar-H), ), 7.47 (A2X2, J = 8.7 Hz, Av = 177 Hz, 2H, Ar-H), 7.48 (A2X2, J = 82.7 Hz, Av = 170 Hz, 2H, Ar-H), 8.03 (s, 1H, CH), 8.04 (s, 1H, CH), 10.92 (s, 2H, NOH)ppm. MS m/z (relative intensity): 572(M+H, 100). HRMS: calcd for C32H50N3O6, 532.3700; found, 532.3690. IR (KBr) v 3308, 2923, 2852, 1606, 1514, 1458, 1302, 1250, 1173,
1035,	954, 830 cm-1.
4,4'-(((tetradecylazanediyl)bis(2-hydroxypropane-3,1-diyl))bis(oxy))dibenzaldehyde (10e)
Yield 63%. 1H NMR (300 MHz, DMSO-d6): 5 0.85 (m, 3H, CH3), 1.18 (m, 22H, CH2), 1.34 (m, 2H, CH2), 2.41 (m, 4H, CH2), 2.67 (m, 2H, CH2), 3.93 (m, 6H, CH, CH2), 4.85 (s, 2H, OH), 6.89 (A2X2, J= 8.7 Hz, Av = 175 Hz, 2H, Ar-H), 6.92 (A2X2, J = 8.7 Hz, Av = 172 Hz, 2H, Ar-H), ), 7.46 (A2X2, J = 8.7 Hz, Av = 175 Hz, 2H, Ar-H), 7.48 (A2X2, J = 82.7 Hz, Av = 172 Hz, 2H, Ar-H), 8.03 (s, 1H, CH), 8.04 (s, 1H, CH), 10.91 (s, 2H, NOH)ppm. MS m/z (relative intensity): 600(M+H, 100). HRMS: calcd for C34H54N3O6, 600.4013; found, 600.4017. IR (KBr) v 3307, 29246 2852, 1606, 1514, 1458, 1302, 1250, 1173,
1036,	954, 829 cm-1.
3. 7. General Procedure for the Synthesis of Galactose Oximes16
1(£/Z)2S,3Ä,4S,5Ä)-2,3,4,5-tetrahydroxy-6-(octy-loxy)hexanal oxime (15a)16
1(£/Z)2S,3Ä,4S,5Ä)-2,3,4,5-tetrahydroxy-6-(decy-loxy)hexanal oxime (15b)
Yield 68%. A 80/20 mixture of (E)- and (Z)-oxime. 1H NMR (pyridine-^, 300 MHz) (E)-oxime: 5 0.86 (t, 3H, J = 6.9 Hz, -CH2-CH3), 1.18-1.33 (m, 14H, -(CH2)7 -CH3), 1.51-1.58 (m, 2H, -O-CH2-CH2-(CH2)7-CH2)7 3.43-3.51 (m, 2H, -O-CH2-CH2-(CH2)7-CH3), 4.03-4.07
1(£/Z)2S,3fl,4S,5fl)-2,3,4,5-tetrahydroxy-6-(dodecy-loxy)hexanal oxime (15c)
Yield 72%. A 81/19 mixture of (E)- and (Z)-oxime. 1H NMR (pyridine-d5, 300 MHz) (E)-oxime: 5 0.87 (t, 3H, J = 6.72 Hz, -CH2-CH3), 1.23-1.31 (m, 18H, -(CH2)9 -CH3), 1.52-1.58 (m, 211, -O-CH2-CH2-(CH2)9-CH3)9 3.43-3.51 (m, 2H, -O-CH2-CH2-(CH2)9-CH3), 42.03-4.07 (m, 2H, -O-CH2CH(OH)-), 4.64-4.70 (m, 2H, 2 x CH -OH), 4.96-5.01 (m, 1H, CH-OH), 5.55 (dd, 1H, J = 1.6, 6.94 Hz, -CH(OH)-CH=N-), 8.47 (d, 1H, J = 6.93, -CH=N-), 12.87 (s, 1H, =N-OH) ppm. The hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~6.36, ~7.71 and ~13.07 ppm (corresponding to the (Z)-oxime) are visible. MS m/z (relative intensity): 362 (M-H+, 100). IR (KBr) v 3394, 3272, 2953, 2922, 2850, 2366, 2345, 1667, 1490, 1465 1438, 1379, 1317, 1304, 1262, 1228, 1126, 1102, 1072, 1036, 1002, 987, 724 cm-1, mp 165-167 °C.
1(£/Z)2S,3fl,4S,5fl)-2,3,4,5-tetrahydroxy-6-(tetradecy-loxy)hexanal oxime (15d)
Yield 71%. A 60/40 mixture of (E)- and (Z)-oxime. 1H NMR (pyridine-d5, 300 MHz) (E)-oxime: 5 0.87 (t, 3H, J = 7.1 Hz, -CH2-CH3), 1.22-1.30 (m, 22H, -(CH2)11 -CH3), 1.53-1.60 (m, 2H, -O-CH2-CH2-(CH2)n-CH3), 3.45-3.55 (m, 2H, -O-CH2-CH2-(CH2)11-CH3), 4.05-4.09 (m, 2H, -O-CH2CH(OH)-), 4.65-4.73 (m, 2H, 2 x CH -OH), 4.95-5.01 (m, 1H, CH-OH), 5.66-5.74 (m, 1H, -CH(OH)-CH=N-), 8.50 (d, 1H, J = 6.93, -CH=N-), 12.90 (s, 1H, =N-OH) ppm. The hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~6.39, ~7.73 and ~13.10 ppm (corresponding to the (Z) -oxime) are visible. MS m/z (relative intensity): 203 (100), 392 (M+H+, 50). IR (KBr) v 3394, 3272, 2953, 2922, 2849, 2362, 2344, 1670, 1491, 1464 1441, 1379, 1317, 1304, 1262, 1228, 1211, 1126, 1102, 1074, 1036, 1012, 997, 724 cm-1, mp 172-174 °C.
1(£/Z)2S,3fl,4S,5fl)-2,3,4,5-tetrahydroxy-6-(hexadecy-loxy)hexanal oxime (15e)
Yield 70%. A 59/41 mixture of (E)- and (Z)-oxime. 1H NMR (pyridine-d5, 300 MHz) (E)-oxime: 5 0.87 (t, 3H, J = 6.72 Hz, -CH2-CH3), 1.23-1.31 (m, 26H, -(CH2)13
-CH3), 1.52-1.58 (m, 2H, -O-CH2-CH2-(CH2)13-CH3), 3.43-3.51 (m, 2H, -O-CH2-CH2-(CH2)13-CH3), 4.(34-4.08 (m, 2H, -O-CH2CH(OH)-), 4.64-4.69) (m, 2H, 2 x CH -OH), 4.96-5.01 (m, 1H, CH-OH), 5.58-5.70 (m, 1H, -CH(OH)-CH=N-), 8.49 (d, 1H, J = 6.93, -CH=N-), 12.89 (s, 1H, =N-OH) ppm. The hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~6.38, ~7.72 and ~13.09 ppm (corresponding to the (Z) -oxime) are visible. MS m/z (relative intensity): 420 (M+H+, 100). IR (KBr) v 3395, 3273, 2952, 2921, 2849, 2369, 1670, 1491, 1464 1442, 1378, 1317, 1304, 1262, 1228, 1126, 1102, 1077, 1036, 999, 986, 935, 724 cm-1, mp 152-154 °C.
3. 8. General Procedure for the Synthesis of Glucose Bisoximes Derivatives (22a-22d)16
N-((E/Z,2S,3R,4S,5R,E/Z)-3,4,5,-trihydroxy-1,6-bis (hydroxyimino)hexan-2-yl)-decanamide (22a)
Yield 81%. A mixture of four isomers was formed (the predominant (E,E)-form in 58% yield) as a colourless viscous oil. 1H NMR (pyridine-d5, 300 MHz) predominant (E,E)-oxime: 5 0.79 (t, 3H, J = 6.5 Hz, -CH2-CH3),
I.12-1.34	(m, 8H, -(CH2)4-CH3), 1.72-1.85 (m, 2H, -CO -CH2-CH2-(CH2)4-CH3)," 2.43 (t, 2H, J = 7.75 Hz, -CO -CH2-CH2-(CH2)4-CH3), 3.62 (s, 1H, -OH), 4.60 (dd, 1H, J = 2.83, 7.86 Hz, HO-N=CH-CH(OH)-CH(OH) -CH(OH)-CH(NH-)-CH=N-OH), 5.05 (dd, 1H, J = 2.65, 5.97 Hz, -CH(OH)-CH(NH-)-CH=N-), 5.25-5.32 (m, 1H, HO-N=CH-CH(OH)-), 5.83-5.89 (m, 1H, -CH(NH-) -CH=N-), 8.29 (d, 1H, J = 7.2, -CH=N-OH), 8.33 (d, 1H, J = 5.9, -CH=N-OH), 8.81 (d, 1H, J = 8.0 Hz, -NH-CO),
II.62	(s, 1H, =N-OH), 12.91 (s, 1H, =N-OH) ppm. All hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~4.70, ~4.96, ~5.96, ~6.14, ~6.39, ~7.52, ~8.36, ~8.75, -11.25 and ~11.4 ppm (corresponding to other oximes) are visible. MS m/z (relative intensity): 332 (M-H+, 100); IR (KBr) v 3242, 2926, 2855, 2360, 2343 1651, 1645, 1634, 1557, 1435, 1375, 1323, 1303, 1089, 1043, 987 cm-1.
N-((E / Z ,2S ,3R ,4S ,5R,E/Z )-3,4,5,-trihydroxy-1,6-bis(hydroxyimino)hexan-2-yl)-dodecanamide (22b)
Yield 84%. A mixture of four isomers was formed (the predominant (E,E)-form in 77% yield) as a white solid. 1H NMR (pyridine-d5, 300 MHz) predominant (E,E) -oxime: 5 0.87 (t, 3H, J = 6.6 Hz, -CH2-CH3), 1.18-1.35 (m, 16H, -(CH2)8-CH3), 1.74-1.84 (m, 2H, -CO-CH2 -CH2-(CH2)8-CH3"), 2.444 (t, 2H, J = 7.5 Hz, -CO-CH2 -CH2-(CH2)8-CH3), 4.60 (dd, 1H, J = 2.8, 7.6 Hz, HO -N=CH-CH(OH)-CH(OH)-CH(OH)-CH(NH-)-CH=N -OH), 5.04 (dd, 1H, J = 2.8, 5.8 Hz, -CH(OH)-CH(NH-) -CH=N-), 5.24-5.29 (m, 1H, HO-N=CH-CH(OH)-), 5.83-5.89 (m, 1H, -CH(NH-)-CH=N-), 8.29 (d, 1H, J = 7.3, -CH=N-OH), 8.32 (d, 1H, J = 5.9, -CH=N-OH), 8.78
(d, 1H, J = 8.0 Hz, -NH-CO), 12.89 (s, 1H, =N-OH), 12.96 (s, 1H, =N-OH) ppm. All hydroxyl groups are not visible due to exchange with residual water. Small resonances at -4.70, -4.96, -5.96, -6.12, -6.39, -7.51, -8.35, -8.68, -13.24 and -13.40 ppm (corresponding to other oximes) are visible. MS m/z (relative intensity): 388 (M-H+, 100); IR (KBr) v 3286, 2915, 2849, 2365, 2345, 1655, 1618, 1560, 1465, 1376, 1324, 1294, 1251, 1221, 1197, 1144, 1090, 1065, 1047, 1016, 985 cm-1, mp 158-159 °C.
N-((E / Z ,2S ,3R ,4S ,5R,E/Z)-3,4,5,-trihydroxy-1,6-bis(hydroxyimino)hexan-2-yl)-tetradecanamide (22c)16
N-((E / Z ,2S ,3R ,4S ,5R,E/Z)-3,4,5,-trihydroxy-1,6-bis(hydroxyimino)hexan-2-yl)-hexadecanamide (22d)
Yield 86%. A mixture of four isomers was formed (the predominant (E,E)-form in 87% yield) as a white solid. 1H NMR (pyridine-d5, 300 MHz) predominant (E,E) -oxime: 5 0.87 (t, 3H, J = 6.4 Hz, -CH2-CH3), 1.18-1.35 (m, 24H, -(CH2)^-CH3), 1.74-1.83 (m, 2H, -CO-CH2 -CH2-(CH2)12-CH3), 2.434 (t, 2H, J = 7.5 Hz, -CO-CH2 -CH2-(CH2)12-CH3), 3.61 (s, 1H, -OH), 4.58 (dd, 1H, J = 2.5, 7.5 Hz, HO-N=CH-CH(OH)-CH(OH)-CH(OH) -CH(NH-)-CH=N-OH), 5.03 (dd, 1H, J = 2.7, 5.8 Hz, -CH(OH)-CH(NH-)-CH=N-), 5.23-5.30 (m, 1H, HO -N=CH-CH(OH)-), 5.81-5.87 (m, 1H, -CH(NH-)-CH=N -), 8.27 (d, 1H, J = 7.2, -CH=N-OH), 8.31 (d, 1H, J = 5.8, -CH=N-OH), 8.88 (d, 1H, J = 8.2 Hz, -NH-CO), 11.10 (bs, 1H, =N-OH), 11.68 (s, 1H, =N-OH) ppm. All hydrox-yl groups are not visible due to exchange with residual water. Small resonances at -4.68, -4.94, -5.94, -6.11, -6.37, -7.50, -8.10, -8.34, -12.90 and -13.33 ppm (corresponding to other oximes) are visible. MS m/z (relative intensity): 444 (M-H+, 100); IR (KBr) v 3422, 2917, 2849, 2369, 2345, 1654, 1560, 1458, 1376, 1294, 1229, 1090, 1046, 1018, 988 cm-1, mp 100-101 °C.
3. 9. General Procedure for the Synthesis of
Glucose Oximes Derivatives (23a-23d)16
N-((2S,3R,4S,5R,E/Z)-3,4,5,6-tetrahydroxy-1-(hydrox-yimino)hexan-2-yl)-decanamide (23a)
N-((2S,3R,4S,5R,E/Z)-3,4,5,6-tetrahydroxy-1-(hydrox-yimino)hexan-2-yl)-dodecanamide (23b)
Yield 65%. A 70/30 mixture of (E)- and (Z)-oxime as a white solid. 1H NMR (pyridine-d5, 300 MHz) (E)-oxi-me: 5 0.86 (t, 3H, J = 6.62 Hz, -CH2-CH3), 1.17-1.34 (m, 16H, -(CH2)8-CH3), 1.72-1.82 (m, 2H, -CO-CH2-CH2 -(CH2)8-CH3), 2.42 (t, 2H, J = 7.55 Hz, -CO-CH2-CH2 -(CH2)8-CH3), 4.28-4.33 (m, 1H, HO-CH2-CH(OH)-), 4.44-4.57 (m, 3H, HO-CH2-CH(OH)-CH(OH)-CH(OH) -CH(NH-)-CH=N-), 5.02 (dd, 1H, J = 2.27, 5.91 Hz, -CH(OH)-CH(NH-)-CH=N-), 5.76-5.82 (m, 1H, -CH (NH-)-CH=N-), 8.28 (d, 1H, J = 6.01, -CH=N-), 8.77 (d,
1H, J = 7.96 Hz, -NH-CO), 13.38 (bs, 1H, =N-OH) ppm. The hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~2.44, ~4.36, ~5.20, ~6.30, and ~7.46 ppm (corresponding to the (Z)-oxime) are visible. MS m/z (relative intensity): 399 (M+Na+, 100), 377 (M+H, 39); HRMS: calcd for C18H37N2O6, 377.2652; found, 377.2633. IR (KBr) v 3288, 2955, 29177, 2850, 1994, 1649, 1546, 1403, 1307, 1252, 1082, 1027, 932, 878 cm-1, mp 115-117 °C.
N-((2S,3fl,4S,5fl,£/Z)-3,4,5,6-tetrahydroxy-1-(hydrox-yimino)hexan-2-yl)-tetradecanamide (23c)
Yield 76%. A 70/30 mixture of (E)- and (Z)-oxime as a white solid. 1H NMR (pyridine-d5, 300 MHz) (E)-oxi-me: 5 0.88 (t, 3H, J = 6.45 Hz, -CH2-CH3), 1.19-1.37 (m, 20H, -(CH2)^-CH3), 1.76-1.85 (m, 2H, -CO-CH2-CH2 -(CH2)10-CH3), 2.42 (t, 2H, J = 7.55 Hz, -CO-CH2-CH2 -(CH2)10-CH3), 4.29-4.35 (m, 1H, HO-CH2-CH(OH)-), 4.46-4.557 (m, 3H, HO-CH2-CH(OH)-CH(OH)-CH(OH) -CH(NH-)-CH=N-), 5.03 (dd, 1H, J = 2.27, 5.85 Hz, -CH(OH)-CH(NH-)-CH=N-), 5.78-5.85 (m, 1H, -CH (NH-) -CH=N-), 8.30 (d, 1H, J = 5.98, -CH=N-), 8.76 (d, 1H, J = 8.40 Hz, -NH-CO), 12.92 (bs, 1H, =N-OH) ppm. The hydroxyl groups are not visible due to exchange with residual water. Small resonances at ~2.54, ~4.36, ~5.22, ~6.33, and ~7.47 ppm (corresponding to the (Z)-oxime) are visible. MS m/z (relative intensity): 427 (M+Na+, 100), 405 (M+H, 61); HRMS: calcd for C20H41N2O6, 405.2965; found, 405.2971. IR (KBr) v 3292, 2955, 2918, 2850, 2346, 1701, 1648, 1543, 1467, 1406, 1308, 1284, 1260, 1238, 1216, 1082, 1027, 931, 877 cm-1, mp 119-120 °C.
N-((2S,3fl,4S,5fl,£/Z)-3,4,5,6-tetrahydroxy-1-(hydrox-yimino)hexan-2-yl)-hexadecanamide (23d)
Yield 68%. A 70/30 mixture of (E)- and (Z)-oxime as a white solid. 1H NMR (pyridine-d5, 300 MHz) (E)-oxi-me: 5 0.88 (t, 3H, J = 6.41 Hz, -CH2-CH3), 1.20-1.35 (m, 24H, -(CH2)^-CH3), 1.76-1.85 (m, 2H, -CO-CH2-CH2 -(CH2)12-CH3), 2.42 (t, 2H, J = 7.55 Hz, -CO-CH2-CH;; -(CH2)12-CH3), 4.28-4.34 (m, 1H, HO-CH2-CH(OH)-), 4.45-163 (m, 3H, HO-CH2-CH(OH)-CH(OH)-CH(OH) -CH(NH-)-CH=N-), 5.03 (dd, 1H, J = 2.29, 5.85 Hz, -CH(OH)-CH(NH-)-CH=N-), 5.77-5.84 (m, 1H, -CH(NH-) -CH=N-), 8.29 (d, 1H, J = 5.99, -CH=N-), 8.76 (d, 1H, J = 8.10 Hz, -NH-CO), 12.91 (bs, 1H, =N-OH) ppm. The hy-droxyl groups are not visible due to exchange with residual water. Small resonances at ~2.43, ~4.39, ~5.23, ~6.33, ~7.47 and ~13.37 ppm (corresponding to the (Z)-oxime) are visible. MS m/z (relative intensity): 467 (M+Cl-, 100), 431 (M-H+, 20); HRMS: calcd for C22H43N2O6, 431.3121; found, 431.3104. IR (KBr) v 33293, 3292, 3050, 2953, 2917, 2849, 2361, 2344, 2018, 1654, 1648, 1636, 1558, 1541, 1463, 1405, 1313, 1285, 1250, 1230, 1211, 1083, 1017, 935, 880 cm-1, mp 162-163 °C.
3. 10. Calculation of HLB Values
The HLB (hydrophilic lipophilic balance) parameter was calculated according to Griffin's method22 as follows: HLB = Mh / M x 20, where Mh correspond to the molecular mass of the hydrophilic part of the molecule and M to the molecular mass of the whole molecule. For all synthesized compounds, an aliphatic tail was considered as li-pophilic part of the molecule.
3. 11. The DPPH- Assay
Total antioxidant capacity assay was performed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH') method.23 The radical scavenging activity was evaluated through the degree of DPPH' reduction, followed by monitoring the decrease in its absorbance at 516 nm during the reaction. Various concentrations of synthesized compounds (10 and 5 mM for benzamidoxime and benzoxime derivatives and 0.5, 1, and 5 mM for glycolipid derivatives) were prepared in methanol and each solution (1 mL) was added to 2 mL of methanolic DPPH' solution (0.063 mM). The absorbance was recorded (Hewlett Packard UV/VIS 8453 spec-trophotometer (Germany)) every minute for a 30 min period. All measurements were performed in duplicate.
The remaining DPPH' concentration in the reaction medium was calculated from a calibration curve obtained with DPPH' at 516 nm. The percentage of remaining DPPH' (DPPH' rem) was calculated as follows: % DPPH' rem = (Af / A0) x 100, where Af is the absorbance of the DPPH' solution with the sample at the final state and A0 is the absorbance of the DPPH' solution without the sample (2 mL of DPPH' solution plus 1 mL of methanol).
4. Conclusion
New amphiphilic benzamidoxime (4a-e) and benzoxime (8a-e; 10a-e) derivatives were synthesized with more pronounced hydrophilic properties compared to previously synthesized oxime derivative TDBO. The antioxi-dant activity was estimated using DPPH assay. The radical-scavenging ability data obtained for synthesized amp-hiphilic compounds against DPPH radical can be correlated with their molecular structure: it is the highest in ben-zamidoxime series, followed by derivatives of glucose with two oxime functionalities and compounds constituting benzoxime series; it is lower when only one oxime group is introduced on glucose derivatives, and is the lowest for compounds with two oxime moieties and galactose derivatives. Glycolipid derivatives have the advantage of being synthesized from natural products, whereas all of these novel agents provide a value-added use for two-phase or lipid-based systems due to their amphiphilic character. Due to their notable antioxidant properties, especially amidoximes and glycolipid mimetics with two oxi-
me functionalities show great promise for use as antioxi-dants in topical formulations.
5. References
1.	A. R. Barnes, in: M. E. Aulton (Ed.) Aulton's Pharmaceutics. The design and manufacture of medicines. 3rd Ed, Elsevier, 2007, pp. 650-665
2.	S. J. M. Maxwell, G. Y. H. Lip, Br. J. Clin. Pharmacol. 1997, 44, 307-317.
3.	M. Valko, D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Ma-zur, J. Telser, Int. J. Biochem. Cell Biol. 2007, 39, 44-84.
4.	O. Sorg, C R Biol. 2004, 327, 649-662.
5.	B. J. Day, Drug Discov. Today 2004, 9, 557-566.
6.	B. Halliwell, J. M. C. Gutteridge: Free Radicals in Biology and Medicine, Oxford Sci., 4th Ed. 2007.
7.	J. Kristl, B. Volk, M. Gasperlin, M. Sentjurc, P. Jurkovic, Eur. J. Pharm. Sciences 2003, 19, 181-189.
8.	M. Gasperlin, M. Gosenca, Expert Opin. Drug Deliv. 2011, 8 (7), 905-919.
9.	M. Gosenca, A. Obreza, S. Pecar, M. Gasperlin, AAPS PharmSciTech. 2010, 11 (3), 1485-1492.
10. G. O. Puntel, N. R. de Carvalho, P. Gubert, A. Schwertner Palma, C. L. D. Dorte, D. S. Avila, M. E. Pereira, V. S. Car-ratu, L. Bresolin, J. B. T. da Rocha, F. A. A. Soares, Chem. Biol. Interact. 2009, 177, 153-160.
11.	F. Worek, H. Thiermann, L. Szinicz, P. Eyer, Biochem. Pharmacol. 2004, 68, 2237-2248.
12.	R. De Lima Portella, R. P. Barcelos, A. F. de Bem, V. S. Car-ratu, L. Bresolin, J. B. T. da Rocha, F. A. A. Soarea, Life Sciences 2008, 83, 878-885.
13.	E. Szabados, P. Literati-Nagy, B. Farkas, B. Sumegi, Biochem. Pharmacol. 2000, 59, 937-945.
14.	T. Welss, D. A. Basketter, K. R. Schröder, Toxicol. Vitro 2004, 18, 231-243.
15.	D. Kitamoto, T. Morita, T. Fukuoka, M.-a. Konishi, T. Imura, Curr. Opin. Coll. Int. Sci. 2009, 14, 315-328.
16.	J. Mravljak, A. Obreza, Tetrahedron Lett. 2012, 53, 22342235.
17.	R. Frlan, F. Perdih, N. Cirkvenčič, S Pečar, A. Obreza, Acta Chim. Slov. 2009, 56, 580-590.
18.	R. Frlan, A. Kovač, D. Blanot, S. Gobec, S. Pečar, A. Obreza, Acta Chim. Slov. 2011 58 (2), 295-310.
19.	A. Obreza, F. Perdih, J. Struct. Chem. 2012, 53, 793-799.
20.	A. Hafner, M. Hrast, S. Pečar, J. Mravljak, Tetrahedron Lett. 2009,50 (5), 564-566.
21.	J. Mravljak, S. Pečar, Tetrahedron Lett. 2009, 50 (5), 567569.
22.	W. C. Griffin, J. Soc. Cosmet. Chem. 1954, 5, 249-258.
23.	C. Sanchez-Moreno, J. A. Larrauri, F. Saura-Calixto, Food Res. Int. 1999, 32, 407-412.
24.	W. Brand-Williams, M. E. Cuvelier, C. Berset. Lebensm.-Wiss. u.-Technol. 1997, 28, 25-30.
Povzetek
Sintetizirali smo nove amfifilne spojine benzamidoksimskega in benzoksimskega tipa ter oksimske derivate glikolipid-nih mimetikov z alkilno verigo. Celokupno antioksidativno kapaciteto amfifilnih derivatov smo ovrednotili z DPPH metodo. Benzamidoksimi in glikolipidni mimetiki z dvema oksimskima skupinama imajo najmočnejše antioksidativno delovanje, sledijo jim benzoksimski derivati, glikolipidni mimetiki z eno oksimsko skupino ter dimeri oksimov. Zaradi amfifilne strukture, ki je bila vodilo pri načrtovanju in sintezi, bi nove sintetizirane amfifilne spojine lahko uporabili kot potencialne antioksidante za omejitev oksidativnih procesov v dvofaznih sistemih, tako bioloških (celične membrane) kot umetnih (emulzije).