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724
Quinoxaline Derivatives: Novel and Selective Butyrylcholinesterase Inhibitors Aurang Zeb1, Abdul Hameed1, Latifullah Khan1, Imran Khan1, Kourosh Dalvandi1, M. Iqbal Choudhary1,2 and Fatima Z. Basha1,* 1
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan; 2Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah-21412, Saudi Arabia Abstract: Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine (ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase (AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives 1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against chymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0 M) and 7 (IC50 = 9.7 ± 0.9 M) were found to be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ± 0.38 M). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors. Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.
Keywords: Alzheimer’s disease (AD), acetylcholine (ACh), quinoxaline, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), galantamine, urease, chymotrypsin. INTRODUCTION Alzheimer’s disease is a common form of dementia in which severe loss of cholinergic cells occurs, which subsequently leads to low levels of the neurotransmitter ACh in brain [1]. Such neurological changes in the nervous system may contribute to various cognitive and behavioral symptoms that appear during AD [1, 2]. The most common neurological hallmarks which are associated with this disease include aging, -amyloid plaques and synaptic loss on axon terminals [3]. AD is now a matter of global concern, especially in developed countries where the average life expectancy is high due to healthy life style [4]. As the brain ACh level in AD depends upon the activity of AChE and BChE, targeting these enzymes would be an effective way to control AD symptoms [5]. Both AChE and BChE are serine hydrolase enzymes, with >65% homologous structures, which regulate the breakdown of ACh [6]. Evidences showed that the activity of AChE decreases in AD, while BChE activity remains unchanged [1, 7], or even increases in advanced AD [7]. This description suggests that the hydrolysis of ACh in AD is due to the elevated level of BChE activity. The selective inhibition of BChE is a promising way to treat AD to enhance ACh level in brain regions [8]. *Address correspondence to this author at the H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan; Tel: (+ 92).(21) (99261767); Fax: (+ 92).(21).(4819018-9); E-mail:
[email protected] /14 $58.00+.00
The usage of small molecules as BChE inhibitors provides a good alternate against AD symptoms [9]. The single crystal X-ray diffraction studies on AChE and BChE along with biochemical research have provided the threedimensional structures of different types of small molecules within the binding sites of AChE and BChE [10-12]. Although previous literature revealed many small organic molecules as cholinesterase inhibitors, most of them are found to be non-selective towards AChE and BChE [13]. However, there are only a few studies which have reported selective inhibitors of AChE and BChE [8, 9], yet the area remains elusive to find a lead for the development of selective therapeutic agent against BChE. In this study, we have tested a series of seventeen quinoxaline derivatives 1-17 to evaluate their biological activities. Quinoxalines are nitrogen containing heterocyclic compounds which exhibit various biological activities of pharmaceutical interests such as antibacterial [14, 15], antifungal [15], anti- inflammatory [16], anticancer [17-19], antitubercular [20], antileishmanial [21], antimalarial [22] and antidepressant activities [23]. In view of such interesting biological activities, we have synthesized a series of quinoxaline derivatives (1-17) and evaluated them against the cholinesterases i.e. BChE and AChE. The quinoxaline derivatives were also tested for chymotrypsin and urease inhibitory activities. All the compounds were found completely inactive against AChE, -chymotrypsin and urease activities. However, promising results were obtained for BChE inhibition which varies with substituents on the phenyl ring. © 2014 Bentham Science Publishers
Quinoxaline Derivatives: Novel and Selective Butyrylcholinesterase Inhibitors
O
Medicinal Chemistry, 2014, Vol. 10, No. 7
NH2
O
R
H R
1) SeO2, reflux I
R
2) H2O, reflux
725
O
N NH2
H2O
1,4-Dioxane, r.t.
II
R = Substituted group (H, CH3, I, Br, Cl, F, OCH3, OH, NO2)
N Quinoxaline Analogues (1-17) 64-97%
Scheme 1. Synthesis of Quinoxaline Analogues 1-17.
RESULTS AND DISCUSSION
Table 1.
Chemistry As described above, quinoxaline and related analogues have exhibited significant biological potential, so to pursue our interest to inhibit cholinesterase we required an efficient method for the synthesis of quinoxaline derivatives. After considering several synthetic options, we prepared the desired quinoxaline analogues to investigate cholinesterases inhibition via a reported procedure [24]. Following the literature procedure, the -methyl group of the corresponding acetophenones I was oxidized to the aldehyde moiety with selenium dioxide in 50% aqueous dioxane solvent at high temperature (100-103°C). The reaction was monitored by TLC analysis until the complete consumption of starting material I. The resultant dicarbonyl compound II was then treated with 1,2-diaminobenzene to furnish the desired fused bicyclic core ring of quinoxaline (Scheme 1). The final product was obtained after column chromatography in 64-97% yield (Scheme 1). The structures of all quinoxaline derivatives were confirmed by using NMR spectroscopy and mass spectrometry.
R N
N
Bioactivities The bioactivities of all the synthesized quinoxaline analogues 1-17 were tested in vitro against the AChE and BChE enzymes by using the standard activity protocol [9, 25]. The in vitro enzymes inhibition results (Table 1) showed no activity toward AChE, while a trend in enzyme inhibition activity, ranging from IC50 = 7.7 ± 1.0 M to IC50 = 57.1 ± 4.0 M, have been observed for the compounds 1-17 against BChE. For both -chymotrypsin and urease, the compounds (1-17) demonstrated no activity. Their considerable BChE inhibitory activity, make them selective candidates for further studies in this area. In the series, seven compounds 1, 2, 4-7, and 9 showed significant activity as BChE inhibitors, while the compounds 3, 8, and 10-17 were found completely inactive against BChE. The compounds 6 (IC50 = 7.7 ± 1.0 M), and 7 (IC50 = 9.7 ± 0.9 M) exhibited promising bioactivity which are comparable with the IC50 value of the standard galantamine (IC50 = 6.6 ± 0.38M). The bioactivity of the compounds 1, 2, 4, 5 and 9 was found weak as compared to standard inhibitor with IC50 values ranging from 20 ± 0.4 to 57.1 ± 4.0 M (Table 1). An earlier BChE inhibition study by Darvesh et al. [9] with amide derivatives of phenothiazine revealed the – interaction of two aromatic rings of phenothiazine with two aromatic amino acid residues, F329 and Y332, of BChE (Fig. 1) [9, 26]. So, due to the very close structural similarity
Synthesis and BChE inhibitory activity of quinoxaline analogues 1-17.
Compounds
R
Yield (%)
IC50 ± SEMa (M)
1
H
77
57.1± 4.0
2
4-Me
87
39 ± 1.0
3
2-OMe
70
NAb
4
3-OMe
64
36 ± 3.0
5
4-OMe
66
24 ± 4.0
6
3-OH
80
7.7 ± 1.0
7
4-OH
93
9.7 ± 0.9
8
3-F
84
NAb
9
4-F
96
20 ± 0.4
10
2-Cl
85
NAb
11
4-Cl
97
NAb
12
3-Br
92
NAb
13
4-Br
95
NAb
14
3-I
70
NAb
15
2-NO2
66
NAb
16
3-NO2
68
NAb
17
4-NO2
70
NAb
-
6.6 ± 0.38
Galantaminec a
SEM: standard error mean, bNA: not active, cGalantamine: standard BChE inhibitor Note: The compounds 1-17 in (Table 1) are found inactive against AChE, achymotrypsin and urease.
S
N
Ar
N N H Quinoxaline Phenothiazine Ar = Substitute aromatic ring
Fig. (1). Typical structure of phenothiazine and quinoxaline ring systems.
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between quinoxaline and phenothiazine skeletons, it is reasonable to study the SAR of quinoxaline analogues. The SAR has been established on the basis of different substituents on the phenyl ring of quinoxaline derivatives 1-17. Compounds 6 (3-OH analogue), and 7 (4-OH analogue) were found to be the most active analogues in the series. The high BChE inhibitory activity might be attributed to the Hbonding of 6 and 7 with the active site amino acid residues of the enzyme. The small difference in activities may be due to different position of OH (i.e. meta and para) on the phenyl ring. The compounds 9 (IC50 = 20 ± 0.4 M) and 5 (IC50 = 24 ± 4.0 M) were found to be ~ 3 times weaker than the compound 6 (7.7 ± 1.0 M). It might be due to the lack of OH-group which resulted in insufficient H-bonding capacity of the molecule. Compounds 2 (4-Me analogue), 4 (3OMe analogue) and compound 1 were found to be least active among the series. The decline in activity might be due to low level of hydrogen bonding and - interaction with BChE. The SAR reveals that the substitutions on phenyl ring, as well as the position of substituents, affect the enzyme inhibitory activity of these compounds (Table 1). Altogether, this study identifies a new class of potential BChE inhibitors. CONCLUSION In conclusion, a series of quinoxaline derivatives 1-17 was synthesized and evaluated for BChE, AChE, chymotrypsin and urease enzymes inhibition activities. As a result of this study, the quinoxaline derivatives were found to be selective inhibitors for BChE. The compounds 6 and 7 presented comparable activity with the standard galantamine and thus, serve as leads for the further development of selective BChE inhibitors. MATERIALS AND METHODS Assay for AChE and BChE All the experiments were performed in triplicate in a 96well micro-plate on SpectraMax340 (Molecular Devices, USA). Electric eel AChE, equine serum BChE, ACh iodide, butyrylcholine chloride, and 5,5’-dithiobis(2-nitrobenzoic acid) or DTNB were bought from Sigma Aldrich. Buffers and other chemicals of analytical grades were utilized. AChE and BChE inhibiting activities were measured by slightly modifying the spectrophotometric method developed by Ellman et al. [25]. ACh iodide and butyrylcholine chloride were used as reacting substrates and DTNB was applied to determine cholinesterase activity. 150 L of 100 mM Na3PO4 buffer (pH = 8), 10 L of each compound solution (0.2 mM) and 20 L AChE or BChE solution were well mixed. The mixture was then incubated for fifteen minutes at room temperature. 10 L DTNB and 10 L, ACh or BCh were then added to initiate the reaction. The hydrolysis of these substrates produces yellow colored 5-thio-2nitrobenzoate anion due to the reaction between DTNB and thiocholine. The enzymatic hydrolysis of the reacting substrates with ACh iodide or butyrylcholine chloride was determined by spectrophotometer at a wavelength of 412 nm. A polar solvent methanol was used to dissolve all compounds and the control [9].
Zeb et al.
The urease and -chymotrypsin enzymes inhibition studies were carried out according to the literature protocols [27, 28]. General Experimental All the acetophenone derivatives were purchased from Sigma Aldrich. The melting points were determined using a Büchi 434 apparatus. 1H NMR (300, 400 MHz) and 13C NMR (75, 100, 150 MHz) spectra were recorded on Bruker Avance NMR spectrometers in appropriate solvents (i.e. CDCl3 and DMSO-d6) using TMS as an internal standard. Chemical shifts ( values) are presented in ppm (parts per million) and the coupling constants (J values) are in Hertz. Finnigan MAT-311A mass spectrometer was used to obtain Electron impact mass spectra (EI MS). Silica gel pre-coated aluminium plates (silica gel 60 254, E. Merck, Germany) were used for thin layer chromatography. Chromatograms were visualized by UV at 254 and 365 nm. General Procedure for the Synthesis of Compounds 1-17 An oven dried round-bottom flask was charged with the corresponding acetophenone (0.01mol) in 1,4-dioxane/water mixture (10:0.5, v/v). Selenium dioxide (0.01 mol), was then added in one portion to the stirred solution. The resulting mixture was then heated at reflux for 3 h until the starting material was consumed as judged by TLC analysis. The reaction mixture was allowed to cool and then the mixture was filtered. The filtrate was then evaporated under vacuum on a rotary evaporator. Water (10 mL) was added to the residue and the resulting mixture was heated at 101-103 °C for further 3 h. The solution of 1, 2-diaminobenzene (0.012 mol) in dioxane (20 mL) was added in one portion to the reaction mixture and stirred for 30 min at room temperature. The reaction mixture was diluted with water (100 mL) and the resulting precipitates were collected by filtration. The crude mixture was purified on silica gel column (EtOAc / Hexane, 1/9 3/7) to afford the desired quinoxalines in good to excellent yields (64-97%) [24]. The structures of all quinoxaline derivatives 1-17 were confirmed with different spectroscopic techniques. 2-Phenylquinoxaline (1) [29, 30] Off-white solid; Yield: 77%; mp: 77-79 °C; 1H NMR (300 MHz, CDCl3): 9.31 (1H, s, N=CH), 8.16 (4H, m, ArH), 7.80 (2H, m, ArH), 7.54 (3H, m, ArH); MS (EI) m/z (rel. abund. %): 206 (M+, 100), 207 (28), 179 (88), 178 (31), 103 (17), 76 (25), 44 (36); HRMS (EI): calcd for C14H10N2 [M+] 206.0838, found 206.0835. 2-p-Tolylquinoxaline (2) [29, 30] Off-white solid; Yield: 87%; mp: 94-96 °C; 1H NMR (400 MHz, CDCl3): 9.30 (1H, s, N=CH), 8.10 (4H, m, ArH), 7.74 (2H, m, ArH), 7.37 (2H, m, ArH), 2.44 (3H, s, CH3); MS (EI) m/z (rel. abund. %): 220 (M+, 100), 221 (23), 193 (30), 192 (21), 43 (20); HRMS (EI): calcd for C15H12N2 [M+] 220.0995, found 220.0996. 2-(2-Methoxyphenyl)quinoxaline (3) [31] White solid; Yield: 70%; mp: 114-115 °C; 1H NMR (400 MHz, CDCl3): 9.31 (1H, s, N=CH), 8.13 (2H, m, ArH), 7.87 (1H, dd, J = 7.6 Hz, J = 2.0 Hz, ArH), 7.74 (2H, m,
Quinoxaline Derivatives: Novel and Selective Butyrylcholinesterase Inhibitors
ArH), 7.46 (1H, app td, J = 8.4 Hz, J = 1.6 Hz, ArH), 7.14 (1H, app td, J = 7.6 Hz, J = 0.8 Hz, ArH), 7.04 (1H, d, J = 8.4 Hz, ArH), 3.89 (3H, s, OCH3); MS (EI) m/z (rel. abund. %): 236 (M+, 92), 235 (100), 219 (63), 207 (53), 131 (25), 44 (26); HRMS (EI): calcd for C15H12N2O [M+] 236.0944, found 236.0950. 2-(3-Methoxyphenyl)quinoxaline (4) [31] White solid; Yield: 64%; mp: 97-98 °C; 1H NMR (400 MHz, CDCl3): 9.30 (1H, s, N=CH), 8.13 (2H, m, ArH), 7.76 (4H, m, ArH), 7.46 (1H, t, J = 8.0 Hz, ArH), 7.05 (1H, app dd, J = 7.6 Hz, J = 2.4 Hz, ArH), 3.92 (3H, s, OCH3); MS (EI) m/z (rel. abund. %): 236 (M+, 100), 235 (91), 206 (34), 179 (13); HRMS (EI): calcd for C15H12N2O [M+] 236.0944, found 236.0930. 2-(4-Methoxyphenyl)quinoxaline (5) [29, 30] White solid; Yield: 66%; mp: 102-104 °C; 1H NMR (400 MHz, CDCl3): 9.27 (1H, s, N=CH), 8.16 (2H, d, J = 8.8 Hz. ArH), 8.08 (2H, app td, J = 9.6 Hz, J = 1.2 Hz, ArH), 7.74 (2H, m, ArH), 7.06 (2H, d, J = 8.8 Hz, ArH), 3.89 (3H, s, OCH3); MS (EI) m/z (rel. abund. %): 236 (M+, 100), 237 (72), 221 (93), 209 (72), 166 (45), 133 (28), 76 (17); HRMS (EI): calcd for C15H12N2O [M+] 236.0944, found 236.0930. 2-(3-Hydroxyphenyl)quinoxaline (6) Yellow solid; Yield: 80%; mp: 177-178 °C; 1H NMR (400 MHz, CDCl3): 9.30 (1H, s, N=CH), 8.12 (2H, app td, J = 8.4 Hz, J = 1.6 Hz, ArH), 7.75 (4H, m, ArH), 7.42 (1H, t, J = 8.0 Hz, ArH), 7.0 (1H, m, ArH), 5.50 (1H, br s, ArOH); 13 C NMR (150 MHz, DMSO-d6): 158.1 (C-OH), 150.9, 143.7, 141.4, 141.1, 137.3, 130.6, 130.2, 129.8, 129.2, 128.8, 118.3, 117.6, 113.9. MS (EI) m/z (rel. abund. %): 222 (M+, 100), 223 (63), 221 (43), 195 (88), 194 (39), 167 (78), 76 (14); HRMS (EI): calcd for C14H10N2O [M+] 222.0788, found 222.0787. 2-(4-Hydroxyphenyl)quinoxaline (7) [30] Yellow solid; Yield: 93%; mp: 208-210 °C; 1H NMR (400 MHz, CDCl3): 9.18 (1H, s, N=CH), 8.0 (4H, m, ArH), 7.70 (2H, m, ArH), 6.95 (2H, d, J = 8.8 Hz, ArH), 5.50 (1H, br s, ArOH); MS (EI) m/z (rel. abund. %): 222 (M+, 100), 223 (64), 221 (39), 195 (91), 167 (59), 119 (27), 76 (13); HRMS (EI): calcd for C14H10N2O [M+] 222.0788, found 222.0790. 2-(3-Fluorophenyl)quinoxaline (8) Light brown solid; Yield: 84%; mp: 113-115 °C; 1H NMR (400 MHz, CDCl3): 9.30 (1H, s, N=CH), 8.14 (2H, m, ArH), 7.95 (2H, m, ArH), 7.76 (2H, m, ArH), 7.53 (1H, m, ArH), 7.20 (1H, m, ArH); 13C NMR (75 MHz, DMSOd6): 164.3 (C-F), 161.1, 149.6, 143.7, 141.3, 138.5, 131.3, 130.7, 130.2, 129.2, 128.8, 123.5, 117.3, 114.1. MS (EI) m/z (rel. abund. %): 224 (M+, 100), 225 (28), 197 (87), 76 (16), 50 (7); HRMS (EI): calcd for C14H9FN2 [M+] 224.0744, found 224.0752. 2-(4-Fluorophenyl)quinoxaline (9) [29, 30]
Medicinal Chemistry, 2014, Vol. 10, No. 7
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J = 8.8 Hz, ArH); MS (EI) m/z (rel. abund. %): 224 (M+, 100), 225 (28), 223 (11), 197 (85), 76 (17), 50 (7); HRMS (EI): calcd for C14H9FN2 [M+] 224.0744, found 224.0777. 2-(2-Chlorophenyl)quinoxaline (10) [32] Light pink solid; Yield: 85%; mp: 94-96 °C; 1H NMR (400 MHz, CDCl3): 9.20 (1H, s, N=CH), 8.16 (2H, m, ArH), 7.80 (2H, m, ArH), 7.70 (1H, m, ArH), 7.54 (1H, m, ArH), 7.45 (2H, m, ArH); MS (EI) m/z (rel. abund. %): 240 (M+, 80), 242 (34), 205 (100), 178 (48), 76 (18), 50 (7); HRMS (EI): calcd for C14H9ClN2 [M+] 240.0744, found 240.0777. 2-(4-Chlorophenyl)quinoxaline (11) [29, 33] White crystals; Yield: 97%; mp: 138-140 °C; 1H NMR (400 MHz, CDCl3): 9.29 (1H, s, N=CH), 8.15 (4H, m, ArH), 7.77 (2H, m, ArH); 7.53 (2H, m, ArH); MS (EI) m/z (rel. abund. %): 240 (M+, 100), 242 (60), 241 (31), 205 (60), 178 (55), 76 (25), 44 (85); HRMS (EI): calcd for C14H9ClN 2 [M+] 240.0744, found 240.0770. 2-(3-Bromophenyl)quinoxaline (12) [33] Gray solid; Yield: 92%; mp: 134-136 °C; 1H NMR (300 MHz, CDCl3): 9.28 (1H, s, N=CH), 8.38 (1H, br s, ArH), 8.12 (3H, m, ArH), 7.76 (2H, m, ArH), 7.63 (1H, d, J = 8.1 Hz, ArH), 7.42 (1H, t, J = 7.8 Hz, ArH); MS (EI) m/z (rel. abund. %): 286 (M+, 100), 284 (95), 205 (60), 178 (47), 44 (40); HRMS (EI): calcd for C14H9BrN2 [M+] 283.9944, found 283.9962. 2-(4-Bromophenyl)quinoxaline (13) [29, 30] White solid; Yield: 95%; mp: 137-138 °C; 1H NMR (400 MHz, CDCl3): 9.30 (1H, s, N=CH), 8.12 (4H, m, ArH), 7.76 (2H, m, ArH), 7.69 (2H, d, J = 8.8 Hz, ArH); MS (EI) m/z (rel. abund. %): 286 (M+, 93), 284 (100), 205 (38), 178 (36), 44 (76); HRMS (EI): calcd for C14H9BrN2 [M+] 283.9944, found 283.9961. 2-(3-Iodophenyl)quinoxaline (14) Yellow solid; Yield: 70%; mp: 137-138 °C; 1H NMR (300 MHz, CDCl3): 9.26 (1H, s, N=CH), 8.56 (1H, t, J = 1.2 Hz, ArH), 8.13 (3H, m, ArH), 7.84 (1H, d, J = 7.6 Hz, ArH), 7.77 (2H, m, ArH), 7.30 (1H, t, J = 7.6 Hz, ArH); 13C NMR (100 MHz, DMSO-d6): 149.4, 143.6, 141.2, 138.9, 138.1, 135.7, 133.7, 131.1, 130.7, 130.2, 129.3, 128.8, 126.8, 95.6 (C-I). MS (EI) m/z (rel. abund. %): 332 (M+, 75), 205 (100), 178 (18), 44 (20); HRMS (EI): calcd for C14H9IN2 [M+] 331.9805, found 331.9821. 2-(2-Nitrophenyl)quinoxaline (15) [34] Brown solid; Yield: 66%; mp: 115-117 °C; 1H NMR (300 MHz, CDCl3): 8.94 (1H, s, N=CH), 8.13 (3H, m, ArH), 7.80 (4H, m, ArH), 7.68 (1H, td, J = 8.4 Hz, J = 2.0 Hz, ArH); MS (EI) m/z (rel. abund. %): 251 (M+, 14), 221 (25), 220 (24), 219 (63); HRMS (EI): calcd for C14H9N3O2 [M+] 251.0689, found 251.0702. 2-(3-Nitrophenyl)quinoxaline (16) [33]
1
Light brown solid; Yield: 96%; mp: 123-124 °C; H NMR (300 MHz, CDCl3): 9.28 (1H, s, N=CH), 8.20 (2H, m, ArH), 8.10 (2H, m, ArH), 7.75 (2H, m, ArH), 7.26 (2H, t,
Brown solid; Yield: 68%; mp: 162-164 °C; 1H NMR (400 MHz, CDCl3): 9.37 (1H, s, N=CH), 9.10 (1H, t, J = 2.0 Hz, ArH), 8.54 (1H, dq, J = 8.0 Hz, J = 0.8 Hz, ArH),
728 Medicinal Chemistry, 2014, Vol. 10, No. 7
8.36 (1H, dq, J = 8.0 Hz, J = 1.2 Hz, ArH), 8.16 (2H, m, ArH), 7.80 (2H, m, ArH), 7.74 (1H, t, J = 8.0 Hz, ArH); MS (EI) m/z (rel. abund. %): 251 (M+, 90), 221 (50), 205 (100), 178 (21), 76 (18), 44 (52); HRMS (EI): calcd for C14H9N3O2 [M+] 251.0689, found 251.0699.
Zeb et al. [12]
[13]
2-(4-Nitrophenyl)quinoxaline(17) [29, 33] Brown solid; Yield: 70%; mp: 188-190 °C; 1H NMR (300 MHz, CDCl3): 9.37 (1H, s, N=CH), 8.40 (4H, br s, ArH), 8.16 (2H, m, ArH), 7.83 (2H, m, ArH); MS (EI) m/z (rel. abund. %): 251 (M+, 100), 221 (78), 205 (84), 178 (39), 76 (26), 43 (50); HRMS (EI): calcd for C14H9N3O2 [M+] 251.0689, found 251.0699.
[14]
[15]
CONFLICT OF INTEREST
[16]
The authors confirm that this article content has no conflict of interest.
[17]
ACKNOWLEDGEMENTS We are thankful to the Higher Education Commission (HEC) of Pakistan, and the H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi75270, Pakistan for providing financial support in this project. REFERENCES [1]
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Received: August 13, 2013
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Revised: May 10, 2014
Accepted: May 21, 2014
