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Article

Phenoxyacetohydrazide Schiff Bases: β-Glucuronidase Inhibitors

1
Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
2
Institute of Advance Research Studies in Chemical Sciences, University of Sindh Jamshoro, Hyderabad 76080, Pakistan
3
Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Bandar Puncak Alam, Selangor Darul Ehsan 42300, Malaysia
4
Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Bandar Puncak Alam, Selangor Darul Ehsan 42300, Malaysia
5
Faculty of Applied Science UiTM, Shah Alam, Selangor 40450, Malaysia
6
PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman, Karachi 75280, Pakistan
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(7), 8788-8802; https://doi.org/10.3390/molecules19078788
Submission received: 7 May 2014 / Revised: 6 June 2014 / Accepted: 11 June 2014 / Published: 25 June 2014
(This article belongs to the Section Medicinal Chemistry)

Abstract

:
Phenoxyacetohydrazide Schiff base analogs 128 have been synthesized and their in vitro β-glucouoronidase inhibition potential studied. Compounds 1 (IC50 = 9.20 ± 0.32 µM), 5 (IC50 = 9.47 ± 0.16 µM), 7 (IC50 = 14.7 ± 0.19 µM), 8 (IC50 = 15.4 ± 1.56 µM), 11 (IC50 = 19.6 ± 0.62 µM), 12 (IC50 = 30.7 ± 1.49 µM), 15 (IC50 = 12.0 ± 0.16 µM), 21 (IC50 = 13.7 ± 0.40 µM) and 22 (IC50 = 22.0 ± 0.14 µM) showed promising β-glucuronidase inhibition activity, better than the standard (D-saccharic acid-1,4-lactone, IC50 = 48.4 ± 1.25 µM).

1. Introduction

A range of bioactivities are reported for hydrazide-hydrazone compounds, such as antibacterial, anticonvulsant, antimalarial, analgesic, antiinflammatory, antiplatelets, antifungal, antituberculosis, and anticancer activities [1,2,3,4,5,6]. A variety of semicarbazones, thiosemicarbazones and guanyl hydrazones are found to be key compounds for drug design [7], for metal complexes [8], organocatalysis [9], and are used for the preparation of heterocyclic rings [10]. A few pyrazole carbohydrazide hydrazone derivatives [11] and novel 3-aryl-1-arylmethyl-1H-pyrazole-5-carbohydrazide hydrazones were found to be proliferation inhibitors of A549 cells [12,13] Some evidence proposes a pharmacophoric character for the hydrazone moiety present in phenylhydrazone derivatives in the inhibition of cyclooxygenase [14]. Antioxidant [15,16,17,18], antiglycation [19,20,21,22] and antileishmanial [23] activity have recently been reported, as well as applications in mass spectrometry [24].
The present work aimed to investigate the potential activity of a series of aryl hydrazide-hydrazones as in vitro β-glucouoronidase inhibitors. In our designed analogues substituted phenoxy-acetohydrazides were treated with different aromatic aldehydes to scrutinize their potential activity. The earlier reported literature [25] showed that β-glucouoronidase is a lysosomal enzyme, present in many organs like the spleen, kidney, lung, bile, serum and urine, etc., where its specific task is to catalyze the cleavage of glucuronosyl-O-bonds [26,27,28]. It degrades glucuronic acid-containing glycosaminoglycans, like heparan sulfate, chondroitin sulfate and dermatan sulfate [29]. An elevated level of β-glucouoronidase was observed in various types of malignancies, such as breast, lung and gastrointestinal tract carcinomas, and melanomas. Its high expression also observed in bronchial tumors [30]. On the other hand, mucopolysaccharidosis type VII (MPS VII; Sly Syndrome) is caused by the deficiency of human β-glucuronidase [31]. The circulating level of β-glucuronidase is also useful as a lysosomal enzyme in children affected by leprosy. In borderline tuberculoid patients and lepromatous patients higher activity of this enzyme was also observed.

2. Results and Discussion

2.1. Chemistry

Lead identification is a well defined tool in drug design and discovery. Our research group has been involved for a decade in lead discovery programs in search of novel therapeutic agents. We have earlier reported Schiff bases of different classes of organic compounds in the search for lead molecules with different biological activities [32,33,34]. Earlier, our group reported the leishmanicidal and β-glucurinodase inhibition potential of hydrazides derived from the corresponding esters [35,36,37,38]. In view of the formerly reported work we synthesized hydrazide Schiff bases and screened their potential biological activities [39,40,41,42]. Acylhydrazide Schiff base derivatives 128 were synthesized from an acylhyrazide by condensing it with different aromatic aldehydes and acetophenones under reflux conditions in ethanol for 2–3 h (Scheme 1). The crude products (Table 1) were further recrystallized from methanol and needle-like crystals were obtained in most of the cases. The starting acylhydrazide was synthesized from ester of ethyl 2-(4-chloro-2-methylphenoxy) acetate by refluxing with hydrazine hydrate.
Scheme 1. Synthetic scheme for benzohydrazide followed by synthesis of Schiff bases 128.
Scheme 1. Synthetic scheme for benzohydrazide followed by synthesis of Schiff bases 128.
Molecules 19 08788 g002
Table 1. Synthesis of acylhydrazide Schiff base derivatives 128.
Table 1. Synthesis of acylhydrazide Schiff base derivatives 128.
Compound No.R1R2Yield (%)Compound No.R1R2Yield (%)
1 Molecules 19 08788 i001 H8115 Molecules 19 08788 i002 H88
2 Molecules 19 08788 i003 H8516 Molecules 19 08788 i004 H92
3 Molecules 19 08788 i005 H9317 Molecules 19 08788 i006 CH394
4 Molecules 19 08788 i007 H8718 Molecules 19 08788 i008 H89
5 Molecules 19 08788 i009 H8319 Molecules 19 08788 i010 CH387
6 Molecules 19 08788 i011 H8620 Molecules 19 08788 i012 H84
7 Molecules 19 08788 i013 H8921 Molecules 19 08788 i014 H94
8 Molecules 19 08788 i015 H9122 Molecules 19 08788 i016 H93
9 Molecules 19 08788 i017 H9423 Molecules 19 08788 i018 H91
10 Molecules 19 08788 i019 H8224 Molecules 19 08788 i020 CH395
11 Molecules 19 08788 i021 H8825 Molecules 19 08788 i022 H91
12 Molecules 19 08788 i023 H9126 Molecules 19 08788 i024 H88
13 Molecules 19 08788 i025 H8627 Molecules 19 08788 i026 H81
14 Molecules 19 08788 i027 H9328 Molecules 19 08788 i028 H93

2.2. β-Glucuronidase

Synthetic acyl hydrazides Schiff bases 128 were screened for their in vitro potential as β-glucoronidase inhibitors. The in vitro β-glucornidase inhibitory potential was evaluated by using the literature protocol [43]. Compounds 128 showed diversified β-glucoronidase inhibitory activities, with IC50 values ranging between 9.20–30.7 µM. Compounds 1, 5, 7, 8, 11, 12, 15, 21, and 22 showed excellent β-glucoronidase inhibitory activities, with IC50 values of 9.20 ± 0.32, 9.47 ± 0.16, 14.7 ± 0.19, 15.4 ± 1.56, 19. ± 0.62, 30.7 ± 1.49, 12.0 ± 0.16, 13.7 ± 0.40, and 22.0 ± 0.14 µM, respectively, and the remaining compounds exhibited no activity (Table 2).
Table 2. In vitro β-glucuronidase activity of compounds 128.
Table 2. In vitro β-glucuronidase activity of compounds 128.
CompoundsIC50 (μM ± SEM a)CompoundsIC50 (μM ± SEM a)
19.20 ± 0.321512.0 ± 0.16
2NA b16NA b
3NA b17NA b
4NA b18NA b
59.47 ± 0.1619NA b
6NA b20NA b
714.7 ± 0.192113.7 ± 0.40
815.4 ± 1.562222.0 ± 0.14
9NA b23NA b
10NA b24NA b
1119.6 ± 0.6225NA b
1230.7 ± 1.4926NA b
13NA b27NA b
14NA b28NA b
D-saccharic acid-1,4-lactone c48.4 ± 1.25--
SEM a is the standard error of the mean; NA b Not active; c standard inhibitor for β-glucuronidase.
It was observed that both the substituents’ nature and their position at the benzilidine part have great importance in the β-glucoronidase inhibition activity of a compound, and apparently the acylium part does not take part in the activity (Figure 1).
Figure 1. The two parts of molecule on which activity is based.
Figure 1. The two parts of molecule on which activity is based.
Molecules 19 08788 g001
The best activity was shown by compound 1 (IC50 = 9.20 ± 0.32 µM, fivefold better than the standard D-saccharic acid-1,4-lactone, IC50 value 48.4 ± 1.25 µM) which has a methoxy group at the ortho position. Surprisingly, a marked decline in activity (to the point of being inactive) was observed in analog 2 which has a methoxy residue at the para position instead of the ortho position as in compound 1. This huge difference in the activities of compounds 1 and 2 clearly indicates that a specific group at a specific position of the benzylidine phenyl ring part plays a vital role in making a potent β-glucornidase inhibitor in this type of compounds. The excellent activity of compound 5 (IC50 = 9.47 ± 0.16 µM) having an ortho nitro group on the phenyl ring as compared to the inactivity of its closely related derivative 6 having a meta nitro group on phenyl ring proves our hypothesis that a suitable group at a suitable position of the phenyl ring of benzilidine part of molecules is a prerequisite for β-glucornidase inhibitory potential in these N-acylhydrazone Schiff bases. Comparison of activity of chloro-containing compounds 7 (IC50 = 14.7 ± 0.19 µM), 8 (IC50 = 15.4 ± 1.56 µM), and 9 (inactive) demonstrated that the nature and location of a substitution is important for β-glucornidase inhibitory potential. Dichloro-substituted compounds 9 and 10 were found to be completely inactive which further proves our hypothesis. Compound 11 (IC50 = 19.6 ± 0.62 µM) having an ortho fluoro group showed excellent activity, but a little less than analogous chloro compounds 7 and 8. We also evaluated the effect of heterocyclic ring-containing derivatives, and it was observed that the five membered heterocyclic thiophene ring-containing derivative 12 (IC50 30.7 ± 1.49 µM) produced remarkable activity, while on the other hand five membered heterocyclic rings like furan and its methyl derivatives 13 and 14 were found to be completely inactive. Almost all mono-, di- and trihydroxy substituted compounds 16, 17, 18, 19, and 20 found to be completely inactive, but unexpectedly compound 15 (IC50 = 12.0 ± 0.16 µM) which bears 2,3-dihydroxy substitution, was found to be very efficient and displayed remarkable activity, better than the standard, but, compound 16, also a 3,4-dihydroxy derivative did not show any activity. N-acylhydrazones Schiff base 21 (IC50 = 13.7 ± 0.40 µM) synthesized from 1-napthaldehyde was found to be more active than 22 (IC50 = 22.0 ± 0.14 µM) which was synthesized from 2-napthaldehyde, both without any substitution. Remaining compounds 2328 were found to be completely inactive. This pattern of activity reveals that the substituent and its position on the phenyl ring of benzylidine part is a driving force for β-glucornidase inhibition activity.
In conclusion, a number of potential lead molecules has been identified as β-glucuronidase inhibitors. Compounds 1, 5, 7, 8, 11, 12, 15, 21, and 22 demonstrated excellent activity and it is anticipated that by slight synthetic modification in these molecules, some new most active β-glucuronidase inhibitors can be developed.

3. Experimental

3.1. General Information

1H-NMR experiments were performed on an Avance-Bruker AM 300 MHz instrument (Wissembourg Cedex, France). A Carlo Erba Strumentazione-Mod-1106 (Milan, Italy) used to measure CHN analysis. EI MS was performed on a Finnigan MAT-311A (Bremen, Germany). Thin layer chromatography (TLC) was carried out on pre-coated silica gel glass plates (Kieselgel 60, 254, E. Merck, Darmstadt, Germany). The chromatograms were visualized by UV at 254 and 365 nm or iodine vapours.

3.2. Biological Assays

β-Glucuronidase (E.C. 3.2.1.31 from bovine liver, G-0251) and p-nitrophenyl-β-D-glucuronide (N-1627) were purchased From Sigma Chemical Co. (St. Louis, MO, USA). Anhydrous Na2CO3 and all other reagents of standard grade were obtained from E. Merck. The anhydrous EtOH and CHCl3 used in the experiments were dried employing the standard methods. All other solvents and reagents like the benzoyl chloride were of standard grade.

3.3. Assay for β-D-Glucuronidase

β-D-Glucuronidase inhibition was determined by measuring the absorbance of the p-nitrophenol which is produce from the substrate at 405 nm. The total reaction volume was 250 µL. The reaction mixture contains 5 µL of test compound solution, 185 µL of 0.1 M acetate buffer, and 10 µL of enzyme, and it was incubated at 37 °C for 30 min. The plates were read on a multiplate reader at 405 nm after the addition of 50 µL of 0.4 mM p-nitrophenyl-β-D-glucuronide. All assays were performed in triplicate.

3.4. Typical Method for the Synthesis of Compounds 128

To a mixture of 2-(4-chloro-2-methylphenoxyacetic acid) hydrazide (1 mmol) in methanol (25 mL) was added a substituted aldehyde (1 mmol) and 3 drops of glacial acetic acid and the mixture was refluxed for 3 h. After completion of the reaction (TLC analysis), it was cooled and evaporated on a rotary evaporator. The resultant crude product was crystallized from methanol to afford 80%–90% yields of pure product. The structures of synthetic compounds 128 were determined by different spectroscopic techniques, including 1H-NMR, and EI MS spectroscopy.
2-(4-Chloro-2-methylphenoxy)-N'-[(3-(2-methoxyphenyl)-2-propenylidene]acetohydrazide (1). Yield: 68%; 1H-NMR (DMSO-d6) δ: 8.04 (d, 1H, J = 9.3 Hz, N=CH-CH), 7.63 (dd, 1H, J5',6' = 7.8 Hz, J5',3' = 1.2 Hz, H-6'), 7.34 (dd, 1H, JCH-HC=CH = 8.1 Hz, CH-HC=CH), 7.23 (d, 1H, JHC=CH = 6 Hz, HC=CH), 7.12–7.20 (m, 2H, H-3/5) 6.85–7.06 (m, 3H, H- 3'/4'/5'), 6.80 (d, 1H, J6,5 = 9 Hz, H-6), 5.17 (s, 2H, -OCH2), 3.84 (s, 3H, -OCH3), 2.23 (s, 3H, CH3); EI MS: m/z (%) 358 (M+, 30), 327 (100),189 (40), 175 (55), 159 (100), 125 (75.0), Anal. Calcd for C19H19ClN2O3, C = 63.60, H = 5.34, N = 7.81. Found: C = 63.55, H = 5.31, N = 7.80.
2-(4-Chloro-2-methylphenoxy)-N'-[(3-(4-methoxyphenyl)-2-propenylidene]acetohydrazide (2). Yield: 70%; 1H-NMR (DMSO-d6) δ: 8.02 (d, 1H, J = 9.3Hz, N=CH-CH), 7.55 (d, 2H, J2',3' = J6',5' = 8.7 Hz, H-2'/6'),7.12–7.23 (m, 2H, H-3/5),7.01 (d, 2H, J3',2' = J5',6' = 7.0 Hz, H-3'/5'), 6.76–6.87 (m, 2H, HC = CH), 6.92 (d, 1H, J5,6 = 8.4 Hz, H-6), 5.03 (s, 2H, -OCH2), 3.76 (s, 3H, OCH3), 2.21 (s, 3H, CH3); m/z (%) 358 (M+, 95), 189 (40), 175 (85), 159 (100), 125 (60). Anal. Calcd for C19H19ClN2O3, C = 63.60, H = 5.34, N = 7.81. Found: C = 63.57, H = 5.32, N = 7.79.
2-(4-Chloro-2-methylphenoxy)-N'-[(4-ethoxyphenyl)methylidene]acetohydrazide (3). Yield: 80%; 1H-NMR (DMSO-d6) δ: 8.20 (s, 1H, -N=CH), 7.62 (d, 2H, J2',3' = J6',5' = 8.7 Hz, H-2'/6'), 7.23–7.12 (m, 2H, H-3/5), 6.84 (d, 2H, J3',2' = J5',6' = 8.7 Hz, H-3'/5'), 6.84 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.13 (s, 2H, OCH2), 4.04 (q, 2H, J = 6.9 Hz, -CH2), 2.22 (s, 3H, -CH3), 1.32 (t, 3H, J = 6.9 Hz, -CH3); EI MS: m/z (%) 347 (M+, 56), 205 (95), 155 (89), 147 (92), 119 (73). Anal. Calcd for C18H19ClN2O3, C = 62.34, H = 5.52, N = 8.08. Found: C = 62.33, H = 5.50, N = 8.03.
2-(4-Chloro-2-methylphenoxy)-N'-[(3,4,5-trimethoxyphenyl) methylidene]acetohydrazide (4). Yield: 72%; 1H-NMR (DMSO-d6) δ: 8.43 (s, 1H, -N=CH), 7.56 (d, 1H, J2',6' = 2.7 Hz, H-2'), 7.23 (m, 1H, H-5), 7.13 (d, 1H, J3,5 = 2.7 Hz, H-3), 6.92(s, 1H, H-6'), 6.83 (d, 1H, J5,6 = 8.7 Hz H-6), 5.13 (s, 2H, -OCH2), 3.82 (s, 9H, -OCH3), 2.22 (s, 3H, -CH3); EI MS: m/z (%) 392 (M+, 62.1), 251 (15.5), 193 (100), 179 (88.9), 155 (26.8). Anal. Calcd for C19H21ClN2O5, C = 58.09, H = 5.39, N = 7.13. Found: C = 58.05, H = 5.37, N = 7.11.
2-(4-Chloro-2-methylphenoxy)-N'-[(2-nitrophenyl)methylidene]acetohydrazide (5). Yield: 65%; 1H-NMR (DMSO-d6) δ: 8.09(s, 1H, N=CH), 8.29 (m, 2H, H-4'/5'), 7.98 (d, 2H, J3',4' = J6',5' = 9, H-3'/6') 7.24 (m, 1H, H-5), 7.13 (d, 1H, J3,5 = 2.7 Hz, H-3), 6.89 (d, 1H, J6,5 = 8.7, H-6), 5.22 (s, 2H, -OCH2), 2.22 (s, 3H, -CH3); EI MS: m/z (%) 347 (M+, 72), 206 (100), 155 (83.3), 125 (75.8). Anal. Calcd for C16H14ClN3O4, C = 55.26, H = 4.06, N = 12.08. Found: C = 55.23, H = 4.02, N = 12.04.
2-(4-Chloro-2-methylphenoxy)-N'-[(3-nitrophenyl)methylidene]acetohydrazide (6). Yield: 70%; 1H-NMR (DMSO-d6) δ: 8.40 (s, 1H, -N=CH), 8.51 (d,1H, J5',6' = 7.2 Hz H-6'), 8.12–8.25 (m, 2H, H-2'/5'),7.76 (m, 1H, H-4'), 7.12-7.24 (m, 2H, H-3/5), 6.90 (dd, 1H, J6,5 = 6.2 Hz, H-6),5.22 (s, 2H, OCH2), 2.23 (s, 3H, CH3); EI MS: m/z (%) 347 (M+, 92), 206 (100), 178 (28.4), 141 (17.5), 125 (39.9). Anal. Calcd for C19H21ClN2O5, C = 58.09, H = 5.39, N = 7.13. Found: C = 58.06, H = 5.37, N = 7.12.
2-(4-Chloro-2-methylphenoxy)-N'-[-(4-chlorophenyl)methylidene]acetohydrazide (7). Yield: 63%; 1H-NMR (DMSO-d6) δ: 8.27 (s, 1H, -N=CH), 7.73 (d, 2H, J2',3' = J6',5' = 8.7 Hz, H-2'/6'), 7.51 (d, 2H, J3',2' = J5',6' = 8.1 Hz, H-3'/5'), 7.13–7.23 (m, 2H, H-3/5), 6.89 (d, J6,5 = 7.8 Hz, 1H, H-6), 5.15 (s, 2H, -OCH2), 2.19 (s, 3H, CH3); EI MS: m/z (%) 336 (M+, 20), 195 (35), 155 (55), 125 (80), 89 (100). Anal. Calcd for C16H14Cl2N2O2, C = 56.99, H = 4.18, N = 8.31. Found: C = 56.95, H = 4.15, N = 8.28.
2-(4-Chloro-2-methylphenoxy)-N'-[-(2-chlorophenyl)methylidene]acetohydrazide (8). Yield: 66%; 1H-NMR (DMSO-d6) δ: 8.26 (s,1H, -N=CH), 7.77 (m, 2H, H-3'/6'), 7.48 (br.t, 2H, J4',5' = J5',4' = 8.5 Hz, H-4'/5'), 7.13–7.24 (m, 1H, H-3/5), 6.89 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.15 (s, 2H, -OCH2), 2.23 (s, 3H, -CH3), 2.19 (s, 3H, CH3); EI MS: m/z (%) 336 (M+, 10), 195 (30), 155 (40), 125 (75), 89 (100). Anal. Calcd for C16H14Cl2N2O2, C = 56.99, H = 4.18, N = 8.31. Found: C = 56.96, H = 4.15, N = 8.27.
2-(4-Chloro-2-methylphenoxy)-N'-[(3,4-dichlorophenyl)methylidene]acetohydrazide (9). Yield: 70%; 1H-NMR (DMSO-d6) δ: 8.25 (s, 1H, =N-CH), 7.96 (s, 1H, H-2'), 7.68 (br. s, 2H, 5'/6'), 7.12–7.23 (m, 2H, H-3/5), 6.88 (d, 1H, J6,5 = 7.0 Hz H-6), 5.08 (s, 2H, OCH2), 2.22 (s, 3H, CH3); EI MS: m/z (%) 371 (M+, 92.2), 228 (100), 155 (87.1), 125 (89.8). Anal. Calcd for C16H13Cl3N2O2, C = 51.71, H = 3.53, N = 7.54. Found: C = 51.68, H = 3.50, N = 7.52.
2-(4-Chloro-2-methylphenoxy)-N'-[(2, 6-dichlorophenyl)methylidene]acetohydrazide (10). Yield: 60%; 1H-NMR (DMSO-d6) δ: 8.48 (s,1H, -N=CH), 7.57 (d, 2H, J3',4' = J5',4' = 8.7 Hz, H-3'/5'), 7.44 (dd, 1H, J4,5 = 7.2 Hz, H-4'), 7.24–7.11 (m, 2H, H-3/5), 6.78 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.09 (s, 2H, -OCH2), 2.18 (s, 3H, CH3); EI MS: m/z (%) 370 (M+, 17.3), 229 (39.5), 155 (60.1), 125 (100), 89 (62). Anal. Calcd for C16H13Cl3N2O2, C = 51.71, H = 3.53, N = 7.54. Found: C = 51.66, H = 3.51, N = 7.52.
2-(4-Chloro-2-methylphenoxy)-N'-[-(2-fluorophenyl)methylidene]acetohydrazide (11). Yield: 74%; 1H-NMR (DMSO-d6) δ: 8.52 (s, 1H, -N=CH), 7.95 (dd, 1H, J4',5' = 8.1 H-5') 7.48 (dd, 1H, J6',5' = 6.9 Hz, H-6'), 7.25-7.31 (m, 2H, H-3'/4'), 7.12–7.21 (m, 2H, H-3/5), 6.90 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.17 (s, 2H, -OCH2), 2.23 (s, 3H, CH3); EI MS: m/z (%) 320 (M+, 12), 179 (80), 125 (100), 89 (75.8). Anal. Calcd for C16H14ClFN2O2, C = 59.91, H = 4.40, N = 8.73. Found: C = 59.89, H = 4.39, N = 8.72.
2-(4-Chloro-2-methylphenoxy)-N'-[3-thienylmethylidene]acetohydrazide (12). Yield: 68%; 1H-NMR (DMSO-d6) δ: 8.07 (s, 1H, -N=CH), 7.12–7.24 (m, 3H, H-3, 5, 6), 6.73–9.92 (m, 3H, H-2'/4'/5'), 5.10 (s, 2H, -OCH2), 2.22 (s, 3H, CH3); EI MS: m/z (%) 308 (M+, 15), 199 (10), 155 (45), 125 (100). Anal. Calcd for C14H13ClN2O2S, C = 54.46, H = 4.24, N = 9.07. Found: C = 54.45, H = 4.22, N = 9.04.
2-(4-Chloro-2-methylphenoxy)-N'-[-2-furylmethylidene]acetohydrazide (13). Yield: 70%; 1H-NMR (DMSO-d6) δ: 8.17 (s, 1H, -N=CH), 7.11–7.23 (m, 2H, H-3,5), 6.90 (d, 2H, J3',4'= J5',4' = 3.3 Hz, H-3'/5'), 6.81(d, 1H, J6,5 = 8.7 Hz, 6), 6.62 (dd, 1H, J4,3= J4,5 = 3.3 Hz, 4'), 5.07 (s, 2H, -OCH2), 2.22 (s, 3H, -CH3); EI MS: m/z (%) 292 (M+, 35), 155 (50), 151 (80.), 125 (100). Anal. Calcd for C14H13ClN2O3, C = 57.44, H = 4.48, N = 9.57. Found: C = 57.44, H = 4.46, N = 9.56.
2-(4-Chloro-2-methylphenoxy)-N'-[-(5-methyl-2-furyl)methylidene]acetohydrazide (14). Yield: 72%; 1H-NMR (DMSO-d6) δ: 8.07 (s, 1H, -N=CH), 7.11–7.23 (m, 2H, H-3,5), 6.88 (d, 1H, J5,6 = 8.7 Hz, H-6), 6.80 (d, 1H, J3',4' = 5.4 Hz, 3'), 6.24 (d, 1H, J4',3' = 2.7 Hz, 4'), 5.07 (s, 2H, -OCH2), 2.21 (s, 3H, -CH3) 2.19 (s, 3H, -CH3); EI MS: m/z (%) 306 (M+, 20), 65 (30), 137 (100), 125 (40). Anal. Calcd for C15H15ClN2O3, C = 58.73, H = 4.93, N = 9.13. Found: C = 58.70, H = 4.96, N = 9.10.
2-(4-Chloro-2-methylphenoxy)-N'-[-(2,3-dihydroxyphenyl)methylidene]acetohydrazide (15). Yield: 76%; 1H-NMR (DMSO-d6) δ: 8.41 (s,1H, -N=CH), 7.24 (m, 1H, H-5), 7.13 (d, 1H, J3,5 = 2.7 Hz, H-3), 6.89 (d, 1H, J5',6' = 8.7 Hz, H-6'), 6.83 (d, 1H, J6,5 = 8.7 Hz, H-6), 6.71 (m, 2H, H-3'/4'), 5.15 (s, 2H, -OCH2), 2.19 (s, 3H, -CH3); EI MS: m/z (%) 334 (M+, 100),300 (9), 175 (89.7), 193 (35), 179 (50), 137 (65), 125 (60). Anal. Calcd for C16H15ClN2O4, C = 57.41, H = 4.5, N = 8.37. Found: C = 57.40, H = 3.50, N = 8.36.
2-(4-Chloro-2-methylphenoxy)-N'-[-(3,4-dihydroxyphenyl)methylidene]acetohydrazide (16). Yield: 68%; 1H-NMR (DMSO-d6) δ: 8.06 (s, 1H, -N=CH), 7.12-7.19 (m, 2H, H-3/5),7.24 (d, 1H, J2',6' = 2.7 Hz, H-2'), 6.85–6.92 (m, 2H ,H-5'/6'), 6.76 (d, J6,5 = 8.1 Hz, 1H, H-6), 5.10 (s, 2H, -OCH2), 2.22 (s, 3H, CH3); EI MS: m/z (%) 334 (M, 36.8), 193 (23.9), 155 (71.6), 125 (88.8), 77 (100). Anal. Calcd for C16H15ClN2O4, C = 57.41, H = 4.5, N = 8.37. Found: C = 57.39, H = 3.50, N = 8.37.
2-(4-Chloro-2-methylphenoxy)-N'-[1-(4-hydroxyphenyl)ethylidene]acetohydrazide (17). Yield: 70%;1H-NMR (DMSO-d6) δ: 7.65 (d, 2H, J2',3' = J6',5' = 8.7 Hz , H-2'/6'), 7.23 (m, 1H, Hz H-6), 7.12 (d, 1H, J = 2.4 Hz, H-3), 6.90 (d, J3',2' = J5',6' = 8.7 Hz, 2H, H-3'/5'), 6.77 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.16 (s, 2H, -OCH2), 2.19 (s, 6H, CH3); EI MS: m/z (%) 332 (M+, 56.7), 191 (100), 177 (24.5), 149 (34.5), 134 (37.9). Anal. Calcd for C17H16ClN2O3, C = 61.36, H = 5.15, N = 8.42. Found: C = 61.34, H = 5.14, N = 8.40.
2-(4-Chloro-2-methylphenoxy)-N'-[(3-hydroxyphenyl)methylidene]acetohydrazide (18). Yield: 61%; 1H-NMR (DMSO-d6) δ: 8.18 (s, 1H, -N=CH), 7.04-7.24 (m, 5H, Ar-H), 6.79–6.89 (m, 2H, H-5-6), 5.14 (s, 2H, -OCH2), 2.22 (s, 3H,-CH3); EI MS: m/z (%) 318 (M+, 97.6), 177 (100), 155 (71), 125 (65.3). Anal. Calcd for C16H15ClN2O3, C = 60.29, H = 4.74, N = 8.79. Found: C = 69.27, H = 3.49, N = 8.34.
2-(4-Chloro-2-methylphenoxy)-N'-[1-(2,4,6-trihydroxyphenyl)ethylidene]acetohydrazide (19). Yield: 62%; 1H-NMR (DMSO-d6) δ: 8.16 (s, 1H, -N=CH), 7.21 (br.s, 2H, H-3'/5'), 7.16–7.23 (m, 2H, H-3/5), 6.86 (d, J6,5 = 8.7 Hz, 1H, H-6), 4.98 (s, 2H, -OCH2), 2.18 (s, 3H, CH3), 1.93 (s, 3H, CH3); EI MS: m/z (%) 254 (M+, 100), 155 (91.2), 142 (75.5), 125 (100), 113 (100), 99 (86.6).
2-(4-Chloro-2-methylphenoxy)-N'-[(4-hydroxyphenyl)methylidene]acetohydrazide (20). Yield: 72%; 1H-NMR (DMSO-d6) δ: 7.88 (s, 1H, -N=CH), 7.52 (d, 2H, d, 2H, J2',3' = J6',5' = 8.7 Hz , H-2'/6'), 7.24 (d, 1H, J5,6 = 8.1 Hz, H-5), 7.13(d, 1H, J = 2.4 Hz, H-3), 6.88 (d, 2H, J3',2' = J5',6' = 8.7 Hz, H-3'/5'), 6.79 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.11 (s, 2H, -OCH2), 2.22 (s, 3H, CH3); EI MS: m/z (%) 318 (M+, 9.30), 199 (10.78), 177 (27.43), 155 (44), 125 (67.50), 77 (100). Anal. Calcd for C16H15ClN2O3, C = 60.29, H = 4.74, N = 8.79. Found: C = 69.26, H = 3.50, N = 8.34.
2-(4-Chloro-2-methylphenoxy)-N'-[-1-naphthylmethylidene]acetohydrazide (21). Yield: 68%; 1H-NMR (DMSO-d6) δ: 8.66 (s, 1H, N=CH), 8.83 (d, J = 8.1 Hz 1H, H-8'), 8.61 (d, 1H, J4',3' = 8.4 Hz, H-4'), 8.02 (br, d, 2H, J = 7.8 Hz, H-2'/5'), 7.93 (d, 1H, J3',4' = 7.8 Hz, H-3') 7.65 (m, 2H, H-6'/7'), 7.14–7.25 (m,2H, H-3/5), 6.95 (d, J6,5 = 8.4 Hz, 1H, H-6), 5.24 (s, 2H, -OCH2), 2.26 (s, 3H, -CH3); EI MS: m/z (%) 352 (M+, 100), 211(65), 199. Anal. Calcd for C20H17ClN2O2, C = 68.09, H = 4.86, N = 7.94. Found: C = 68.06, H = 4.84, N = 7.92.
2-(4-Chloro-2-methylphenoxy)-N'-[-2-naphthylmethylidene]acetohydrazide (22). Yield: 70%; 1H-NMR (DMSO-d6) δ: 8.43 (s, 1H, N=CH), 8.16 (t, 2H, J = 8.4 Hz, H-3',6'), 7.94 (br, s, 2H, H-5/4') 7.56 (t, 2H, J5',6' = J8',7' = 9.6 Hz, H-5'/8'), 7.22 (s, 1H, H-1'), 7.17 (d, 1H, J7',8' = 8.7 Hz, H-7'), 6.92 (m, 2H, H-5/6), 5.23 (s, 2H, OCH2), 2.23 (s, 3H, CH3); EI MS: m/z (%) 352 (M+, 72), 211 (60) 199 (35), 169 (45), 153 (100), 127 (60). Anal. Calcd for C20H17ClN2O2, C = 68.09, H = 4.86, N = 7.94. Found: C = 68.04, H = 4.85, N = 7.91.
2-(4-Chloro-2-methylphenoxy)-N'-[(5-Chloro-2-hydroxyphenyl)methylidene]acetohydrazide (23). Yield: 66; 1H-NMR (DMSO-d6) δ: 8.23 (s,1H, -N=CH), 7.70 (d, 1H, J6',4' = 2.7 Hz H-6'),7.12–7.23 (m, 2H, H-3/5), 7.31 (m, 1H, H-4'), 6.93 (d, 1H, J3',4' = 7.8Hz, H-3'),6.86 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.17 (s, 2H, -OCH2), 2.22 (s, 3H, -CH3); EI MS: m/z (%) 352 (M+, 83.8), 210 (7.4), 197 (62.6), 155 (100), 141 (46.8). Anal. Calcd for C16H14Cl2N2O3, C = 54.41, H = 4.00, N = 7.93. Found: C = 54.39, H = 4.00, N = 7.92.
2-(4-Chloro-2-methylphenoxy)-N'-[1(2,4-dihydroxy-5-nitrophenyl)ethylidene]acetohydrazide (24). Yield: 70%; 1H-NMR (DMSO-d6) δ: 8.23 (s, 1H, H-6'), 7.17–7.23 (m, 2H, H-3/5), 6.89 (d, 1H, J6,5 = 8.7 Hz, H-6), 6.51 (s, 1H, H-3'), 4.82 (s, 2H, -OCH2), 2.26 (s, 3H, CH3), 2.21 (s, 3H, CH3); EI MS: m/z (%) 392 (M+, 64.4), 251 (72.1), 237 (100), 125 (89.9), 77 (68.5). Anal. Calcd for C16H14ClN3O6, C = 50.60, H = 3.72, N = 11.07. Found: C = 50.57, H = 3.70, N = 11.05.
2-(4-Chloro-2-methylphenoxy)-N'-[(4-hydroxy-3-methoxyphenyl)methylidene]acetohydrazide (25). Yield: 59%; 1H-NMR (DMSO-d6) δ: 8.11 (s, 1H, -N=CH), 7.12–7.23 (m, 2H, H-3/5), 7.03 (s, 1H, H-2'), 6.86–6.96 (m, 2H, H-5'/6') 6.83 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.12 (s, 2H, -OCH2), 3.78 (s, 3H, OCH3), 2.23 (s, 3H, CH3); EI MS: m/z (%) 348 (M+, 88.5), 207 (51), 193 (100), 155 (43), 125 (46.9). Anal. Calcd for C17H17ClN2O4, C = 58.54, H = 4.91, N = 8.03. Found: C = 58.53, H = 4.90, N = 8.02.
2-(4-Chloro-2-methylphenoxy)-N'-{-[4-(methylsulfanyl)phenyl]methylidene}acetohydrazide (26). Yield: 63%; 1H-NMR (DMSO-d6) δ: 8.22 (s, 1H, -N=CH), 7.63 (d, 2H, J2,3 = J6,5 = 8.4 Hz, H-2'/6'), 7.31 (d, 2H, J3,2 = J5,6 = 8.4 Hz, H-3'/5'),7.23 (m, 1H, H-5), 7.13 (d, 1H, J = 2.7 Hz, H-3), 6.89 (d, J6,5 = 8.4Hz, 1H, H-6), 5.15 (s, 2H, -OCH2), 2.19 (s, 3H, CH3); EI MS: m/z (%) 348 (M+, 60), 207 (25), 149 (100), 125 (35), 118 (35). Anal. Calcd for C17H17ClN2O2S, C = 58.53, H = 4.91, N = 8.03. Found: C = 58.51, H = 4.90, N = 8.02.
2-(4-Chloro-2-methylphenoxy)-N'-[(2-methylphenyl)methylidene]acetohydrazide (27). Yield: 67%; 1H-NMR (DMSO-d6) δ: 8.25 (s, 1H, -N=CH), 7.78 (d, J = 7.5 Hz, 1H, H-6'), 7.30–7.21 (m, 3H, H-3'/4'/5'), 7.13-7.17 (m, 2H, H-3/5), 6.84 (d, 1H, J6,5 = 8.7 Hz, H-6), 5.15 (s, 2H, -OCH2), 2.23 (s,3H, -CH3), 2.19 (s, 3H, CH3); EI MS: m/z (%) 316 (M+, 79.4), 199 (78.9), 175 (89.7), 155 (100), 141 (93.2), 118 (94.2). Anal. Calcd for C17H17ClN2O2, C = 64.46, H = 4.41, N = 8.84. Found: C = 64.45, H = 4.40, N = 8.83.
2-(4-Chloro-2-methylphenoxy)-N'-[(4-methylphenyl)methylidene]acetohydrazide (28). Yield: 63%; 1H-NMR (DMSO-d6) δ: 8.23 (s, 1H, -N=CH), 7.59 (d, 2H, J2',3' = J6',5' = 7.8 Hz, H-2'/6'), 7.24 (d, 2H, J3',2'= J5',6' = 8.1 Hz, H-3'/5'),7.13 (d, J = 2.7 Hz, 1H, H-3), 7.17 (m, 1H, H-5), 6.85 (d, J6,5 = 8.7 Hz, 1H, H-6), 5.15 (s, 2H, -OCH2), 2.32 (s, 3H, CH3), 2.19 (s, 3H, CH3); EI MS: m/z (%) 316 (M+, 9.61), 199 (10.80), 175 (36.26), 155 (47.70), 125 (71.62). Anal. Calcd for C17H17ClN2O2, C = 64.46, H = 4.41, N = 8.84. Found: C = 64.44, H = 4.40, N = 8.82.

4. Conclusions

A number of potential lead molecules 1, 5, 7, 8, 11, 12, 15, 21, and 22 have been identified as β-glucuronidase inhibitors and it is anticipated that by slight synthetic modification in these molecules, some new most active β-glucuronidase inhibitors can be developed.

Supplementary Materials

Supplementary materials can be accessed at: https://www.mdpi.com/1420-3049/19/7/8788/s1.

Acknowledgments

Syed Adnan Ali Shah would like to acknowledge Universiti Teknologi MARA (UiTM) for the financial support under the Principal Investigator Support Initiative (PSI) Grant Scheme with reference number UiTM 600-RMI/DANA 5/3/PSI (251/2013) and Cumulative Impact Factor Initiative (CIFI) Grant Scheme with reference number UiTM 600-RMI/DANA 5/3/CIFI (117/2013) and The authors are thankful to Organization for Prohibition of Chemical Weapons (OPCW), Netherlands (Project No. L/ICA/ICB/173681/12) and Higher Education Commission (HEC) Pakistan under “National Research Support Program for Universities” (Project No. 1910) for financial support.

Author Contributions

All authors equally contributed.

Conflicts of Interest

The authors declare no conflict of interest.

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MDPI and ACS Style

Jamil, W.; Perveen, S.; Shah, S.A.A.; Taha, M.; Ismail, N.H.; Perveen, S.; Ambreen, N.; Khan, K.M.; Choudhary, M.I. Phenoxyacetohydrazide Schiff Bases: β-Glucuronidase Inhibitors. Molecules 2014, 19, 8788-8802. https://doi.org/10.3390/molecules19078788

AMA Style

Jamil W, Perveen S, Shah SAA, Taha M, Ismail NH, Perveen S, Ambreen N, Khan KM, Choudhary MI. Phenoxyacetohydrazide Schiff Bases: β-Glucuronidase Inhibitors. Molecules. 2014; 19(7):8788-8802. https://doi.org/10.3390/molecules19078788

Chicago/Turabian Style

Jamil, Waqas, Shagufta Perveen, Syed Adnan Ali Shah, Muhammad Taha, Nor Hadiani Ismail, Shahnaz Perveen, Nida Ambreen, Khalid M. Khan, and Muhammad I. Choudhary. 2014. "Phenoxyacetohydrazide Schiff Bases: β-Glucuronidase Inhibitors" Molecules 19, no. 7: 8788-8802. https://doi.org/10.3390/molecules19078788

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