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Article

Diversity Oriented Design of Various Benzophenone Derivatives and Their in Vitro Antifungal and Antibacterial Activities

by
Li Sun
,
Jie Wu
,
Min Luo
,
Xiaoli Wang
,
Man Pan
,
Zhaopin Gou
and
Dequn Sun
*
Marine College, Shandong University, Weihai Wenhua West Road, No.180, Weihai 264209, China
*
Author to whom correspondence should be addressed.
Molecules 2011, 16(11), 9739-9754; https://doi.org/10.3390/molecules16119739
Submission received: 3 October 2011 / Revised: 9 November 2011 / Accepted: 14 November 2011 / Published: 23 November 2011
(This article belongs to the Section Medicinal Chemistry)
Browse Figures
Versions Notes

Abstract

:
A series of new substituted benzophenone derivatives was designed, synthesized and screened for their antifungal and antibacterial activities. The bioassays indicated that most of the synthesized compounds showed some antifungal activity against the tested phytopathogenic fungi, but lower antibacterial activities towards the five vibrios isolated from marine sources. The preliminary structure activity relationship (SAR) of the compounds was also discussed.

1. Introduction

Resistance and cross-resistance are easily found in the field when a class of agrochemicals has been used for a long time [1], thus exploring new agrochemical candidates with different modes of action is always meaningful. Metrafenone (I, Figure 1) is a novel benzophenone-derived fungicide [2] recently registered in several countries for control of powdery mildews in different crops [3,4] and eye spot in cereals [5]. It possess a different mode of action that might interfere with processes which are essential to establish and maintain polar action organization [6]. The carboxylic acid amide (CAA) fungicides, dimethomorph (II, Figure 1) and flumorph (III, Figure 1) [7,8] are derivatives of benzophenone and are common agrochemicals in the field in China nowadays. They have been widely used for years to control the diseases caused by Oomycete foliar plant pathogens (e.g., Phytophthora infestans (Mont.) de Bary and Peronosporaceae) with the mode of inhibiting cellulose synthesis [8]. Recently, Qin [9] synthesized a novel fungicide, pyrimorph (IV, Figure 1), which was actually an analog of II and III and exhibited excellent activity against oomycetes. Dimethomorph, flumorph and pyrimorph have both a benzophenone skeleton and a morpholine ring in their chemical structures. The morpholine group is likely to be a pharmacophore in fungicidal chemicals since it exists in a number of other commercial fungicides, such as tridemorph (V, Figure 1), dodemorph (VI, Figure 1) and fenpropimorph (VII, Figure 1) [10].
Molecules 16 09739 g001 550
Figure 1. The chemical structures of several commercial fungicides.
Figure 1. The chemical structures of several commercial fungicides.
Molecules 16 09739 g001
To the best of our knowledge, studies concerning metrafenone analogs as antifungal or antibacterial agents have seldom been reported. In an attempt to screen for new agrochemicals and predict their relatively detailed SAR, a diverse series of benzophenone derivatives, some of which contained a morpholine group, were designed on the basis of bioisosterism principles [11] and synthesized (Scheme 1, Scheme 2 and Scheme 3). Among the compounds, twelve new compounds and five known compounds were tested on the phytopathogenic fungi and vibrios. Compounds 1b [12] and 3a [13] were synthesized before, but no studies on their bioactivity were reported. The silica gel-mediated synthesis and cytotoxic activity of 1c were reported [14]. Compound 1d was studied by Jie [15] with respect to its potential antiproliferative activity. Compounds 1e and 3b were already reported in our previous work [16].
As suggested by the SAR of metrofenone, one benzene ring of metrafenone was replaced by other potentially active moieties, such as aryl, aryloxy or aromatic heterocycles to give the first kind of new benzophenone derivatives 1a–e (Scheme 1). The second series of novel substituted benzophenone derivatives 3a, 3b and 3c, containing morpholine groups, were synthesized as shown in Scheme 2.
Molecules 16 09739 g002 550
Scheme 1. The synthetic routes of compounds 1a–e.
Scheme 1. The synthetic routes of compounds 1a–e.
Molecules 16 09739 g002
Molecules 16 09739 g003 550
Scheme 2. The synthetic routes of compounds 3a–c.
Scheme 2. The synthetic routes of compounds 3a–c.
Molecules 16 09739 g003
To learn more about SAR of the compounds containing benzophenone skeletons and morpholine groups, the new oxime derivatives 7 were designed by replacing the C atom of dimethomorph or flumorph with an isosteric N atom, and after reduction of the double bond, ethers 9 and amines 11 were obtained (Scheme 3).
Molecules 16 09739 g004 550
Scheme 3. The synthetic routes of compounds 7, 9 and 11.
Scheme 3. The synthetic routes of compounds 7, 9 and 11.
Molecules 16 09739 g004

2. Results and Discussion

2.1. Chemistry

As shown in Scheme 1, 1a and 1b were synthesized via the classic Friedel-Crafts reaction from the appropriate benzoyl chlorides and 3,4,5-trimethoxytoluene. Compound 1b was also synthesized using a different method from the literature [12] in similar yield. Oxidation of the methyl group on 3,4,5-trimethoxytoluene followed by condensation with morpholine, 6-hydroxy-2-isopropyl-4-methylpyrimidine and 1H-benzotriazole gave 1c, 1d and 1e, respectively. Compounds 3a and 3c were prepared using Et3N and DMAP in DCM (73% and 72% respectively) and 3c was obtained using K2CO3 and TBAB in DCM in a yield of 63%.
The synthetic routes to 7, 9 and 11 are outlined in Scheme 3. The benzophenone skeleton (compound 5) was synthesized from the 4-halosubstituted benzoyl chloride and 1,2-dimethoxybenzene starting materials via the classic Friedel-Crafts reaction. Compound 6 was obtained (in 96.7% yield) through coupling of 5 with NH4OH·HCl using CH3COONa as base and the generated CH3COOH as catalyst. The etherification reaction between compound 6 and 4 gave 7a and 7b, the esterification reaction between 6 and 2 gave 7c and 7d under the corresponding conditions with good conversion.
The substituted benzophenone 5 was reduced to diphenyl methanol 8 with NaBH4 in DCM cleanly and almost quantitatively (98%). Etherification of 8 with 4-(2-chloroacetyl) morpholine (4) gave 9a and 9b in yields of 91% and 84% respectively using NaH in THF. Reductive ammoniation of compound 6 with zinc dust in 30% ammonia afforded amine 10, which was treated with 4 in the presence of K2CO3 and KI to give 11a and 11b or with 2 using Et3N and DMAP to give 11c with yields higher than 70%.

2.2. Bioactivity

All of the tested compounds had the purity of more than 95%. The oximes were tested using a mixture of (Z)- and (E)-isomers and the enantiomers were tested as racemic mixtures. The bioactivities towards phytopathogenic fungi and five vibrios were evaluated. The phytopathogenic fungi chosen included Alternaria kukuchiana (AK), Alternaria mali (AM), Botrytis cinerea (BC), Bipolaris maydi (BM), Cercospora arachidicola (CA), Gibberella zeae (GZ), Gibberella fujikuroi (GF), Macrophoma kuwatsukai (MK), Rhizoctonia solani (RS), Sclerotinia sclerotiorum (SS), Thanatephorus cucumeris (Frank), Domk (TC) and Fusarium oxysporum f. sp. Vasinfectum. All these fungi are different typical genera, often found in the Chinese agro-ecosystem. The five tested vibrios (Vibrio Parahaemolyticus, Vibrio harvyi, Vibrio anguillarum, Vibrio alginolyticus, Vibrio vulnificus) were isolated from marine organism. The bioactivity results are outlined in Tables respectively.

2.2.1. Antifungal Activity to Phytopathogenic Fungi

2.2.1.1. Antifungal Activity of Compounds 1 to ten Phytopathogenic Fungi

Table
Table 1. The antifungal activity of the synthesized compounds 1.
Table 1. The antifungal activity of the synthesized compounds 1.
Compd. No.Fungicidal activities (50 μg/mL, inhibition rate %)
AKBCBMCAGFGZMKRSSSTC
1a45.5 7.4 34.8 6.7 33.3 11.1 0 66.7 0 21.6
1b53.611.135.14.539.27.8068.3033.3
1c22.7 11.1 8.7 20 6.7 3.7 37.5 44.4 13.3 7.8
1d 22.7 7.4 13.0 0 20 3.7 37.5 61.9 6.7 3.9
1e31.8 14.8 26.1 6.7 20 7.4 40.6 63.5 66.7 9.8
Flu.18.2 7.4 17.4 0 13.3 7.4 21.9 61.9 0 9.8
Dim.22.7 18.5 17.4 0 20 0 6.3 68.3 20 23.5
Flu. = flumorph, Dim. = dimethomorph.
Among compounds 1 (Table 1), more than one compound showed similar or better activity than flumorph and dimethomorph towards the tested fungi. Compounds 1a and 1b were more potent to most of the tested fungi belonging to the different genera. Both 1c and 1e had certain inhibitory activity against all of the tested fungi. Compound 1e containing a 3,4,5-trimethoxybenzene ring and pyrimidine group exhibited good activity compared to controls, especially to MK and SS, while 1e showed remarkable inhibition rates that were about 1-fold and 2-fold higher than controls, respectively (40.6%/21.9%, 66.7%/20%). It’s interesting that compounds 1c-1e all had activity on MK and SS, while 1a and 1b had no effect, which suggested that N-containing heterocycles might be the necessary groups to inhibit MK and SS. Compounds 1a, 1b and 1e could be better fungicidal candidates since they showed better inhibition rates and relatively good broad-spectrum activity towards the tested fungi of diverse genera.

2.2.1.2. Antifungal Activity of Compounds 3 to Nine Phytopathogenic Fungi

After the 3,4,5-trimethoxybenzene rings in 1c, 1d and 1e were replaced by morpholine groups to obtain new compounds, the structures of which are very different from metrofenone and flumorph or dimethomorph, compounds 3a–c showed similar or higher activity to nine fungi compared with flumorph and dimethomorph. Compounds 3b and 3c showed better broad-spectrum activity. According to the SAR discussion on compounds 1 and 3, a trimethoxybenzene ring was favorable for increased fungicidal activity.
Table
Table 2. The antifungal activities of compounds 3.
Table 2. The antifungal activities of compounds 3.
Compd. No.Fungicidal activities (50 μg/mL, inhibition rate %)
AKBCBMCAGFGZMKRSTC
3a22.7 7.4 17.4 6.7 20 22.2 21.9 65.1 0
3b 40.9 18.5 17.4 6.7 6.7 7.4 31.3 61.9 19.6
3c13.6 14.8 30.4 6.7 13.3 7.4 28.1 57.1 23.5
Flu.18.2 7.4 17.4 0 13.3 7.4 21.9 61.9 9.8
Dim.22.7 18.5 17.4 0 20 0 6.3 68.3 23.5

2.2.1.3. Antifungal Activity of Compounds 7, 9 and 11 to ten Phytopathogenic Fungi

As shown in Table 3, compounds 7c and 11a displayed better wide-spectrum activity than the controls. Compound 9b showed significant inhibition of endophytic Alternaria spp. fungi such as AK and AM (27.3% and 57.1%, respectively).
Table
Table 3. The antifungal activities of 7, 9 and 11.
Table 3. The antifungal activities of 7, 9 and 11.
Compd. No.Fungicidal activities (50 μg/mL, inhibition rate %)
AKAMBCBMCAGFGZMKRSTC
7a18.2 0 7.4 13.0 20 20 7.4 12.5 68.3 0
7b22.7 0 14.8 13.0 6.7 20 11.1 25.0 61.9 3.9
7c22.7 7.1 11.1 26.1 20 6.7 7.4 18.8 65.1 5.9
7d 27.3 0 3.7 34.8 6.7 20 14.8 0 61.9 27.5
9a18.2 14.3 3.7 17.4 6.7 20 7.4 18.8 63.5 0
9b27.3 57.1 3.7 13.0 0 6.7 0 18.8 63.5 2.0
11a13.6 7.1 22.2 13.0 6.7 13.3 14.8 6.3 54.0 2.0
11b18.2 0 7.4 13.0 13.3 13.3 0 15.6 54.0 0
11c18.2 14.3 11.1 13.0 0 13.3 3.7 40.6 58.7 15.7
Flu.18.2 21.4 7.4 17.4 0 13.3 7.4 21.9 61.9 9.8
Dim.22.7 7.1 18.5 17.4 0 20 0 6.3 68.3 23.5
Replacement of the F atom on the benzene ring of 7a, 7c, 9a, 11a with Cl (7b, 7d, 9b, 11b) led to a lightly increase in the inhibition of AK (18.2%/27.3%, 13.6%/18.2%, 18.2%, 22.7%, 22.7%/27.3%, respectively). Introduction of a -CH2 into the bridge between the morpholine group and the substituted benzophenone skeleton was favorable to the antifungal activity against AM; for example, 9b was much more potent (57.1%) than dimethomorph (7.1%) and flumorph (21.4%); with respect to CA, most of the compounds showed activities, except 9b, 11c (0%), while flumorph and dimethomorph had no effect. Among the tested compounds, derivatives containing C=N, F and morpholine moieties such as 7a, 7c exhibited relatively higher inhibition rates (20%, 20%) than others (13.3%, 6.7% or 0) towards CA.

2.2.1.4. Antifungal Activity Towards Fusarium oxysporum f. sp. Vasinfectum

Fusarium wilt, the “cancer” of cotton, caused by Fusarium oxysporum f. sp. vasinfectum is a global and serious threat to cotton, which is a high-value crop [17]. The pesticides carbendazim and dimethomorph are the two main chemicals used widely to prevent Fusarium wilt of cotton in the field in China, therefore carbendazim and dimethomorph were used as positive controls, and the antifungal activity of compounds 7b–d to Fusarium oxysporum f. sp. vasinfectum was screened by the similar poisoned food technique at the concentrations of 500, 250 and 125 μg/mL, respectively (Table 4). Compounds 7b–d all have higher activity than dimethomorph at different concentrations and this result revealed that replacing the C atom in dimethomorph with an isosteric atom N results in higher activity to Fusarium wilt; furthermore, inserting one CH2 the between carbonyl and oxygen in 7b enhanced the activity, especially at the higher concentration. The Cl substituted compound 7d is more potent than the F substituted compound 7c.
It was interesting that 7b showed better inhibition at the concentration of 500 μg/mL but lower activity than carbendazim at the concentrations of 250 and 125 μg/mL, indicating that 7b might have a lower concentration than carbendazim when the inhibition rate reached to 100%. It might be better choice than carbendazim and represent another type of compound to prevent Fusarium wilt since its structure is totally different from carbendazim and might possess a different mode of inhibitory action.
Table
Table 4. The inhibition rates to Fusarium oxisporum f. sp. Vasinfectum.
Table 4. The inhibition rates to Fusarium oxisporum f. sp. Vasinfectum.
500 μg/mL250 μg/mL125 μg/mL
Compd.Inhibition rate (%)Compd.Inhibition rate (%)Compd.Inhibition rate (%)
Carb.44.2Carb.39.3Carb.33.0
Dim.12.5Dim.5.9Dim.3.1
7b50.07b19.77b5.8
7c27.47c10.67c3.9
7d33.17d13.37d4.7
Carb.: carbendazim.

2.2.2. Antibacterial Activity Towards Five Vibrios

Vibrios cause vibriosis, a common disease in marine aquaculture worldwide and a number of species are also human pathogens [18]. Antibiotics are widely used to treat vibrios and the most potent compounds are used to control vibriosis, which increases the resistance of the bacteria to commercially available antibiotics [19,20], in addition to their negative impact on the environment and residues in cultured marine animals. Nowadays, though many studies focus on the bacterial sensitivity to the extracts from seaweed or herbal plants, and discovery of the bacterial biocontrol agents [21], there are few reports about screening of synthetic compounds as potential bactericides which have good activity against vibrios. Therefore, the synthesized compounds were tested on five vibrios by simplified disc diffusion method [22]. Unfortunately, they exhibited different levels of inhibitory effects against the five vibrios at a relatively high concentration and were all much less effective than streptomycin and gentamicin sulfate.

3. Experimental

3.1. Chemistry

3.1.1. General

Anhydrous solvents were distilled prior to use. All reactions using air- or moisture-sensitive reagents were conducted under an inert nitrogen atmosphere. The products were purified by column chromatography using silica gel (200–300 mesh). Melting points of the products were determined in open capillary tubes and are uncorrected. The IR spectra were recorded on a Bruker VERTEX 70 FT-IR instrument. 1H-NMR spectra were recorded on Varian-400 at r.t. using TMS as an internal reference. Mass spectra were recorded with a JEOL MS-D 300 mass spectrometer. Elemental analysis was performed on a Carlo-1106 model automatic instrument.

3.1.2. Syntheses

(4-Fluorophenyl)(2,3,4-trimethoxy-6-methylphenyl)methanone (1a). A suspension of AlCl3 (0.52 g, 3.9 mmol) in DCM (35 mL) was placed in a salt-ice bath for 10 minutes. After a solution of 3,4,5-trimethoxytoluene (0.55 g, 3 mmol) in DCM (10 mL) was added dropwise, 4-fluorobenzoyl chloride (0.62 g, 3.9 mmol) dissolved in DCM (15 mL) was slowly added dropwise at the same temperature. The resulting yellow solution was warmed to room temperature and stirred for 8 h. The mixture was washed by 0.5 N HCl aqueous (20 mL × 2) and the water layer was extracted with DCM (30 mL) once. The combined DCM layer was washed with sat. Na2CO3 and water, respectively, dried over anhydrous MgSO4, and concentrated to give a crude product which was purified by column chromatography (petroleum: ethyl acetate 3:1, Rf = 0.18) to give compound 1a as a white solid (0.59 g, 65%), mp 114–116 °C; IR (film, cm−1) 2939, 2841, 1730, 1670, 1597, 1502, 1332, 1228, 1199, 1151, 1118, 989, 858; 1H-NMR (CDCl3, 300 MHz) δ (ppm): 2.11 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.55 (s, 1H, Ph-H), 7.08–7.15 (m, 2H, Ph-H), 7.81–7.87 (m, 2H, Ph-H). m/z (EI) 304 (M+). Anal. Calc. for C17H17FO4 (304.31): C, 67.10; H, 5.63; found: C, 67.07; H, 5.66.
(4-Chlorophenyl)(2,3,4-trimethoxy-6-methylphenyl)methanone (1b). 1b was prepared from 3,4,5-trimethoxytoluene and 4-chlorobenzoyl chloride using the same procedure as described for 1a to afford a white solid (69%). mp 99–101 °C (lit. 99.5–100.0 °C) [12]; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 2.15 (s, 3H, CH3), 3.67 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.63 (s, 1H, Ph-H), 7.01–7.12 (m, 2H, Ph-H), 7.79–7.86 (m, 2H, Ph-H).
3,4,5-Trimethoxybenzoic acid. To a solution of 3,4,5-trimethoxytoluene (1 g, 5.5 mmol) in acetone (20 mL) was added KMnO4 (0.76 g, 5.5 mmol) and water (20 mL) at room temperature, followed by 5 drops of concentrated sulphuric acid. More KMnO4 (2.28 g, 16.5 mmol) was added in portions during the reaction. The mixture was stirred for 10 h. The precipitate was filtered off and acetone was removed in vacuo. The obtained solution was extracted with DCM (30 mL × 2) and the water layer was acidified to pH 2–3 and extracted with DCM (35 mL × 3). The combined DCM layers were dried over anhydrous MgSO4, concentrated and crystallized to yield as 3,4,5-trimethoxybenzoic acid as a white solid (0.74 g, 64%).
Morpholino(3,4,5-trimethoxyphenyl)methanone (1c). To a solution of 3,4,5-trimethoxybenzoic acid (0.21 g, 1 mmol) and morpholine (0.13 g, 1.5 mmol) in DCM (20 mL) was added EDCI (0.23 g, 1.2 mmol) at room temperature. The mixture was stirred for 1 h. The solution was diluted with DCM (40 mL) and washed with water (30 mL × 3). The separated organic layer was dried over anhydrous MgSO4, concentrated and crystallized to give 1c as a white solid (0.17 g, 61%). mp 96–99 °C (lit. 96–98 °C) [14]; IR (film, cm−1) 3508, 3492, 2960, 2927, 2852, 1737, 1633, 1583, 1461, 1423, 1326, 1230, 1124, 1002; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.69 (m, 8H, morpholine–H), 3.86 (s, 3H, OCH3), 3.88 (s, 6H, 2OCH3), 6.63 (s, 2H, Ph–H).
Benzotriazol-1-yl(2,3,4-trimethoxyphenyl)methanone (1d). To a solution of 3,4,5-trimethoxybenzoic acid (0.21 g, 1 mmol) and 1H-benzotriazole (0.14 g, 1.2 mmol) in DCM (20 mL) was added EDCI (0.23 g, 1.2 mmol), followed by the addition of DMAP (0.025 g, 0.2 mmol). The mixture was stirred for 1 h, then diluted with DCM (50 mL) and washed by water (30 mL × 3). The organic layer was dried over anhydrous MgSO4 and concentrated. The obtained crude product was purified by column chromatograph (petroleum-ethyl acetate 15:1, Rf = 0.15) to give 1d as a white solid (0.24 g, 77%). mp 119–122 °C (lit. mp 126–128 °C) [15]; IR (film, cm−1) 3442, 1737, 1705, 1587, 1450, 1373, 1134, 995, 750; 1H-NMR (CDCl3, 300 MHz) δ (ppm): 3.96 (s, 6H, 2OCH3), 3.99(s, 3H, OCH3), 7.55–7.59 (m, 3H, 2Ph–H, BTA-H), 7.73 (t, J = 8 Hz, 1H, BTA-H), 8.18 (d, J = 8.4Hz, 1H, BTA-H). 8.38 (d, J = 8.0 Hz, 1H, BTA-H). m/z (EI) 313 (M+).
2-Isopropyl-6-methylpyrimidin-4-yl-3,4,5-trimethoxybenzoate (1e). To a solution of 3,4,5-trimethoxy-benzoic acid (0.21 g, 1 mmol) and 6-hydroxy-2-isopropyl-4-methylpyrimidine (0.15 g, 1 mmol) in DCM (10 mL) was added EDCI (0.28 g, 1.5 mmol). The mixture was stirred for 4 h, then diluted with 90 mL of DCM. The mixture was washed by water and the organic layer was separated, dried over anhydrous MgSO4. The solvent was evaporated and the crude product was purified by chromatograph (petroleum-ethyl acetate 10:1, Rf = 0.17) on gel silica to give 1e as a white solid (0.19 g, 55%). mp 97–99 °C; IR (film, cm−1): 2970, 2943, 2841, 1739, 1587, 1504, 1415, 1326, 1207, 1128, 974, 750. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 1.35 (d, J = 6.8 Hz, 6H, 2CH3), 2.57 (s, 3H, CH3), 3.20 (m, 1H, CH), 3.94 (s, 6H, 2OCH3), 3.95 (s, 3H, OCH3), 6.91 (s, 1H, pyrimidine-H), 7.26 (s, 1H, Ph-H), 7.45 (s, 1H, Ph-H). m/z (EI) 346 (M+). Anal. Calc. for C18 H22 N2O5 (346.38): C, 62.42; H, 6.40; N, 8.09; found: C, 62.43; H, 6.42; N, 8.06.
4-Morpholinecarbonyl chloride (2). Triphosgene (1.49 g, 5 mmol) was dissolved in DCM (150 mL), then a solution of morpholine (0.87 g, 10 mmol) and triethylamine (1.52 g, 15 mmol) in DCM (30 mL) was slowly added dropwise in a salt-ice bath. After the addition, the reaction was monitored by TLC (iodine vapor detection) until the reaction was completed. Phosgene was blowed off by N2, then the mixture was filtered and the filtrate was concentrated to give 2 as a light-brown oil (1.47 g, 98%, with a content of about 70%), which was used freshly in the next step without further purification.
Phenylmorpholine-4-carboxylate (3a). To a solution of crude compound 2 (0.96 g, with a content of about 70%, 4.5 mmol), Et3N (0.90 g, 9 mmol) and DMAP (0.13 g, 1.1 mmol) in DCM (20 mL) was added a solution of phenol (0.28 g, 3 mmol) in DCM (10 mL) dropwise at room temperature. The mixture was allowed to stir overnight. 100 mL of DCM was added and the mixture was washed successively with sat. Na2CO3, 0.5 N HCl and brine. The organic layer was dried over anhydrous MgSO4, concentrated to give a crude product which was purified by column chromatography (petroleum-ethyl acetate 5:1, Rf = 0.30) to give 3a as a light-yellow solid (0.45 g, 73%). mp 54–56 °C; IR (film, cm−1): 2858, 1722, 1419, 1205, 1116, 1064, 856, 742, 690; 1H-NMR (CDCl3, 300 MHz) δ (ppm): 3.57–3.76 (m, 8H, morpholine–H), 7.10–7.12 (m, 2H, Ph-H), 7.18–7.23 (m, 1H, Ph-H), 7.34–7.39 (m, 2H, Ph-H). m/z (EI) 207 (M+). Anal. Calc. for C11H13NO3 (207.23): C, 63.76; H, 6.32; N, 6.76; found: C, 63.71; H, 6.36; N, 6.77.
2-Isopropyl-6-methylpyrimidin-4-yl morpholine-4-carboxylate (3b). To a stirred solution of 6-hydroxy-2-isopropyl-4-methylprimidine (0.15 g, 1 mmol) and 4-morpholinecarbonyl chloride (crude product, 0.28 g, about 1.3 mmol) in DCM (15 mL) was added a solution of Et3N (0.20 g, 2 mmol) in DCM (5 mL), followed by addition of DMAP (0.03 g, 0.25 mmol). The mixture was stirred at room temperature for 5 h. DCM (80 mL) was added and the mixture was washed sequentially with cold sat. Na2CO3 and water. The DCM layer was separated and dried over anhydrous MgSO4, concentrated in vacuo to give the crude product, which was purified by column chromatography (petroleum-ethyl acetate 3:1, Rf = 0.21) to give 3b as a light-yellow oil (0.19 g, 72%). IR (film, cm−1): 2968, 2927, 2864, 1733, 1585, 1421, 1342, 1274, 1230, 1155, 1118, 1060, 848, 746. 1H-NMR (CDCl3, 300 MHz) δ (ppm): 1.32 (d, J = 6.8 Hz, 6H, 2CH3), 2.52 (s, 3H, CH3), 3.14 (m, 1H, CH), 3.58–3.78 (m, 8H, morpholine-H), 6.86 (s, 1H, pyrimidine-H). m/z (EI) 265 (M+). Anal. Calc. for C13 H19N3O3 (265.31): C, 58.85; H, 7.22; N, 15.84; found: C, 58.78; H, 7.25; N, 15.88.
1-Phenyl-1H-1,2,4-triazol-3-yl morpholine-4-carboxylate (3c). To a solution of 1-phenyl-1H-1,2,4-triazol-3-ol (1.62 g, 10 mmol) in DCM (50 mL) was added K2CO3 powder (2.07 g, 15 mmol). After the mixture was stirred at r.t. for 0.5 h, a solution of 4-morpholinecarbonyl chloride (crude product, 2.8 g, 13 mmol) in DCM (15 mL) was added, followed by the addition of TBAB (0.64 g, 2 mmol). The mixture was allowed to stir at r.t. overnight. Another 30 mL of DCM was added and the mixture was washed with water (30 mL × 3). The DCM layer was dried over anhydrous MgSO4, concentrated in vacuo to give crude product, which was purified by column chromatography (petroleum-ethyl acetate 5:1, Rf = 0.31) to give 3c as a light-yellow solid (2.46 g, 90%). mp 114–115 °C; IR (film, cm−1): 3114, 2922, 2862, 1730, 1533, 1415, 1326, 1230, 1109, 1060, 854, 759. 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.65–3.78 (m, 8H, morpholine-H); 7.36 (m, 1H, Ph-H); 7.53–7.69 (m, 4H, Ph-H); 9.17 (s, 1H, triazole-H). m/z (EI) 274 (M+). Anal. Calc. for C13H14N4O3 (274.28): C, 56.93; H, 5.14; N, 20.43; found: C, 56.92; H, 5.17; N, 20.40.
2-Chloro-1-morpholinoethanone (4). To a solution of morpholine (8.7 g, 100 mmol) in THF (250 mL) was added K2CO3 powder (27.6 g 200 mmol). A solution of chloracetyl chloride (13.6 g, 120 mmol) in THF was added dropwise in an ice-water bath under stirring. After the mixture was stirred for 1 h at the same temperature, the morpholine was converted to a single product nearly quantitatively as monitored by TLC (iodine vapor detection). The reaction mixture was filtered and the filtrate was concentraed in vacuo. The residue was dissolved in dichloromethane (200 mL) and washed with sat. aqueous Na2CO3 and brine, respectively. The organic layer was dried over anhydrous MgSO4 and concentrated to give colorless oil which was used in the next steps without further purification.
General procedure for the preparation of (3,4-dimethoxyphenyl)(4-halogenated-phenyl)methanones 5a and 5b. To a suspension of AlCl3 (0.81 g, 6 mmol) in DCM (20 mL) was added a solution of 1,2-dimethoxybenzene (0.57 g, 5 mmol) in DCM (10 mL) dropwise in an ice-water bath (0–5 °C), followed by the slow addition of a solution of the appropriate 4-halogenated benzoyl chloride (6 mmol) in DCM dropwise while the temperature was maintained under 10 °C. The mixture was stirred at the same temperature for 2.5 h. DCM (100 mL) was added and the solution was washed successively with 0.5 N aqueous HCl (20 mL) and water. The organic layer was dried over anhydrous MgSO4 and filtered. Removal of the solvent gave a white solid which was crystallized from methanol to separately give 5a and 5b in yields of 76% and 73%.
(3,4-Dimethoxyphenyl)(4-halogenated phenyl)methanone oximes 6a and 6b. To a refluxing solution of compounds 5a or 5b (10 mmol) in anhydrous ethanol was added CH3COONa (8.23 g, 100 mmol) and NH2OH·HCl (7.03 g, 100 mmol) in portions. The mixture was stirred at reflux for 2.5 h. The reaction was completed and produced only one product as indicated by TLC. After the solid was filtered off, the filtrate was concentrated in vacuo to afford a residue, which was dissolved in DCM (250 mL), then washed with water (100 mL × 2). The organic layer was dried over anhydrous MgSO4. The solvent was removed in vacuo to give 6a or 6b as a white solid with the yield of higher than 95%.
2-((((3,4-Dimethoxyphenyl)(4-fluorophenyl)methylene)amino)oxy)-1-morpholinoethanone (7a). To a solution of 6a (0.28 g, 1 mmol) and compound 4 (0.17 g, 1 mmol) in THF (30 mL) was added K2CO3 powder (0.14 g, 1 mmol) and KI (1.66 g, 1 mmol). The mixture was stirred at reflux for 5 h. After the precipitate was filtered off and the solvent in the filtrate was evaporated in vacuo, DCM (100 mL) was added to the residue. The resulting solution was washed with water (100 mL × 2), dried over anhydrous MgSO4 and concentrated. The obtained crude product was purified by column chromatograph using petroleum-ethyl acetate (5:1) as the eluent to give 7a as a white solid (0.30 g, 72%). Rf = 0.31 (petroleum-ethyl acetate = 5:1, very close to the Rf of 7b); mp 109–112 °C; IR (film, cm−1): 3853, 3745, 2958, 2825, 2854, 2360, 1658, 1600, 1442, 1413, 1139, 1022.
2-((((3,4-Dimethoxyphenyl)(4-chlorophenyl)methylene)amino)oxy)-1-morpholinoethanone (7b) was prepared by the same procedure as described for 7a as a white solid (0.31 g, 74%). Rf = 0.31 (petroleum: ethyl acetate 5:1); mp 112–115 °C; IR (film, cm−1): 2690, 2931, 2856, 1666, 1600, 1512, 1234, 1139, 1022, 844; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.42–3.66(m, 8H, morpholine–H), 3.86–3.92 (m, 6H, 2OCH3), 4.84 (s, 2H, CH2), 6.76–7.03 (m, 3H, Ph-H), 7.10–7.17 (m, 2H, Ph-H), 7.45–7.48 (m, 2H, Ph-H). m/z (EI) 418 (M+). Anal. Calc. for C21H23ClN2O5 (418.87): C, 60.22; H, 5.53; N, 6.69; found: C, 60.25; H, 5.56; N, 6.63.
(3,4-Dimethoxyphenyl)(4-fluorophenyl)methanone O-morpholine-4-carbonyl oxime (7c). To a solution of 6a (0.28 g, 1 mmol), Et3N (0.15 g, 1.5 mmol) and DMAP (0.03 g, 0.25 mmol) in DCM (15 mL) was added a solution of crude compound 2 (0.32 g, with a content of 70%, 1.5 mmol) in DCM (10 mL) dropwise in ice-water bath. Then the mixture was refluxed for 2 h. DCM (70 mL) was added and the mixture was washed with water. The DCM layer was dried over anhydrous MgSO4, concentrated to give a crude product which was purified by column chromatograph (petroleum-ethyl acetate 2:1, Rf = 0.26, very close to the Rf of 7d) to give 7c as a white solid (0.33 g, 85.1%). mp 136–139 °C; IR (film, cm−1): 1733, 1600, 1514, 1417, 1232, 1139, 1022.
(4-Chlorophenyl)(3,4-dimethoxyphenyl)methanone O-morpholine-4-carbonyl oxime (7d). Compound 7d was prepared by the same procedure as described for 7c as a white solid (0.36 g, 89.1%). Rf = 0.26 (petroleum-ethyl acetate 2:1); mp 130–134 °C; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.21–3.54 (m, 8H, morpholine–H), 3.84 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 6.85–6.94 (m, 3H, Ph-H), 7.02–7.07 (m, 2H, Ph-H), 7.58–7.62 (m, 2H, Ph-H). m/z (EI) 404 (M+). Anal. Calc. for C20H21ClN2O5 (404.84): C, 59.33; H, 5.23; N, 6.92; found: C, 59.37; H, 5.24; N, 6.87.
(3,4-Dimethoxyphenyl)(4-halogenated)methanols 8a and 8b. To a solution of compound 5 (10 mmol) in DCM (40 mL) and methanol (10 mL) was added NaBH4 powder (0.57 g, 15 mmol) in portions at room temperature. The mixture was refluxed for 1 h. The mixture was poured into a beaker and quenched by addition of cold 0.2 N HCl. After the precipitate was filtered off, the filtrate was extracted with DCM (100 mL × 2). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 8a or 8b as a white powder in nearly quantitative yield that was used directly for the next steps.
2-((3,4-Dimethoxyphenyl)(4-fluorophenyl)methoxy)-1-morpholinoethanone (9a). To a solution of 8a (0.52 g, 2 mmol) in THF (25 mL) was added NaH (76%, 0.13 g, 4 mmol), followed by the addition of a solution of 4 (0.33 g, 2 mmol) in THF (10 mL) dropwise at room temperature. The mixture was stirred for 2 h. The mixture was filtered and filtrate was concentrated. The residue was dissolved in DCM (150 mL) and washed with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a crude product, which was purified by column chromatography on silica gel (petroleum-ethyl acetate 3:1, Rf = 0.13) to give 9a as a colorless oil (0.71 g, 91.6%). IR (film, cm−1): 3531, 2931, 2856, 1651, 1508, 1463, 1261, 1234, 1112, 1026, 846; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.46–3.67 (m, 8H, morpholine–H), 3.83(s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.09–4.18 (s, 2H, CH2), 5.45 (s, 1H, CH), 6.81–6.86 (m, 3H, Ph-H), 6.99–7.03 (m, 2H, Ph-H), 7.26–7.33 (m, 2H, Ph-H). m/z (EI) 389 (M+). Anal. Calc. for C21H24FNO5 (389.42): C, 64.77; H, 6.21; N, 3.60; found: C, 64.81; H, 6.20; N, 3.57.
2-((4-Chlorophenyl)(3,4-dimethoxyphenyl)methoxy)-1-morpholinoethanone (9b) The title compound was prepared using the same procedure as described for 9a to give a light-yellow oil (83.9%). Rf = 0.13 (petroleum-ethyl acetate 3:1); IR (film, cm−1): 3491, 2956, 2925, 2854, 1651, 1510, 1461, 1263, 1234, 1112, 1026, 846; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.46–3.67 (m, 8H, morpholine–H), 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.09–4.18 (m, 2H, CH2), 5.45 (s, 1H, CH), 6.81–6.86 (m, 3H, Ph-H), 6.99–7.01 (m, 2H, Ph-H), 7.26–7.33 (m, 2H, Ph-H). m/z (EI) 405 (M+). Anal. Calc. for C21H24ClNO5 (405.87): C, 62.14; H, 5.96; N, 3.45; found: C, 62.19; H, 5.92; N, 3.43.
(4-Halogenated phenyl)(3,4-dimethoxyphenyl)methanamines 10a and 10b. To a solution of compound 6a or 6b (2 mmol) in ethanol (10 mL) was added a 3% aqueous solution of ammonia, NH4OAC (0.26 g, 3.6 mmol) and water (10 mL). The mixture was refluxed and Zn powder (0.65 g, 10 mmol) was added in portions during the reaction, after being refluxed for 6 h, the solid was filtered off. The solvent in the filtrate was evaporated, and DCM (100 mL) and water (100 mL) were added. The DCM layer was separated, washed with water, dried over MgSO4 and concentrated to give 10a or 10b as a colorless and viscous oil (0.47 g, 91% for 10a, 0.51g, 92% for 10b), which was used for the next step without further purification.
2-(((4-Fluorophenyl)(3,4-dimethoxyphenyl)methyl)amino)-1-morpholinoethanone (11a). To a mixture of 10a (0.26 g, 1 mmol), K2CO3 (0.24 g, 2 mmol) and KI (0.17 g, 1 mmol) in CH3CN (30 mL) was added dropwise a solution of compound 4 (2.3 g, 1.5 mmol) in CH3CN (10 mL). The mixture was stirred at room temperature for about 15 h. After the solid was filtered off, the solvent in the filtrate was removed in vacuo. The residue was dissolved in DCM (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous MgSO4, filtered and concentrated to give a crude product which was purified by column chromatography (petroleum-ethyl acetate 1:3, Rf = 0.27) to afford 11a as a white powdery solid (0.29 g, 72%). mp 167–170 °C; IR (film, cm−1): 3550, 3492, 2958, 2923, 2854, 1651, 1456, 1232, 1114, 1029, 848, 732; 1H-NMR (CDCl3, 300 MHz) δ (ppm): 3.23–3.34 (m, 4H, morpholine-H), 3.54–3.65 (m, 7H, morpholine-H, -CH2, -CH), 3.84 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 5.35 (m, 1H, -NH), 6.78 (d, J = 11.2 Hz, 1H, Ph-H), 6.91 (d, J = 11.2 Hz, 1H, Ph-H), 6.95–7.03 (m, 3H, Ph-H), 7.40–7.46 (m, 2H, Ph-H). m/z (EI) 388 (M+). Anal. Calc. for: C21H25FN2O4 (388.43): C, 64.93; H, 6.49; N, 7.21; found: C, 64.95; H, 6.45; N, 7.23.
2-(((4-Fluorophenyl)(3,4-dimethoxyphenyl)methyl)amino)-1-morpholinoethanone (11b). The title compound was prepared as a white solid (0.29 g, 71%) by the same procedure as described for 11a. Rf = 0.27 (petroleum-ethyl acetate 1:3); mp 179–181 °C; IR (film, cm−1): 2956, 2923, 2854, 1643, 1506, 1454, 1267, 1232, 1114, 1029, 848.
N-((4-Chlorophenyl)(3,4-dimethoxyphenyl)methyl)morpholine-4-carboxamide (11c). To a solution of compound 10b (0.28 g, 1 mmol) in DCM (15 mL) was added Et3N (0.15 g, 1.5 mmol) and DMAP (0.025 g, 0.2 mmol), followed by the addition of a solution of compound 2 in DCM (5 mL). The mixture was stirred at room temperature overnight, then DCM (60 mL) was added. The organic layer was washed with water (50 mL × 2) and dried over anhydrous MgSO4. The DCM was evaporated in vacuo to give a crude product which was purified by column chromatography (petroleum- ethyl acetate 1:1, Rf = 0.34) to give compound 11c as a white solid (0.28 g, 71.8%). mp 90–93 °C; IR (film, cm−1): 2956, 2923, 2852, 1627, 1510, 1461, 1253, 1116, 1026, 831, 746, 657; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 3.36–3.40 (m, 4H, morpholine–H), 3.67–3.71 (m, 4H, morpholine-H), 3.81 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.88 (d, J = 6.6Hz, 1H, CH), 6.06 (d, J = 6.6 Hz, 1H, NH), 6.73–6.83 (m, 3H, Ph-H), 6.98–7.03 (m, 2H, Ph-H), 7.20–7.26 (m, 2H, Ph-H). m/z (EI) 390 (M+). Anal. Calc. for: C20H23ClN2O4 (390.86): C, 61.46; H, 5.93; N, 7.17; found: C, 61.49; H, 5.95; N, 7.12.

3.2. Biological Tests

3.2.1. Antifungal Methods

The synthetic compounds were dissolved in DMSO and sterilized water (containing 1% Tween) and diluted with PDA in a Petri dish. The antifungal activity was tested in vitro by the poisoned food technique [22,23] at a final concentration of 50 μg/mL. The widely used and commercial available fungicides dimethomorph and flumorph were used as positive controls.

3.2.2. Antibacterial Methods

About 10 mL of sterilized 2216E medium was poured into the sterilized Petri dish. After solidification, 1 mL of inoculum of each test vibrio was added and sprayed uniformly. Then a 4 mm well was made in the centre of each plate using a sterilized cork-borer. Each well received 20 μL of solution of the tested compounds dissolved in DMSO. The diameters were measured after the plates were incubated at 28 °C for about 24 h. Two antibiotics, streptomycin and gentamicin sulfate were used as the positive controls. The blank control (DMSO) was of no inhibition to the vibrios.

4. Conclusions

A series of benzophenone compounds was designed and synthesized. The biological activity evaluation indicated that the synthesized compounds were quite potent on most of the tested fungi, but much less effective on the five tested vibrios. At least one of the novel benzophenone derivatives gave higher activity than flumorph and dimethomorph towards the tested fungi. Compounds 1a and 1b exhibited relatively good activity against five fungi, making them interesting leads for the design and optmization of new fungicides. Six compounds (1c, 1e, 3b, 3c, 7c and 11a) had effects on all of the tested fungi from different genera and showed better wide-spectrum activity. A Cl atom, three methoxy groups on the benzene ring and a pyrimidine group might be favorable for increasing the antifungal activity. The screened compound 7b might be a better candidate than carbendazim to inhibit Fusarium oxysporum f. sp. vasinfectum. The structure-activity relationships were discussed preliminarily and should be somewhat helpful for further studies to design more potent derivatives and discovery better fungicides with different modes of action.

Supplementary Information

Supplementary materials can be accessed on: https://www.mdpi.com/1420-3049/16/11/9739/s1.

Acknowledgments

We are profoundly grateful to Zhijin Fan and his group from Nankai University for their great help and generous suggestions concerning in antifungal bioactivity tests. The authors also thank Zongjun Du for supplying the vibrios for the assays.

References and Notes

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MDPI and ACS Style

Sun, L.; Wu, J.; Luo, M.; Wang, X.; Pan, M.; Gou, Z.; Sun, D. Diversity Oriented Design of Various Benzophenone Derivatives and Their in Vitro Antifungal and Antibacterial Activities. Molecules 2011, 16, 9739-9754. https://doi.org/10.3390/molecules16119739

AMA Style

Sun L, Wu J, Luo M, Wang X, Pan M, Gou Z, Sun D. Diversity Oriented Design of Various Benzophenone Derivatives and Their in Vitro Antifungal and Antibacterial Activities. Molecules. 2011; 16(11):9739-9754. https://doi.org/10.3390/molecules16119739

Chicago/Turabian Style

Sun, Li, Jie Wu, Min Luo, Xiaoli Wang, Man Pan, Zhaopin Gou, and Dequn Sun. 2011. "Diversity Oriented Design of Various Benzophenone Derivatives and Their in Vitro Antifungal and Antibacterial Activities" Molecules 16, no. 11: 9739-9754. https://doi.org/10.3390/molecules16119739

APA Style

Sun, L., Wu, J., Luo, M., Wang, X., Pan, M., Gou, Z., & Sun, D. (2011). Diversity Oriented Design of Various Benzophenone Derivatives and Their in Vitro Antifungal and Antibacterial Activities. Molecules, 16(11), 9739-9754. https://doi.org/10.3390/molecules16119739

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