Synthesis and Antifungal Activities of 2-(N-Arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones

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Introduction

Recently, thiazinanone derivatives have gained widespread interest due to their key role in medi- cally important species, such as those exhibiting potent cyclooxygenase (COX-2) inhibitory activity (Zebardast et al., 2009), antitumour activity (Kamel et al., 2010), antimalarial activity (Kumawat et al., 2010), and antifungal activity against three human pathogenic fungi (Verma et al., 2010). However, to the best of our knowledge, little attention has been paid to the activities of thiazinanone fragment- based derivatives against phytopathogenic fungi.

Many crops are infected by phytopathogenic fungi which are hard to control; therefore, the development of bioactive compounds for managing those agricultural diseases is highly desirable (Lee et al., 2008; Xu and Qu, 2010). As a consequence and in continuation of our program aimed at the discov- ery and development of bioactive molecules (Xu et al., 2007, 2009; Xu and Wang, 2010), here we report the antifungal activities of a series of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-one derivatives (Fig. 1) against seven phytopathogenic fungi.

Experimental

Synthesis of 2-(N-arylsulfonylindol-3-yl)-3-aryl- 1,3-thiazinan-4-ones 4a − 4j

A mixture of 3-formyl-N-arylsulfonylindole (1, 0.8 mmol), 3-mercaptopropionic acid (2,

1.2 mmol), arylamine (3, 0.4 mmol), and N,N- diisopropylcarbodiimide (DIC, 0.6 mmol) in THF was stirred at 0 °C for 10 min (Scheme 1) (Verma et al., 2010). Then the reaction mixture was warmed to room temperature (rt) and stirred for 4 – 7 h. The solvent was evaporated, and the residue was dissolved in EtOAc, washed with 1 M

HCl (20 mL x 3), water (30 mL), saturated aque- ous NaHCO3 (30 mL x 2), and brine (30 mL), and dried over anhydrous Na2SO4. Finally, the mixture was concentrated in vacuo and puriﬁed by silica gel column chromatography to give the pure compounds 4a − 4j.

4a: Yield 47.6%. – White solid. – M.p. 172 °C.

– ¹H NMR (500 MHz, CDCl3): δ = 2.81 – 3.01 (m, 4H), 6.04 (s, 1H), 7.18 – 7.27 (m, 6H), 7.34 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 2H), 7.52 – 7.58 (m, 3H), 7.80 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.5 Hz, 1H). –¹³C NMR (125 MHz, CDCl3): δ = 23.2, 34.3, 59.5, 114.0, 120.3, 121.5, 123.6, 125.1, 125.6, 126.5, 126.6, 127.4, 127.5, 129.1, 129.3, 134.0, 135.9, 137.8, 142.4, 169.0. – ESI-MS: m/z = 449.00 [M+H]⁺ (100).

4b: Yield 25.4%. – White solid. – M.p.

178 – 179 °C. – ¹H NMR (500 MHz, CDCl3): δ = 2.84 – 3.02 (m, 4H), 6.05 (s, 1H), 7.18 – 7.28 (m, 6H), 7.34 – 7.37 (m, 3H), 7.53 – 7.56 (m, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H). –

13C NMR (125 MHz, CDCl3): δ = 23.2, 34.4, 59.4, 113.9, 120.5, 121.9, 123.8, 124.9, 125.8, 126.5, 127.4, 127.7, 128.0, 129.1, 129.7, 135.8, 136.1, 140.8, 142.2, 169.0. – ESI-MS: m/z = 482.90 [M+H]⁺ (100).

2-(N-Arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones

Huan Qu, Rui Zhang, Ying Hu, Yazhen Ke, Zhinan Gao, and Hui Xu*

Laboratory of Pharmaceutical Design & Synthesis, College of Sciences,

Northwest A & F University, Yangling 712100, P. R. China. Fax: +86-29-87091952.

E-mail: orgxuhui@nwsuaf.edu.cn

* Author for correspondence and reprint requests

Z. Naturforsch. 68 c, 77 − 81 (2013); received March 14/June 28, 2012

A series of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-one derivatives were synthesized and evaluated in vitro against seven phytopathogenic fungi, namely Fusarium graminearum, Alternaria solani, Fusarium oxysporium f. sp. vasinfectum, Alternaria brassi- cae, Valsa mali, Alternaria alternata, and Pyricularia oryzae. Among all derivatives, especially compound 4j exhibited a potential antifungal activity against four phytopathogenic fungi.

Key words: 2-(N-Arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones, Antifungal Activity, Phytopathogenic Fungi

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4c: Yield 24.5%. – White solid. – M.p. 168 °C.

– ¹H NMR (500 MHz, CDCl3): δ = 1.18 (t, J = 7.5 Hz, 3H), 2.62 (q, J = 7.5 Hz, 2H), 2.81 – 3.01 (m, 4H), 6.04 (s, 1H), 7.18 – 7.27 (m, 8H), 7.33 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.5 Hz, 1H). –¹³C NMR (125 MHz, CDCl3): δ = 14.8, 23.2, 28.8, 34.3, 59.5, 114.0, 120.2, 121.2, 123.4, 125.2, 125.5, 126.6, 126.8, 127.4, 127.5, 128.8, 129.1, 135.1, 135.9, 142.4, 151.3, 169.0. – ESI-MS: m/z = 477.00 [M+H]⁺ (100).

4d: Yield 39.5%. – White solid. – M.p. 94 – 96 °C.

– ¹H NMR (500 MHz, CDCl3): δ = 2.82 – 3.01 (m, 4H), 3.80 (s, 3H), 6.04 (s, 1H), 6.84 (d, J = 8.5 Hz, 2H), 7.18 – 7.28 (m, 6H), 7.32 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.99 (d, J = 8.5 Hz, 1H). –¹³C NMR (125 MHz, CDCl3): δ = 23.2, 34.3, 55.7, 59.5, 114.0, 114.5, 120.2, 121.1, 123.4, 125.2, 125.5, 126.6, 127.3, 127.5, 129.0, 129.1, 129.3, 135.9, 142.4, 163.9, 169.1.

– ESI-MS: m/z = 501.00 [M+Na]⁺ (100).

4e: Yield 83%. – White solid. – M.p. 194 °C. – ¹H NMR (500 MHz, CDCl3): δ = 2.28 (s, 3H), 2.35 (s, 3H), 2.79 – 3.00 (m, 4H), 6.00 (s, 1H), 7.05 – 7.10 (m, 4H), 7.19 – 7.25 (m, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 1H). –¹³C NMR (125 MHz, CDCl3): δ = 21.0, 21.6, 23.1, 34.3, 59.5, 114.0, 120.2, 121.2, 123.4, 125.1, 125.5, 126.4, 126.7, 127.6, 129.8, 129.9, 134.9, 135.9, 137.2, 139.9, 145.2, 169.0. – ESI-MS: m/z = 477.00 [M+H]⁺ (100).

4f: Yield 68.9%. – White solid. – M.p.

202 – 204 °C. – ¹H NMR (500 MHz, CDCl3): δ = 2.29 (s, 3H), 2.82 – 3.00 (m, 4H), 6.01 (s, 1H), 7.06 (s, 4H), 7.25 – 7.28 (m, 1H), 7.34 – 7.38 (m, 3H), 7.52 – 7.54 (m, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H). –¹³C NMR (125 MHz, CDCl3):

δ = 21.0, 23.2, 34.4, 59.3, 113.9, 120.4, 122.0, 123.8, 124.8, 125.8, 126.3, 127.7, 128.0, 129.7, 129.8, 135.8, 136.2, 137.4, 139.7, 140.8, 169.0. – ESI-MS: m/z = 518.90 [M+Na]⁺ (100).

4g: Yield 37.8%. – White solid. – M.p. 82 – 84 °C.

– ¹H NMR (500 MHz, CDCl3): δ = 2.47 (s, 3H), 2.80 – 2.99 (m, 4H), 6.00 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.18 – 7.27 (m, 5H), 7.39 – 7.44 (m, 3H), 7.49 (s, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.79 (t, J = 8.0 Hz, 3H). –¹³C NMR (125 MHz, CDCl3): δ = 21.9, 23.1, 34.3, 59.5, 114.0, 119.9, 121.5, 124.5, 125.1, 125.3, 126.5, 126.6, 127.3, 129.1, 129.3, 133.9, 136.0, 136.4, 138.0, 142.4, 169.0. – ESI-MS: m/z = 463.00 [M+H]⁺ (100).

4h: Yield 64.5%. – White solid. – M.p. 74 – 76 °C.

– ¹H NMR (500 MHz, CDCl3): δ = 2.36 (s, 3H), 2.46 (s, 3H), 2.80 – 2.99 (m, 4H), 6.00 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.19 – 7.27 (m, 7H), 7.39 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.80 (s, 1H). –¹³C NMR (125 MHz, CDCl3):

δ = 21.6, 21.9, 23.1, 34.3, 59.6, 114.0, 119.8, 121.2, 124.6, 125.0, 125.3, 126.5, 126.7, 127.3, 129.1, 129.9, 135.0, 135.9, 136.3, 142.4, 145.1, 169.1. – ESI-MS:

m/z = 477.00 [M+H]⁺ (100).

4i: Yield 28.6%. – White solid. – M.p. 206 – 208 °C.

– ¹H NMR (500 MHz, CDCl3): δ = 2.57 (s, 3H), 2.74 – 3.08 (m, 4H), 6.24 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.19 – 7.23 (m, 4H), 7.25 – 7.29 (m, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.54 – 7.56 (m, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.5 Hz, 1H). –¹³C NMR (125 MHz, CDCl3): δ = 20.7, 21.3, 34.3, 60.3, 111.8, 122.3, 124.8, 125.6, 126.0, 126.3, 126.74, 126.77, 127.4, 129.2, 129.3, 131.4, 134.0, 136.4, 137.8, 142.8, 168.9. – ESI-MS: m/z = 463.00 [M+H]⁺ (100).

4j: Yield 33.5%. – Yellow solid. – M.p.

196 – 197 °C. – ¹H NMR (500 MHz, CDCl3): δ = 2.83 – 3.02 (m, 4H), 6.06 (s, 1H), 7.16 – 7.28 (m, 5H), 7.46 (t, J = 7.5 Hz, 2H), 7.58 – 7.63 (m, 2H), 7.69 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H). –¹³C NMR (125 MHz, CDCl3): δ = 23.3, 34.3, 59.0, 107.4, 114.8, 118.8, 121.1, 125.6, 126.6, 126.7, 127.0, 127.6, 128.5, 129.3, 129.7, 134.7, 137.3, 137.5, 142.0, 168.9. – ESI-MS:

m/z = 496.00 [M+Na]⁺ (100).

Antifungal assay

Compounds 4a − 4j were screened for their antifungal activities in vitro against seven phytopathogenic fungi by the “poisoned food” tech- nique (Xu et al., 2007). The phytopathogenic fungi used were: Fusarium graminearum, Alternaria solani, Fusarium oxysporium f. sp. vasinfectum, Alternaria brassicae, Valsa mali, Alternaria alter- nata, and Pyricularia oryzae. Potato dextrose agar (PDA) medium was prepared in fl asks and sterilized. Compounds 4a − 4j were dissolved in ace- tone before mixing with PDA, and the fi nal concentration of test compounds in the medium was fi xed at 50 μg/mL. The medium was then poured into sterilized Petri dishes. All fungi were incubated in PDA at (28  1) °C for 5 d to obtain fresh mycelium for the antifungal assays. Then, mycelium disks of approx. 5 mm diameter were cut from the culture medium and inoculated in the center of the PDA Petri dishes with a sterilized inocu-

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lation needle. The inoculated Petri dishes were incubated at (28  1) °C for 4 d. Acetone mixed with PDA served as a control, while hymexazole (Binzhou Dedong Chemical Engineering Co., Ltd., Binzhou, Shangdong province, China), a commercial agricultural fungicide, severed as a positive control. For each treatment, three repli- cates were conducted. The radial growth of the fungal colonies was measured and the data were statistically analysed. The inhibitory effects of the test compounds on the fungi in vitro were calcu- lated by the formula: inhibition rate (%) = (C − T)

· 100/C, where C represents the diameter of fungal growth on untreated PDA, and T represents the diameter of fungal growth on treated PDA.

Results and Discussion

Compounds 4a−aj (Fig. 1) were synthesized ac- cording to Scheme 1.

As shown in Table I, of all the analogues, compound 4j exhibited a potent antifungal activ- ity against four phytopathogenic fungi at 50 μg/

mL. For example, the percentage inhibition by 4j of the growth of A. solani, A. brassicae, A. al- ternata, and P. oryzae was 39.7%, 48.1%, 57.3%, and 55.1%, respectively. Some compounds were active to some extent against only some of the phytopathogenic fungi. For example, compounds

4a, 4d, 4g, 4i, and 4j inhibited the growth of F.

graminearum by 24.7%, 23.4%, 21.4%, 23.8%, and 27.1%, respectively. Compounds 4a and 4j inhibited the growth of A. solani by 21.1% and 39.7%, respectively. Compounds 4c, 4d, and 4j inhibited the growth of A. brassicae by 25.2%, 23.0%, and 48.1%, respectively.

Some structure-activity relationships of the 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan- 4-ones 4a − 4j against phytopathogenic fungi were observed. Inhibition of A. alternata and P. oryzae by 4a and 4j was 27.7%/57.3% and 22.7%/55.1%, respectively. Introduction of an electron-donating group (methyl) on the indolyl ring of 4a generally made no difference in inhibition rates as compared with 4a (e.g., 4g − 4i). On the contrary, introduction of an electron-withdrawing group (cyano) on the indolyl ring of 4a could generally increased the potency (e.g., 4j).

In conclusion, a series of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones, 4a − 4j, were synthesized and evaluated in vitro against F. graminearum, A. solani, F. oxysporium f. sp.

vasinfectum, A. brassicae, V. mali, A. alternata, and P. oryzae. Among all derivatives, compound 4j exhibited a potent antifungal activity against four phytopathogenic fungi at the concentration of 50 μg/mL.

N SO₂ N S O

4a

N SO₂ N S O

H₃CH₂C 4c

N SO₂ N S O

H3C4e H₃C

N SO₂ N S O

Cl 4b

N SO₂ N S O

H₃CO 4d

N SO₂ N S O

Cl 4f H₃C

N SO₂ N S O

4g

H3C N

SO₂ N S O

H₃C 4h

H₃C N

SO₂

4i

N SO₂ N S O

4j NC CH₃ S

N O

Fig. 1. Chemical structures of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones 4a − 4j.

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Acknowledgement

This work was supported by the program for Changjiang Scholars and Innovative Research Team in University (IRT1035), and the Special

Funds of Central Colleges Basic Scientiﬁ c Re- search Operating Expenses (QN2009045). We also thank Prof. H. L. Zhang for the NMR experiments.

Table I. Antifungal activities of 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones 4a − 4j against phytopathogenic fungi at 50 μg/mL in vitro.

Compound Inhibition (%)^a

Fusarium

graminearum Alternaria

solani Fusarium ox- ysporium f. sp.

vasinfectum

Alternaria

brassicae Valsa

mali Alternaria

alternata Pyricularia oryzae 4a 24.7 ( 1.4) 21.1 ( 0) 14.7 ( 1.2) 14.9 ( 0) 15.9 ( 0) 27.7 ( 1.4) 22.7 ( 0) 4b 7.1 ( 0) 9.7 ( 0.7) 11.8 ( 0.7) 9.4 ( 0.7) 9.9 ( 0) 14.9 ( 0.7) 14.1 ( 0) 4c 9.1 ( 0) 8.1 ( 0) 14.3 ( 0.7) 25.2 ( 0) 10.5 ( 0) 17.6 ( 0) 16.2 ( 0) 4d 23.4 ( 1.4) 10.0 ( 0) 17.9 ( 0.7) 23.0 ( 0) 12.4 ( 0) 19.6 ( 0) 18.0 ( 0)) 4e 17.3 ( 0.7) 11.1 ( 0) 15.3 ( 1.4) 10.6 ( 0.7) 11.0 ( 0) 14.3 ( 0) 17.6 ( 0) 4f 5.8 ( 1.2) 12.2 ( 1.4) 9.9 ( 0) 17.5 ( 0.7) 12.2 ( 0) 12.7 ( 1.2) 8.9 ( 1.2) 4g 21.4 ( 1.4) 8.7 ( 0.7) 20.8 ( 0.7) 10.2 ( 0.7) 19.6 ( 0) 17.7 ( 1.4) 17.8 ( 1.4) 4h 18.2 ( 0) 9.2 ( 0) 16.8 ( 1.4) 13.0 ( 0.7) 15.0 ( 1.2) 10.4 ( 0) 12.9 ( 0)

4i 23.8 ( 0) 16.2 ( 1.2) 13.2 ( 0) 16.4 ( 0) 19.1 ( 0) 14.3 ( 0.7) 14.6 ( 0) 4j 27.1 ( 0) 39.7 ( 0.7) 16.6 ( 1.8) 48.1 ( 0) 16.7 ( 0) 57.3 ( 0.7) 55.1 ( 1.2) Hy^b 51.9 ( 0) 15.8 ( 0) 39.2 ( 0) 71.2 ( 0) 25.0 ( 1.4) 74.1 ( 0) 77.3 ( 0.7)

Acetone^c 0 0 0 0 0 0 0

a Values are means of three experiments, standard deviations are given in parentheses.

b Hymexazole as a reference compound.

c Control.

N

O H

R¹ + HS OH

O +

NH2

R³ SO2

R²

DIC/THF

0^oC - rt, 4 - 7 h R¹ N SO2

R² N S R³ O

1a - i

2 3a, b

4a - j 24.5 - 83%

Scheme 1. Synthetic route to 2-(N-arylsulfonylindol-3-yl)-3-aryl-1,3-thiazinan-4-ones 4a − 4j.

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