English

• 1. INTRODUCTION

  Dihydrobenzofuran was a basic unit of many bioactive heterocycles, which has been used in medical and agricultural applications, such as antibacterial^[1], antileishmanial^{[2, 3]}, herbicide^{[4, 5]}, insecticide^[6], fungicide^[7], etc. Meanwhile, the biological activities of thiadiazole derivatives have been studied in depth, such as antibacterial^[8-13], insecticide^[14-18], fungicide^[19] and anti-inflammatory^[20].

  Shen and co-workers^[21] synthesized seven thiazoles compounds containing 2,3-dihydrobenzofuran (1a-1g) (Fig. 1) and found that compounds 1a and 1f have great inhibition activity (59.8%, 57.9%) against Sclerotonia sclerotiorum, respectively, but have weak activity against Botrytis cinerea, Alternaria alternata, Rhizoctonia solani and Erysiphe graminis.

  Figure 1

  

  Figure 1.  Compound 1

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  Zou and co-workers^[22] synthesized some novel 1,3,4-thiadiazole compounds (Fig. 2) and determined their fungicidal activity. The result showed that compounds 2m, 2n and 2p have the best fungicidal activity against Puccinia recondita with the inhibition of 90%. It could be concluded that with the increase of group hydrophobicity, the fungicidal activity of these compounds increased as well.

  Figure 2

  

  Figure 2.  Compound 2

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  Chen and co-workers^[23] synthesized a few of 1,3,4-thiadi-azoles compounds (Fig. 3) and evaluated their fungicidal activity. Compounds 3a and 3b had great fungicidal activity against Rhizoctonia solani with the inhibition of 90%~99%.

  Figure 3

  

  Figure 3.  Compound 3

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  Both dihydrobenzofuran compounds and 1,3,4-thiadiazole compounds have good fungicidal activity. Based on the active splice principle, a new series of compounds 8 were designed and synthesized by incorporating 1,3,4-thiadiazole into the side chain of 2,2-dimethyl-2,3-dihydrobenzofuran (Scheme 1), the new compounds were expected to achieve great antifungal activity so as to search for broad-spectrum and efficient antifungal drugs, which are of great significance for plant protection. Herein, the synthesis, characterization and bioactivity of N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl) amide compounds (8a-i) were reported. The preparation of compounds 8a-i is shown in Scheme 1.

  Scheme 1

  

  Scheme 1.  Preparation of compounds 8a-i

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  2. EXPERIMENTAL

  2.1 Reagents and instruments

  The whole reagents were obtained from professional reagent companies. Fusion points (℃) were tested on an SGWX-4B micromelting point apparatus (Shanghai Precision Instrument Technology Co., Ltd) and unadjusted. Nuclear Magnetic Resonance spectra were tested on a Bruker advanced instrument at 600 MHz and TMS as the interior label. The Bruker AXS SMART APEX II 4000 CCD diffractometer containing a graphite-monochromatic CuKα (λ = 0.71073 Å) radiation at 273 K was used for crystal structure determination. Q EXACTIVE Mass Spectrometer (Thermo Fisher Scientific) was used to determine the molecular weight.

  2.2 Preparation

  2.2.1   Preparation of compound 5

  Benzofuranol (4, 9.2 mmol, 1.51 g) was put in DMF slowly at 0 ℃, then the admixture reacted at rt for 2 h. Additionally, DMF was dehydrated with NaH early. The color of the reaction solution varied from colorless to black. Ethyl chloroacetate (10.9 mmol, 1.34 g) and the appropriate amounts of KI were added to the mixture and refluxed for 7 h. Until the end of the reaction, the mixture was poured into crushed ice water and then extracted by AcoEt and washed by saturated brine. The obtained organic mixture was dried and evaporated. Then obtained coarse product was separated and purified to give compound 5 with yield of 89%.

  2.2.2   Preparation of compound 6

  Compound 5 (12 mmol, 3.00 g) and 20% NaOH solution (12 mL) in ethanol were reacted for 24 h at 60 ℃. Afterwards, the reaction solution was conditioned to be acidic (pH 1.5) by concentrated hydrochloric under an ice bath. Then the white solid obtained was filtered, washed by distilled water and freeze-dried for 5 h to give compound 6 with a yield of 89%.

  2.2.3   Preparation of compound 7

  Compound 6 (4.5 mmol, 1.00 g) and POCl₃ (22.5 mmol, 3.45 g) were put in dioxane under an ice bath and then reacted for 0.5 h. And thiosemicarbazide (9 mmol, 0.82 g) was mixed lately. 2 h later, an appropriate amount of water was mixed in and the reaction solution was continued to reflux for 7 h. Until the end of the reaction, the mixture was cooled and adjusted to alkalinity (pH 11) by concentrated ammonia to get the crude product. After that, it was filtered, washed by water and freeze-dried for 5 h, then compound 7 was recrystallized from anhydrous EtOH with the yield of 87%.

  2.2.4   Preparation of compounds 8a-i

  Compound 7 (0.36 mmol, 0.10 g) and butyryl chloride (0.4 mmol, 0.04 g) in anhydrous DCM were added under an ice bath and then reacted for 0.5 h at rt. And pyridine (0.36 mmol, 0.03 g) was mixed lately. Until the end of the reaction, DCM was evaporated. Afterwards, the reaction solution was conditioned to be acidic by dilute hydrochloric, and the residue was extracted by AcoEt. The combined organic mixture was dried. Finally, AcoEt was evaporated, and the obtained coarse product was separated and purified to give N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)amide compounds (8a-i).

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-butyramide (8a): Yield 72%, m.p. 162~165 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 13.14 (s, 1H), 6.83 (dd, J = 14.5, 7.7 Hz, 2H), 6.71 (t, J = 7.7 Hz, 1H), 5.52 (s, 2H), 3.02 (s, 2H), 2.71 (t, J = 7.4 Hz, 2H), 1.82 (dd, J = 14.7, 7.4 Hz, 2H), 1.52 (s, 6H), 1.03 (t, J = 7.4 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ: 172.13, 162.04, 161.84, 148.19, 142.29, 129.32, 120.49, 119.36, 114.97, 88.01, 66.14, 43.28, 38.18, 28.37, 19.02, 13.82. HRMS-ESI m/z calcd. for C₁₇H₂₁N₃O₃S [M+H]⁺ 348.1376, found 348.1369.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-benzamide (8b): Yield 74%, m.p. 203~205 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 11.54 (s, 1H), 8.14 (d, J = 7.7 Hz, 2H), 7.64 (d, J = 7.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 6.84 (dd, J = 17.9, 7.7 Hz, 2H), 6.72 (t, J = 7.7 Hz, 1H), 5.55 (s, 2H), 3.04 (s, 2H), 1.53 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ: 165.06, 162.64, 155.68, 147.79, 142.37, 133.52, 131.31, 129.35, 129.16, 128.36, 120.56, 119.40, 115.01, 88.05, 66.32, 43.32, 28.41. HRMS-ESI m/z calcd. for C₂₀H₁₉N₃O₃S [M+Na]⁺ 404.1039, found 404.1029.

  4-Chloro-N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadia-zol-2-yl)benzamide (8c): Yield 67%, m.p. 215~217 ^oC. ¹H NMR (600 MHz, DMSO) δ: 8.12 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.3 Hz, 1H), 6.71 (t, J = 7.7 Hz, 1H), 5.32 (s, 2H), 2.99 (s, 2H), 1.42 (s, 6H). ¹³C NMR (151 MHz, DMSO) δ: 167.83, 166.58, 156.37, 147.32, 142.34, 136.78, 134.92, 130.01, 128.51, 127.73, 120.13, 118.26, 114.09, 87.03, 65.62, 42.43, 27.87. HRMS-ESI m/z calcd for C₂₀H₁₈ClN₃O₃S [M+H]⁺ 416.0830, found 416.0821.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-acetamide (8d): Yield 82%, m.p. 230 ℃ carbonization. ¹H NMR (600 MHz, CDCl₃) δ: 11.71 (s, 1H), 6.85~6.80 (m, 2H), 6.71 (t, J = 7.7 Hz, 1H), 5.52 (s, 2H), 3.03 (s, 2H), 2.40 (s, 3H), 1.52 (s, 6H). ¹³C NMR (151 MHz, DMSO) δ: 170.46, 158.55, 147.38, 142.04, 128.74, 120.23, 118.65, 114.34, 87.24, 65.15, 42.40, 27.88, 23.49. HRMS-ESI m/z calcd. for C₁₅H₁₇N₃O₃S [M+H]⁺ 320.1063, found 320.1056.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-propionamide (8e): Yield 79%, m.p. 188~190 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 12.76 (s, 1H), 6.82 (t, J = 8.0 Hz, 2H), 6.71 (t, J = 7.7 Hz, 1H), 5.52 (s, 2H), 3.03 (s, 2H), 2.73 (q, J = 7.5 Hz, 2H), 1.52 (s, 6H), 1.30 (t, J = 7.5 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃) δ: 172.69, 162.07, 161.87, 148.20, 142.27, 129.34, 120.51, 119.39, 115.06, 88.03, 66.17, 43.29, 29.58, 28.38, 9.28. HRMS-ESI m/z calcd. for C₁₆H₁₉N₃O₃S [M+H]⁺ 334.1220, found 334.1210.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-4-methylbenzamide (8f): Yield 75%, m.p. 203~205 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 11.21 (s, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 6.72 (t, J = 7.7 Hz, 1H), 5.56 (s, 2H), 3.03 (s, 2H), 2.45 (s, 3H), 1.53 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ: 164.83, 162.66, 161.63, 147.80, 144.43, 142.39, 129.88, 129.33, 128.29, 120.55, 119.37, 115.01, 88.03, 66.35, 43.32, 28.40, 21.84. HRMS-ESI m/z calcd. for C₂₁H₂₁N₃O₃S [M+H]⁺ 396.1376, found 396.1366.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-4-methoxybenzamide (8g): Yield 78%, m.p. 192~194 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 8.16 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.1 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.71 (t, J = 7.7 Hz, 1H), 5.55 (s, 2H), 3.89 (s, 3H), 3.03 (s, 2H), 1.52 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ: 164.65, 163.90, 162.32, 148.25, 147.23, 142.42, 130.65, 129.34, 123.54, 120.55, 119.38, 115.07, 114.37, 88.01, 66.39, 55.69, 43.33, 28.39. HRMS-ESI m/z calcd. for C₂₁H₂₁N₃O₄S [M+Na]⁺ 434.1145, found 434.1136.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-pivalamide (8h): Yield 79%, m.p. 167~169 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 9.29 (s, 1H), 6.82 (dd, J = 12.9, 7.8 Hz, 1H), 6.71 (t, J = 7.7 Hz, 1H), 5.53 (s, 2H), 3.02 (s, 2H), 1.55 (s, 9H), 1.34 (s, 6H). ¹³C NMR (151 MHz, CDCl₃) δ: 177.51, 162.41, 161.39, 147.96, 142.23, 129.03, 120.34, 119.04, 114.48, 114.45, 87.78, 65.81, 43.17, 39.54, 28.26, 27.07. HRMS-ESI m/z calcd. for C₁₈H₂₃N₃O₃S [M+H]⁺ 362.1533, found 362.1524.

  N-(5-(benzofuranol-7-oxymethyl)-1,3,4-thiadiazol-2-yl)-cyclohexanecarboxamide (8i): Yield 84%, m.p. 183~186 ^oC. ¹H NMR (600 MHz, CDCl₃) δ: 12.99 (s, 1H), 6.83 (dd, J = 24.1, 7.7 Hz, 2H), 6.71 (t, J = 7.8 Hz, 1H), 5.52 (s, 2H), 3.02 (s, 2H), 2.82 (tt, J = 11.6, 3.3 Hz, 1H), 1.98 (d, J = 11.8 Hz, 2H), 1.83 (dd, J = 10.2, 3.1 Hz, 2H), 1.73 (d, J = 13.0 Hz, 1H), 1.58 (ddd, J = 24.8, 12.7, 3.2 Hz, 2H), 1.52 (s, 6H), 1.49~1.41 (m, 2H), 1.34~1.25 (m, 1H).¹³C NMR (151 MHz, CDCl₃) δ: 175.17, 162.23, 161.59, 148.16, 142.37, 129.26, 120.45, 119.27, 114.65, 87.98, 66.07, 44.83, 43.31, 29.35, 28.38, 25.76, 25.59. HRMS-ESI m/z calcd. for C₂₀H₂₅N₃O₃S [M+H]⁺ 388.1689, found 388.1681.

  2.3 X-ray structure determination

  Compound 8a was dispersed in the mixture of AcoEt and MeOH (AcoEt:MeOH = 3:1) and kept for self-volatilization. The colorless crystals were obtained after 5 days with dimensions of 0.27mm × 0.23mm × 0.07mm. A total of 9905 reflections were collected within limits of 2.50°<θ<28.29°, 4316 were independent (R_int = 0.0300) and 3873 were considered to be observed (I > 2σ(I)) and used for subsequent refinement. SADABS was used to correct absorption effects of incident and diffracted beams. The structure was solved directly by SHELXL-2018/2 and Fourier difference technique was uesed to expand. All the hydrogen atoms were placed in the theoretical positions, and all the non-hydrogens were asymmetrically refined. The crystal structure was refined through full-matrix least-squares techniques on F² with SHELXL-2018/3^[24]. All the reference data were as follows:

  $ R = 0.0{\text{35, }}wR = 0.{\text{1}}0{\text{5}} $

  $ \left(w=\text{1}/\left[{\sigma }^{\text{2}}\left({F}_{0}^{2}\right)+{\left(0.0\text{545}P\right)}^{\text{2}}+0.\text{3697}P\right],\text{ where }P=\left({F}_{0}^{2}+\text{2}{F}_{\text{c}}^{2}\right)/\text{3}\right) $

  $ S = {\text{1}}.0{\text{35}},{\text{ }}{\left( {\Delta /\sigma } \right)_{{\text{max}}}} = 0.00{\text{1}},{\text{ }}{\left( {\Delta \rho } \right)_{{\text{max}}}} = 0.{\text{25 and }}{\left( {\Delta \rho } \right)_{{\text{min}}}} = - 0.{\text{23}} {\rm{e}} \cdot {\mathbf{Å}^{ - 3}}. $

  2.4 Antifungal activity assay

  Compounds 8a-i were tested for the control of Pseudoperonospora cubensis (Pseudoperonospora c.) and Colletrichum orbiculare (Colletrichum o.) on the first true leaf of cucumber that was fully unfolded. In addition, compounds 8a-i were also tested for the control of Erysiphe graminis (Erysiphe g.) on wheat leaves at the third-leaf stage. Compounds 8a-i and the control drugs, cyazofamid and azoxy-strobin were formulated in water (containing 0.1% Tween 80) to 200 mg/L solutions, which were sprayed to cucumber or wheat leaves using a three-dimensional crop sprayer with spray bulk of 1×10³ dm³/hm² and spray pressure of 1.5 kg/cm². The treated plants were dried naturally in the shade for 24 h. The cucumber leaves were inoculated with the spore suspensions of Pseudoperonospora c. and Colle-trichum o. (3-5×10⁶/mL) and then transferred to artificial climate chamber for cultivation (24±1 ℃, RH>90, no light). 24 h later, the plants were managed for normal in the greenhouse. Additionally, the wheat leaves were cultivated with the spores of Erysiphe g. and cultured in greenhouse. The antifungal activities of compounds 8a-i were evaluated 5~7 days after treatment. The results of survey consulted A Manual of Assessment Keys for Plant Diseases compiled by American Society of Plant Diseases for studying the fungicidal activity about compounds 8a-i. It was represented by 100-0, with "100" representing disease-free and "0" representing the most severe degree of disease.

  3. RESULTS AND DISCUSSION

  In this study, 8a-i were prepared and their structures were confirmed by HRMS and NMR. Additionally, the structure of compound 8a was characterized through single-crystal X-ray diffraction, which was classified as monoclinic system with pace group P2₁. The perspectives of compound 8a with atomic numbering scheme are given in Fig. 4. The part of bond distances and bond angles are showed in Table 1.

  Figure 4

  

  Figure 4.  Crystal structure of compound 8a with atom labels

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  Table 1

  

  Table 1.  Part of Bond Distances (Å) and Angles (°) of 8a

  DownLoad: CSV

  Bond	Dist.		Bond	Dist.		Bond	Dist.
  C(7)–O(2)	1.3731(14)		C(12)–N(3)	1.3671(16)		C(1)–O(1)	1.4721(15)
  C(8)–O(1)	1.3634(14)		C(10)–S(1)	1.7293(13)		C(9)–O(2)	1.4090(14)
  C(11)–N(3)	1.3664(16)		C(11)–S(1)	1.7216(11)		C(3)–C(8)	1.3804(16)
  Angle	(°)		Angle	(°)		Angle	(°)
  O(1)–C(1)–C(17)	106.27(13)		O(1)–C(8)–C(3)	114.09(11)		C(11)–N(2)–N(1)	112.41(10)
  O(1)–C(1)–C(2)	104.95(10)		C(8)–C(3)–C(2)	107.37(11)		N(2)–C(11)–S(1)	114.36(9)
  C(3)–C(2)–C(1)	102.63(10)		C(10)–N(1)–N(2)	111.89(11)		C(11)–S(1)–C(10)	86.380(6)

  As showed in Fig. 4, there were two planes in the crystal structure of 8a: the phenyl ring (C(3)–C(4)–C(5)–C(6)–C(7)– C(8)) and the 1,3,4-thiadiazole ring (N(1)–N(2)–C(11)– S(1)–C(10)), and the dihedral angle between them is 46.2°.

  As outlined in Fig. 4 and Table 1, the bond distances of C(7)–O(2) and C(8)–O(1) are 1.3731(14) and 1.3634(14) Å, which are much shorter than the ordinary value of C–O bond (1.43 Å), because the lone-pair electrons of O(2) and O(1) are conjugated with the π bonds of the benzene ring and C(8)–O(1) is involved in the dihydrobenzofuran ring. The C(11)–N(3) and C(12)–N(3) bond distances are 1.3664(16) and 1.3671(16) Å, much shorter compared to the typical C–N bond (1.47 Å) as the lone-pair electrons of N(3) are conjugated with the π bonds of the thiadiazole ring and the carbonyl group. The bond distances of C(10)–S(1) and C(11)–S(1) are 1.7293(13) and 1.7216(11) Å severally, also shorter than the common value of C–S single bond (1.82 Å) due to the involvement of C(10)–S(1) and C(11)–S(1) in the formation of thiadiazole rings.

  As shown in Fig. 5 and Table 2, an intermolecular hydrogen bond N(3)–H(3)···N(2) forming a one-dimensional chain structure can be seen between the amino and thiadiazole groups, the angle and distance of which are 176.7° and 2.9029(14) Å separately. And a weak V-type hydrogen bond is formed through intermolecular hydrogen bond C(6)– H(6)···O(3) between the benzene and carbonyl groups with the distance of 3.4059(16) Å and angle of 141°. The intermolecular hydrogen bonds played a significant role in stabilizing the structure.

  Figure 5

  

  Figure 5.  Hydrogen bonding diagram

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  Table 2

  

  Table 2.  Hydrogen Bond Distances and Angles of Compound 8a (Å and °)

  DownLoad: CSV

  D–H···A	D–H	H···A	D···A	D–H···A
  N(3)–H(3)···N(2)i	0.80	2.10	2.9029(1)	177
  C(6)–H(6)···O(3)ii	0.93	2.63	3.4059(2)	141
  Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) −x+1, y+1/2, −z+3/2

  Table 3

  

  Table 3.  Control Effect of Compounds 8 on Plant Pathogenic Bacteria (%, 200 mg/L)

  DownLoad: CSV

  Sample	Pseudoperonospora c.		Colletrichum o.	Erysiphe g.
  Compound 8a		75	0	0
  Compound 8b		30	0	25
  Compound 8c		60	0	0
  Cyazofamid		100	0	0
  Azoxystrobin		100	100	100
  Other compounds were inactive

  According to antifungal activity assay, compounds 8a and 8c exhibited good fungicidal activity against Pseudoperonospora c. with the inhibition of 75% and 60% respectively, but had no inhibition activity against Erysiphe g. Additionally, compound 8b showed weak activity against Pseudoperonospora c. and Erysiphe g., whereas none of compounds had activity against Colletrichum o. The compound that was substituted by n-propyl had the best antifungal activity against Pseudoperonospora c. When the substituted group was phenyl, the compound possessed weak antifungal activity. The antifungal activity of the compound was increased against Pseudoperonospora c., on account of the electron absorbing impact of the p-substituted phenyl group. If the p-substituted phenyl groups were electron-absorbing groups (-CH₃ and -OCH₃), the antifungal activity of the compound would be lost. Therefore, 1,3,4-thiadiazol compounds 8a-c possessed good selectivity against fungal activity, and it was of great significance for further study of these compounds.

  4. CONCLUSION

  In summary, a new type of 1,3,4-thiadiazole compound with dihydrobenzofuran was prepared and characterized by spectroscopy, and the structure of compound 8a was confirmed by single-crystal X-ray diffraction. The antifungal activity assay showed that compounds 8a-c had certain activity against plant pathogenic bacteria in vivo.

  
  
• 1. [1]

     Richardson, S. N.; Nsiama, T. K.; Walker, A. K.; McMullin, D. R.; Miller, J. D. Antimicrobial dihydrobenzofurans and xanthenes from a foliar endophyte of Pinus strobus. Phytochemistry 2015, 117, 436–443. doi: 10.1016/j.phytochem.2015.07.009

  2. [2]

     Bernal, F. A.; Gerhards, M.; Kaiser, M.; Wünsch, B.; Schmidt, T. J. (±)-trans-2-phenyl-2, 3-dihydrobenzofurans as leishmanicidal agents: synthesis, in vitro evaluation and SAR analysis. Eur. J. Med. Chem. 2020, 205, 112493. doi: 10.1016/j.ejmech.2020.112493

  3. [3]

     Miert, S. V.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.; Lemière, G.; Pieters, L. Antileishmanial activity, cytotoxicity and QSAR analysis of synthetic dihydrobenzofuran lignans and related benzofurans. Bioorg. Med. Chem. 2005, 13, 661–669. doi: 10.1016/j.bmc.2004.10.058

  4. [4]

     Masi, M.; Cimmino, A.; Boari, A.; Tuzi, A.; Zonno, M. C.; Baroncelli, R.; Vurro, M.; Evidente, A. Colletochlorins E and F, new phytotoxic tetrasubstituted pyran-2-one and dihydrobenzofuran, isolated from colletotrichum higginsianum with potential herbicidal activity. J. Agric. Food Chem. 2017, 65, 1124–1130. doi: 10.1021/acs.jafc.6b05193

  5. [5]

     Lin, D.; Xiao, M. W.; Yang, Z. H.; Li, B. B.; Hu, A. X.; Ye, J. Synthesis and herbicidal activity of N-(2, 2-dimethyl-7-alkoxy-2, 3-dihydrobenzofu-ran-5-yl)-2-(4-arylxoyphenoxy) propionamides. Chem. Res. Chin. U. 2017, 33, 74–79. doi: 10.1007/s40242-016-6305-1

  6. [6]

     Baldin, E. L. L.; Dias, H. J.; Souza, C. M. D.; Soares, M. C. E.; Grundman, C. O.; Santos, T. L. B.; Crotti, A. E. M. Insecticidal and inhibitory effects of dihydrobenzofuran neolignans on Bemisia tabaci. J. Pest. Sci. 2019, 92, 861–869. doi: 10.1007/s10340-018-1053-2

  7. [7]

     Li, W.; Yang, Z. H.; Hu, A. X.; Ye, J.; Ou, X. M.; Pei, H.; He, L.; Li, J. M. Synthesis and fungicidal activities of 2-{[(2-(1H -1, 2, 4-triazol-1-yl)-ethylidene)amino]oxy}alkanamides containing dihydrobenzofuran. Heterocycl. Commun. 2018, 24, 339–344. doi: 10.1515/hc-2017-0245

  8. [8]

     Muğlu, H.; Şener, N.; Mohammad Emsaed, H. A.; Özkınalı, S.; Özkan, O. E.; Gür, M. Synthesis and characterization of 1, 3, 4-thiadiazole compounds derived from 4-phenoxybutyric acid for antimicrobial activities. J. Mol. Struct. 2018, 1174, 151–159. doi: 10.1016/j.molstruc.2018.03.116

  9. [9]

     Sekhar, M. M.; Nagarjuna, U.; Padmavathi, V.; Padmaja, A.; Reddy, N. V.; Vijaya, T. Synthesis and antimicrobial activity of pyrimidinyl 1, 3, 4-oxadiazoles, 1, 3, 4-thiadiazoles and 1, 2, 4-triazoles. Eur. J. Med. Chem. 2018, 145, 1–10. doi: 10.1016/j.ejmech.2017.12.067

  10. [10]

      Gür, M.; Şener, N.; Muğlu, H.; Çavuş, M. S.; Özkan, O. E.; Kandemirli, F.; Şener, İ. New 1, 3, 4-thiadiazole compounds including pyrazine moiety: synthesis, structural properties and antimicrobial features. J. Mol. Struct. 2017, 1139, 111–118. doi: 10.1016/j.molstruc.2017.03.019

  11. [11]

      Güzeldemirci, N. U.; Küçükbasmacı, Ö. Synthesis and antimicrobial activity evaluation of new 1, 2, 4-triazoles and 1, 3, 4-thiadiazoles bearing imidazo[2, 1-b]thiazole moiety. Eur. J. Med. Chem. 2010, 45, 63–68. doi: 10.1016/j.ejmech.2009.09.024

  12. [12]

      Foroumadi, A.; Rineh, A.; Emami, S.; Siavoshi, F.; Massarrat, S.; Safari, F.; Rajabalian, S.; Falahati, M.; Lotfali, E.; Shafiee, A. Synthesis and anti-Helicobacter pylori activity of 5-(nitroaryl)-1, 3, 4-thiadiazoles with certain sulfur containing alkyl side chain. Bioorg. Med. Chem. Lett. 2008, 18, 3315–3320. doi: 10.1016/j.bmcl.2008.04.033

  13. [13]

      Luo, Y.; Zhang, S.; Liu, Z. J.; Chen, W.; Fu, J.; Zeng, Q. F.; Zhu, H. L. Synthesis and antimicrobical evaluation of a novel class of 1, 3, 4-thiadiazole: derivatives bearing 1, 2, 4-triazolo[1, 5-a]pyrimidine moiety. Eur. J. Med. Chem. 2013, 64, 54–61. doi: 10.1016/j.ejmech.2013.04.014

  14. [14]

      Serban, G. 2-Amino-1, 3, 4-thiadiazoles as prospective agents in trypanosomiasis and other parasitoses. Acta Pharm. 2020, 70, 259–290. doi: 10.2478/acph-2020-0031

  15. [15]

      Freitas, R. H. C. N.; Barbosa, J. M. C.; Bernardino, P.; Sueth-Santiago, V.; Wardell, S. M. S. V.; Wardell, J. L.; Decoté-Ricardo, D.; Melo, T. G.; da Silva, E. F.; Salomão, K.; Fraga, C. A. M. Synthesis and trypanocidal activity of novel pyridinyl-1, 3, 4-thiadiazole derivatives. Biomed. Pharmacother. 2020, 127, 110162. doi: 10.1016/j.biopha.2020.110162

  16. [16]

      Mojallal-Tabatabaei, Z.; Foroumadi, P.; Toolabi, M.; Goli, F.; Moghimi, S.; Kaboudanian-Ardestani, S.; Foroumadi, A. 2-(Bipiperidin-1-yl)-5-(nitroaryl)-1, 3, 4-thiadiazoles: synthesis, evaluation of in vitro leishmanicidal activity, and mechanism of action. Bioorg. Med. Chem. 2019, 27, 3682–3691. doi: 10.1016/j.bmc.2019.07.009

  17. [17]

      Lv, M.; Liu, G.; Jia, M.; Xu, H. Synthesis of matrinic amide derivatives containing 1, 3, 4-thiadiazole scaffold as insecticidal/acaricidal agents. Bioorg. Chem. 2018, 81, 88–92. doi: 10.1016/j.bioorg.2018.07.034

  18. [18]

      Al-Qahtani, A.; Siddiqui, Y. M.; Bekhit, A. A.; El-Sayed, O. A.; Aboul-Enein, H. Y.; Al-Ahdal, M. N. Inhibition of growth of Leishmania donovani promastigotes by newly synthesized 1, 3, 4-thiadiazole analogs. Saudi. Pharm. J. 2009, 17, 227–232. doi: 10.1016/j.jsps.2009.08.005

  19. [19]

      Pal, S.; Singh, V.; Kumar, R.; Gogoi, R. Design and development of 1, 3, 4-thiadiazole based potent new nano-fungicides. J. Mol. Struct. 2020, 1219, 128507. doi: 10.1016/j.molstruc.2020.128507

  20. [20]

      Omar, Y. M.; Abdel-Moty, S. G.; Abdu-Allah, H. H. M. Further insight into the dual COX-2 and 15-LOX anti-inflammatory activity of 1, 3, 4-thiadiazole-thiazolidinone hybrids: the contribution of the substituents at 5th positions is size dependent. Bioorg Chem. 2020, 97, 103657. doi: 10.1016/j.bioorg.2020.103657

  21. [21]

      Shen, F.; Hu, A. X.; Luo, X. F.; Ye, J.; Ou, X. M. Synthesis and bioactivity of (E)-2-benzylidenimino-4-(7-methoxy-2, 2-dimethyl-2, 3-dihydroben-zofuran-5-y1) thiazole. Chin. J. Org. Chem. 2012, 32, 388–392. doi: 10.6023/cjoc1108151

  22. [22]

      Zou, X. J.; Jin, G. Y.; Zhang, Z. X. Synthesis, fungicidal activity, and QSAR of pyridazinonethiadiazoles. J. Agric. Food Chem. 2002, 50, 1451−1454. doi: 10.1021/jf0109266

  23. [23]

      Chen, H.; Li, Z.; Han, Y. Synthesis and fungicidal activity against Rhizoctonia solani of 2-alkyl(alkylthio)-5-pyrazolyl-1, 3, 4-oxadiazoles (thiadiazoles). J. Agric. Food Chem. 2000, 48, 5312−5315. doi: 10.1021/jf991065s

  24. [24]

      Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–8.

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  Figure 1  Compound 1

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  Figure 2  Compound 2

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  Figure 3  Compound 3

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  Scheme 1  Preparation of compounds 8a-i

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  Figure 4  Crystal structure of compound 8a with atom labels

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  Figure 5  Hydrogen bonding diagram

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  Table 1.  Part of Bond Distances (Å) and Angles (°) of 8a

  Bond	Dist.		Bond	Dist.		Bond	Dist.
  C(7)–O(2)	1.3731(14)		C(12)–N(3)	1.3671(16)		C(1)–O(1)	1.4721(15)
  C(8)–O(1)	1.3634(14)		C(10)–S(1)	1.7293(13)		C(9)–O(2)	1.4090(14)
  C(11)–N(3)	1.3664(16)		C(11)–S(1)	1.7216(11)		C(3)–C(8)	1.3804(16)
  Angle	(°)		Angle	(°)		Angle	(°)
  O(1)–C(1)–C(17)	106.27(13)		O(1)–C(8)–C(3)	114.09(11)		C(11)–N(2)–N(1)	112.41(10)
  O(1)–C(1)–C(2)	104.95(10)		C(8)–C(3)–C(2)	107.37(11)		N(2)–C(11)–S(1)	114.36(9)
  C(3)–C(2)–C(1)	102.63(10)		C(10)–N(1)–N(2)	111.89(11)		C(11)–S(1)–C(10)	86.380(6)

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  Table 2.  Hydrogen Bond Distances and Angles of Compound 8a (Å and °)

  D–H···A	D–H	H···A	D···A	D–H···A
  N(3)–H(3)···N(2)i	0.80	2.10	2.9029(1)	177
  C(6)–H(6)···O(3)ii	0.93	2.63	3.4059(2)	141
  Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) −x+1, y+1/2, −z+3/2

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  Table 3.  Control Effect of Compounds 8 on Plant Pathogenic Bacteria (%, 200 mg/L)

  Sample	Pseudoperonospora c.		Colletrichum o.	Erysiphe g.
  Compound 8a		75	0	0
  Compound 8b		30	0	25
  Compound 8c		60	0	0
  Cyazofamid		100	0	0
  Azoxystrobin		100	100	100
  Other compounds were inactive

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