Synthesis and Bioactivity Evaluation of Novel Thiochroman-4-One Derivatives Incorporating Carboxamide and 1, 3, 4-Thiadiazole Thioether Moieties

Yu, Lu; Xiao, Lingling; Li, Pei; Chi, Jiyan; Li, Jie; Tan, Shuming

doi:https://doi.org/10.1155/2022/5354088

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Research Article | Open Access

Volume 2022 | Article ID 5354088 | https://doi.org/10.1155/2022/5354088

Synthesis and Bioactivity Evaluation of Novel Thiochroman-4-One Derivatives Incorporating Carboxamide and 1, 3, 4-Thiadiazole Thioether Moieties

Lu Yu,¹Lingling Xiao,¹Pei Li,^1,2Jiyan Chi,¹Jie Li,¹and Shuming Tan¹

Academic Editor: Ajaya Kumar Singh

Received11 Jan 2022

Accepted03 Feb 2022

Published26 Feb 2022

Abstract

A series of novel thiochroman-4-one derivatives incorporating carboxamide and 1, 3, 4-thiadiazole thioether moieties were synthesized. Bioassay results indicated that the EC₅₀ values of compound 6-chloro-N-(5-(methylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5a) against Xanthomonas oryzae pv. Oryzae (Xoo) and Xanthomonas axonopodis pv. Citri (Xac) were 24 and 30 μg/mL, respectively, which were even better than those of bismerthiazol and thiadiazole copper. Meanwhile, compound 6-methyl-4-oxo-N-(5-(propylthio)-1, 3, 4-thiadiazol-2-yl)thiochromane-2-carboxamide (5m) showed a better antifungal activity against Botrytis cinerea (B. cinerea), with an inhibition rate of 69%, than carbendazim. As far as we know, this is the first report on the antibacterial and antifungal activities of this series of novel thiochroman-4-one derivatives incorporating carboxamide and 1, 3, 4-thiadiazole thioether moieties.

1. Introduction

Global food safety/security will remain a worldwide concern for the next 50 years and beyond. Bacterial and fungal diseases of plants have been an enormous impact on the food safety/security at various stages of the food chain from primary production to consumption and have presented serious threats in agricultural production and caused enormous economic losses each year worldwide [1]. Although pesticide application has been a conventional methodology used in plant protection, frequent use of conventional chemical pesticides has resulted in problems in resistance to bacteria and fungi populations, environmental contamination, and human health [2]. With the improvement of human living standards and human health, the demand for high-quality agricultural products as foods makes it necessary to limit the use of conventional chemical pesticides and challenges the control of plant bacterial and fungal diseases [3]. Therefore, the current paradigm of relying almost exclusively on conventional chemical pesticides for bacterial and fungal diseases of plants control may need to be reconsidered.

Natural product pesticides of using innate disease-resistant plants against resist pests and diseases is an innovative stratagem in sustainable agricultural development because these pesticides are safer than the conventional chemical pesticides due to their low toxicity to natural enemies, humans, and other mammals [4–7]. Therefore, natural products can either be used directly in bacterial and fungal control or develop novel synthetic analogs with favorable biological properties. Thiochroman-4-one, an important natural product which is widely found in many plants, showed extensive bioactivities, including antifungal [8], herbicidal [9], insecticidal [10], and antibacterial [11–14] properties. In our previous study, we disclosed a series of novel thiochroman-4-one derivatives (Figure 1) which showed moderate to good antibacterial and antifungal activities [11–14].

(a)

(b)

(c)

(d)

(e)

The carboxamide moiety, an important functional group in pesticide chemistry, had attracted more and more attention to the researchers due to its broad spectrum of pesticidal bioactivities, for example, antibacterial [15, 16], antifungal [17, 18], antiviral [19–21], insecticidal [22, 23], and herbicidal [24] properties. Over the past few decades, many new pesticides containing carboxamide moiety, such as fluxapyroxad, penflufen, and isoflucypram, had been developed. Meanwhile, 1, 3, 4-thiadiazole thioether unit had played an important role in the field of agricultural chemistry, including antibacterial [16, 25], antifungal [26, 27], antiviral [28–31], insecticidal [32], and herbicidal [33] properties.

In view of these facts mentioned above, we aim to replace the benzene ring with a 1, 3, 4-thiadiazole thioether group (Figure 2) to build a series of novel thiochroman-4-one derivatives incorporating carboxamide and 1, 3, 4-thiadiazole thioether moieties, and then their in vitro antibacterial activity against Xanthomonas oryzae pv. Oryzae (Xoo) and Xanthomonas axonopodis pv. Citri (Xac) as well as antifungal activity against Verticillium dahliae (V. dahliae), Botrytis cinerea (B. cinerea), and Fusarium oxysporum (F. oxysporum) were determined.

2. Materials and Methods

2.1. Preparation Procedure of the Target Compounds 5a–5o

As shown in Scheme 1, the key intermediates 2 and 4 were prepared according to our previously reported literature [11–14, 16].

Intermediate 2 (0.022 mol), intermediate 4 (0.02 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 0.03 mol), dimethylaminopyridine (DMAP, 0.0002 mol), and N, N-dimethylformamide (DMF, 50 mL) were added to a 50 mL three-necked round-bottomed flask and then reacted overnight at room temperature. Upon completion, the reaction mixture was quenched by pouring into 100 mL distilled water. The residues were recrystallized from methanol to give the pure target compounds 5a–5o. The structures of the target compounds were characterized using a DRX-400 ¹H and ¹³C nuclear magnetic resonance (NMR; Bruker, Rheinstetten, Germany) and a Waters Xevo G2-S QTOF high-resolution mass spectrum (HRMS; Waters, MA, USA).

2.2. Bioactivity Evaluation

The antibacterial activity against Xoo and Xac and the antifungal activity against B. cinerea, V. dahliae, and F. oxysporum of the target compounds were determined according to the reported methods [34, 35]. Meanwhile, the EC₅₀ values of some of the target compounds against Xoo and Xac were also evaluated and calculated using SPSS 17.0 software.

3. Results and Discussion

3.1. Chemistry

Using different substituted thiols and 2-amino-5-mercapto-1, 3, 4-thiadiazole as the starting materials, as shown in Scheme 1, a series of novel thiochroman-4-one derivatives incorporating carboxamide and 1, 3, 4-thiadiazole thioether moieties were synthesized. The physical characteristics, ¹H NMR, ¹³C NMR, and HRMS data for all the target compounds are shown as follows. The ¹H NMR, ¹³C NMR, and HRMS spectra for all the target compounds can be found in the Supplementary Materials (available here).

Data for compound 6-chloro-N-(5-(methylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5a). White solid; mp 228–230°C; yield 67%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.99 (s, 1H, CONH), 7.90 (d, J = 4.0 Hz, 1H, Ph-H), 7.55 (dd, J1 = 4.0 Hz, J2 = 16.0 Hz, 1H, Ph-H), 7.39 (d, J = 8.0 Hz, 1H, Ph-H), 4.46 (t, J = 4.0 Hz, 1H, SCH), 3.23 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂), 2.68 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.17, 169.58, 161.60, 158.42, 136.53, 133.80, 130.88, 129.91, 127.22, 41.12, 40.41, 16.48; HRMS (ESI) [M + Na]⁺ calcd. for C₁₃H₁₀ClN₃O₂S₃: 369.95509, found 369.95619.

Data for compound 6-chloro-N-(5-(ethylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5b). White solid; mp 236–237°C; yield 60%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 13.00 (s, 1H, CONH), 7.90 (d, J = 4.0 Hz, 1H, Ph-H), 7.55 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, Ph-H), 7.39 (d, J = 8.0 Hz, 1H, Ph-H), 4.47 (t, J = 4.0 Hz, 1H, SCH), 3.31–3.15 (m 4H, CH₂, CH₂CH₃), 1.31 (t, J = 8.0 Hz, 3H, CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.16, 169.61, 159.86, 158.74, 136.52, 133.80, 131.77, 130.89, 129.91, 127.22, 41.10, 40.41, 28.59, 15.17; HRMS (ESI) [M + Na]⁺ calcd. for C₁₄H₁₂ClN₃O₂S₃: 383.97074, found 383.97183.

Data for compound 6-chloro-4-oxo-N-(5-(propylthio)-1, 3, 4-thiadiazol-2-yl)thiochromane-2-carboxamide (5c). White solid; mp 191–193°C; yield 58%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 13.00 (s, 1H, CONH), 7.90 (d, J = 4.0 Hz, 1H, Ph-H), 7.55 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, Ph-H), 7.39 (d, J = 8.0 Hz, 1H, Ph-H), 4.46 (t, J = 4.0 Hz, 1H, SCH), 3.31–3.14 (m, 4H, CH₂, CH₂CH₂CH₃), 1.71–1.62 (m, 2H, CH₂CH₂CH₃), 0.95 (t, J = 8.0 Hz, 3H, CH₂CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.19, 169.68, 159.96, 158.88, 136.59, 133.80, 131.78, 130.86, 129.91, 127.22 41.17, 40.41, 36.03, 22.86, 13.37; HRMS (ESI) [M-H]⁺ calcd. for C₁₅H₁₄ClN₃O₂S₃: 397.98639, found 397.98782.

Data for compound N-(5-(benzylthio)-1, 3, 4-thiadiazol-2-yl)-6-chloro-4-oxothiochromane-2-carboxamide (5d). White solid; mp 234–235°C; yield 69%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 13.00 (s, 1H, CONH), 7.90 (d, J = 4.0 Hz, 1H, Ph-H), 7.55 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, Ph-H), 7.44–7.38 (m, 3H, Ph-H), 7.13 (t, J = 8.0 Hz, 2H, Ph-H), 4.47 (d, J = 4.0 Hz, 3H, SCH, PhCH₂), 3.23 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.19, 163.16, 160.74, 159.26, 159.03, 136.54, 133.81, 133.45, 133.43, 131.76, 131.47, 131.39, 130.89, 129.91, 127.23, 115.91, 115.70, 41.17, 40.41, 37.13; HRMS (ESI) [M + Na]⁺ calcd. for C₁₉H₁₄ClN₃O₂S₃: 465.98289, found 465.99061.

Data for compound 6-chloro-N-(5-((4-fluorobenzyl)thio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5e). White solid; mp 220–222°C; yield 62%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.99 (s, 1H, CONH), 7.90 (d, J = 4.0 Hz, 1H, Ph-H), 7.55 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, Ph-H), 7.43–7.38 (m, 3H, Ph-H), 7.16–7.11 (m, 2H, Ph-H), 4.46 (d, J = 8.0 Hz, 3H, SCH, PhCH₂), 3.22 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.19, 169.63, 161.95 (d, J = 242.0 Hz), 159.05, 136.53, 133.82, 133.45 (d, J = 3.0 Hz), 131.76, 131.48, 131.39, 130.89, 129.92, 127.23, 115.86 (d, J = 5.0 Hz), 41.13, 40.41, 37.12; HRMS (ESI) [M-H]⁺ calcd. for C₁₉H₁₃ClFN₃O₂S₃: 463.97697, found 463.97829.

Data for compound 6-fluoro-N-(5-(methylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5f). White solid; mp 220–222°C; yield 62%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.98 (s, 1H, CONH), 7.69 (d, J = 8.0 Hz, 1H, Ph-H), 7.41 (d, J = 4.0 Hz, 2H, Ph-H), 4.45 (s, 1H, SCH), 3.23 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂), 2.68 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.37, 169.63, 161.81, 161.56, 158.91 (d, J = 95.0 Hz), 133.13, 132.11, 132.05, 130.14 (d, J = 7.0 Hz), 121.83 (d, J = 23.0 Hz), 113.98 (d, J = 23.0 Hz), 41.13, 40.40, 16.47; HRMS (ESI) [M-H]⁺ calcd. for C₁₃H₁₀FN₃O₂S₃: 353.98464, found 353.98612.

Data for compound N-(5-(ethylthio)-1, 3, 4-thiadiazol-2-yl)-6-fluoro-4-oxothiochromane-2-carboxamide (5g). White solid; mp 261–262°C; yield 76%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.98 (s, 1H, CONH), 7.70–7.67 (m, 1H, Ph-H), 7.41 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 2H, Ph-H), 4.45 (t, J = 4.0 Hz, 1H, SCH), 3.30–3.15 (m, 4H, CH₂, CH₂CH₃), 1.30 (t, J = 4.0 Hz, 3H, CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 196.11, 174.39, 172.91, 165.57 (d, J = 198.0 Hz), 164.13, 163.53, 137.88, 137.86, 136.82 (d, J = 6.0 Hz), 134.91 (d, J = 7.0 Hz), 126.61 (d, J = 23.0 Hz), 118.73 (d, J = 17.0 Hz), 45.85, 40.41, 33.34, 19.93; HRMS (ESI) [M + Na]⁺ calcd. for C₁₄H₁₂FN₃O₂S₃: 391.99678, found 391.99632.

Data for compound 6-fluoro-4-oxo-N-(5-(propylthio)-1, 3, 4-thiadiazol-2-yl)thiochromane-2-carboxamide (5h). White solid; mp 226–228°C; yield 70%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.98 (s, 1H, CONH), 7.69 (d, J = 8.0 Hz, 1H, Ph-H), 7.41 (t, J = 4.0 Hz, 2H, Ph-H), 4.44 (t, J = 4.0 Hz, 1H, SCH), 3.30–3.14 (m, 4H, CH₂, CH₂CH₂CH₃), 1.67 (m, 2H, CH₂, CH₂CH₂CH₃), 0.95 (t, J = 8.0 Hz, 3H, CH₂CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.37, 169.67, 160.91 (d, J = 179.0 Hz), 159.38, 133.14 (d, J = 3.0 Hz), 132.06 (d, J = 6.0 Hz), 130.15 (d, J = 8.0 Hz), 121.97, 121.74, 114.09, 113.86, 41.10, 40.41, 36.02, 22.85, 13.36; HRMS (ESI) [M-H]⁺ calcd. for C₁₅H₁₄FN₃O₂S₃: 382.01594, found 382.01732.

Data for compound N-(5-(benzylthio)-1, 3, 4-thiadiazol-2-yl)-6-fluoro-4-oxothiochromane-2-carboxamide (5i). White solid; mp 212–214°C; yield 73%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.99 (s, 1H, CONH), 7.69 (d, J = 8.0 Hz, 1H, Ph-H), 7.41–7.23 (m, 7H, Ph-H), 4.44 (t, J = 4.0 Hz, 3H, SCH, PhCH₂), 3.22 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.40, 169.66, 160.60 (d, J = 243.0 Hz), 159.24, 159.12, 137.05, 133.14, 132.08, 130.16 (d, J = 7.0 Hz), 129.38, 129.01, 128.04, 121.86 (d, J = 23.0 Hz), 113.99 (d, J = 22.0 Hz), 41.14, 40.40, 38.01; HRMS (ESI) [M-H]⁺ calcd. for C₁₉H₁₄FN₃O₂S₃: 430.01594, found 430.01700.

Data for compound 6-fluoro-N-(5-((4-fluorobenzyl)thio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5j). White solid; mp 225–227°C; yield 70%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.98 (s, 1H, CONH), 7.68 (d, J = 8.0 Hz, 1H, Ph-H), 7.42 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 4H, Ph-H), 7.13 (t, J = 8.0 Hz, 2H, Ph-H), 4.44 (t, J = 4.0 Hz, 3H, SCH, PhCH₂), 3.22 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.19, 169.63, 161.95 (d, J = 242.0 Hz), 159.05, 136.53, 133.82, 133.45 (d, J = 3.0 Hz), 131.76, 131.48, 131.39, 130.89, 129.92, 127.23, 115.81 (d, J = 22.0 Hz), 41.13, 40.41, 34.12; HRMS (ESI) [M-H]⁺ calcd. for C₁₉H₁₃F₂N₃O₂S₃: 448.00652, found 448.00777.

Data for compound 6-methyl-N-(5-(methylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5k). White solid; mp 269–270°C; yield 79%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.94 (s, 1H, CONH), 7.79 (s, 1H, Ph-H), 7.30 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, Ph-H), 7.20 (d, J = 8.0 Hz, 1H, Ph-H), 4.41 (t, J = 4.0 Hz, 1H, SCH), 3.17 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂); 2.67 (s, 3H, CH₃), 2.29 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 192.17, 169.72, 161.46, 158.44, 135.61, 135.03, 134.10, 130.34, 128.29, 127.68, 41.19, 40.41, 20.83, 16.47; HRMS (ESI) [M-H]⁺ calcd. for C₁₄H₁₃N₃O₂S₃: 350.00971, found 350.01051.

Data for compound N-(5-(ethylthio)-1, 3, 4-thiadiazol-2-yl)-6-methyl-4-oxothiochromane-2-carboxamide (5l). White solid; mp 227–228°C; yield 76%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.97 (s, 1H, CONH), 7.80 (s, 1H, Ph-H), 7.30 (dd, J1 = 4.0 Hz, J2 = 8.0 Hz, 1H, Ph-H), 7.20 (d, J = 8.0 Hz, 1H, Ph-H), 4.42 (t, J = 4.0 Hz, 1H, SCH), 3.25–3.11 (m, 4H, CH₂, CH₂CH₃), 2.30 (s, 3H, CH₃), 1.31 (t, J = 8.0 Hz, 3H, CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 192.16, 169.77, 159.70, 158.84, 135.60, 135.03, 134.11, 130.33, 128.29, 127.67, 41.20, 40.41, 28.59, 20.83, 15.18; HRMS (ESI) [M-H]⁺ calcd. for C₁₅H₁₅N₃O₂S₃: 364.02536, found 364.02620.

Data for compound 6-methyl-4-oxo-N-(5-(propylthio)-1, 3, 4-thiadiazol-2-yl)thiochromane-2-carboxamide (5m). White solid; mp 198–200°C; yield 72%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 13.00 (s, 1H, CONH), 7.90 (d, J = 4.0 Hz, 1H, Ph-H), 7.39 (d, J = 8.0 Hz, 1H, Ph-H), 4.46 (t, J = 4.0 Hz, 1H, SCH), 3.31–3.14 (m, 4H, CH₂, CH₂CH₂CH₃), 2.29 (s, 3H, CH₃), 1.69–1.64 (m, 2H, CH₂CH₂CH₃), 0.95 (t, J = 8.0 Hz, 3H, CH₂CH₂CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 191.19, 169.68, 159.96, 158.88, 136.59, 133.80, 131.78, 130.86, 129.91, 127.22, 41.17, 40.41, 39.57, 36.03, 22.86, 13.37; HRMS (ESI) [M-H]⁺ calcd. for C₁₅H₁₄ClN₃O₂S₃: 397.98639, found 397.98782.

Data for compound N-(5-(benzylthio)-1, 3, 4-thiadiazol-2-yl)-6-methyl-4-oxothiochromane-2-carboxamide (5n). White solid; mp 224–226°C; yield 76%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.94 (s, 1H, CONH), 7.79 (s, 1H, Ph-H), 7.43–7.11 (m, 7H, Ph-H), 4.45 (s, 2H, PhCH₂), 4.41 (s, 1H, SCH), 3.17 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂), 2.29 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 192.19, 169.80, 159.13, 158.92, 137.07, 135.62, 134.11, 133.48, 131.39, 130.32, 129.37, 129.02, 128.31, 128.04, 127.68, 115.92, 115.70, 41.23, 38.02, 37.14, 20.83; HRMS (ESI) [M + Na]⁺ calcd. for C₂₀H₁₇N₃O₂S₃: 450.03751, found 450.03614.

Data for compound N-(5-((4-fluorobenzyl)thio)-1, 3, 4-thiadiazol-2-yl)-6-methyl-4-oxothiochromane-2-carboxamide (5°). White solid; mp 230–232°C; yield 76%; ¹H NMR (400 MHz, DMSO-d₆, ppm) δ: 12.97 (s, 1H, CONH), 7.79 (s, 1H, Ph-H), 7.38 (dd, J1 = 8.0 Hz, J2 = 16.0 Hz, 4H, Ph-H), 7.30 (d, J = 8.0 Hz, 1H, Ph-H), 7.20 (d, J = 8.0 Hz, 1H, Ph-H), 4.45 (s, 2H, PhCH₂), 4.41 (t, J = 4.0 Hz, 1H, SCH), 3.17 (qd, J1 = 4.0 Hz, J2 = 16.0 Hz, 2H, CH₂), 2.29 (s, 3H, CH₃); ¹³C NMR (100 MHz, DMSO-d₆, ppm) δ: 192.19, 169.80, 159.04 (d, J = 50.0 Hz), 136.42, 135.61, 135.05, 134.11, 132.60, 131.23, 128.96, 128.30, 127.68, 41.21, 37.13, 20.83; HRMS (ESI) [M + Na]⁺ calcd. for C₂₀H₁₆FN₃O₂S₃: 468.09808, found 468.09825.

3.2. Bioassay Activity Test

As shown in Table 1, compounds 5a–5g displayed 74–100% and 60–94% in vitro antibacterial activity against Xoo at 200 and 100 μg/mL, respectively, which were better than those of bismerthiazol and thiadiazole copper. Meanwhile, compounds 5a–5h revealed 60–90% and 48–78% in vitro antibacterial activity against Xac at 200 and 100 μg/mL, respectively, which were better than those of bismerthiazol and thiadiazole copper. Table 2 shows that the EC₅₀ values of compounds 5a, 5b, 5c, 5f, and 5g against Xoo and Xac were 24–54 and 30–61 μg/mL. In particular, compound 6-chloro-N-(5-(methylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5a) had the lowest EC₅₀ values against Xoo (24 μg/mL) and Xac (30 μg/mL) than bismerthiazol and thiadiazole copper. The structure-activity relationship (SAR) analysis was analyzed on the basis of the antibacterial activity values shown in Tables 1 and 2. First, compared with the same substituent at R₁ substituent groups, the presence of the –Cl group at R₂ substituent group showed better in vitro antibacterial activity in the order of 5a > 5f and 5b > 5g. Second, compared with the same substituent at R₂ substituent group, the –CH₃ at R₁ substituent group could cause an increase in the antibacterial activity followed the order 5a > 5b and 5f > 5g.

The preliminary antifungal activity results at 50 μg/mL (Table 3) showed that compound 5m displayed a favorable antifungal activity (69%) than carbendazim against B. cinerea. Meanwhile, compound 6-methyl-4-oxo-N-(5-(propylthio)-1, 3, 4-thiadiazol-2-yl)thiochromane-2-carboxamide (5m) revealed the best antifungal activity against V. dahliae (54%) and F. oxysporum (40%), and it was still lower than that of carbendazim. The SAR analysis was analyzed on the basis of the antifungal activity values shown in Table 3. First, compared with the same substituent at R₁ substituent groups, the presence of the –CH₃ group at the R₂ substituent group showed better in vitro antifungal activity in the order of 5m > 5h and 5l > 5g. Second, compared with the same substituent at the R₂ substituent group, the –CH₂CH₂CH₃ at the R₁ substituent group could cause an increase in the antifungal activity following the order 5m > 5l > 5k and 5h > 5g > 5f.

4. Conclusion

In conclusion, a total of 15 novel thiochroman-4-one derivatives incorporating carboxamide and 1, 3, 4-thiadiazole thioether moieties were synthesized. Bioassay results showed that compound 6-chloro-N-(5-(methylthio)-1, 3, 4-thiadiazol-2-yl)-4-oxothiochromane-2-carboxamide (5a) revealed the best antibacterial activity against Xoo and Xac. Meanwhile, 6-methyl-4-oxo-N-(5-(propylthio)-1, 3, 4-thiadiazol-2-yl)thiochromane-2-carboxamide (5m) showed a better antifungal activity against B. cinerea. This study demonstrated that this series of thiochroman-4-one derivatives incorporating carboxamide and 1, 3, 4-thiadiazole thioether moieties can be used to develop potential agrochemicals.

Data Availability

All data included in this study are available upon request by contact with the corresponding author.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

The authors Lu Yu and Lingling Xiao contributed equally to the article.

Acknowledgments

This research was funded by the National Natural Science Foundation of China (grant no. 32102267), Science and Technology Foundation of Guizhou Province (grant numbers ZK[2021]137 and [2020]1Y130), and Kaili University Doctoral Program (grant no. BS201811).

Supplementary Materials

The supporting information contained 1H NMR, ¹³C NMR, and HRMS spectra for all the target compounds 5a–5o. (Supplementary Materials)

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Copyright © 2022 Lu Yu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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