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Abstract

Objective: Plant pathogens are serious hazards to agricultural production, but existing drugs have problems such as increased resistance of pathogenic bacteria and environmental pollution, and there is a need to find high-efficiency, low-toxicity fungicides with novel chemical structures. Methods: 5-phenyl-1,3,4-thiadiazol-2-amine was used as the starting material, and 20 new thiadiazole-linked compounds were designed and synthesized. Their in vitro inhibitory activities against plant pathogenic fungi were tested using a mycelium growth inhibition assay, and the relationship between the antifungal activity of the target compounds and their molecular structures was preliminarily discussed. Results: Bioassay results revealed that most of the title compounds exhibited excellent in vitro fungicidal activity, in which compound D16 showed the highest activity against Rhizoctonia solani (EC₅₀= 0.0028 μmol·L⁻¹), D12 against Botrytis cinerea (EC₅₀= 0.0024 μmol·L⁻¹), and D5 against Stemphylium lycopersici and Curvularia lunata (EC₅₀= 0.0105 μmol·L⁻¹, 0.005 μmol·L⁻¹). The structure activity relationship (SAR) was also discussed and the results are of great significance for the structural optimization and development of more effective thiadiazole antibacterial compounds. Conclusion: The results of this study are important for structural optimization and development of more potent thiadiazole antimicrobial compounds.

Keywords

1 3 4-thiadiazole synthesis antimicrobial activity structure-activity relationship

Introduction

Phytopathogens have attracted the attention of global agricultural chemists because of their harmful effects on agricultural production. For example, phytopathogens can parasitize many important crops, thus inducing a variety of crop diseases and causing huge economic losses to global agricultural production every year.^1‐3 Compared with other control methods, chemical control has significant advantages, such as high efficiency, low cost, and convenient application. However, due to a large amount of abuse of existing agricultural antimicrobial agents caused by the increasing drug resistance of pathogens, drug control effects, environmental pollution, and other issues, the search for efficient, low-toxicity, and novel chemical structures of fungicides has become a research hotspot in the field of pesticide chemistry^.^4‐6

Nitrogen-containing heterocyclic compounds have become the research focus for new pesticides because of their diverse structural forms and broad-spectrum biological activities.^7,8 Most new heterocyclic compounds have low toxicity to mammals, birds, and fish, but high selectivity to pests and bacteria, which opens up a broad space for pesticide development. Among them, 1,3,4-thiadiazole derivatives are important five-membered heterocyclic compounds, which ‘C-N-S’ structure can chelate with metalions and have a wide range of pharmaceutical and pesticide activities. Commercialized 1,3,4-thiadiazolesinclude the antihypertensive drug tiodazosin, the agricultural fungicide thienone, bismerthiazol, and a novel antibacterial agent of 1,3,4-thiadiazole derivatives containing an amide moiety were designed.^9‐11 The active substructure splicing method is an effective method for discovering highly active pesticide molecules, which is helpful in achieving a synergistic effect between different pharmacophores.¹² 5-phenyl-1,3,4-thiadiazol-2-amine was used as the starting material. Based on the principle of active substructure splicing and condensation with benzoic acid to form the corresponding amide, phenyl 1,2,3-triazole was introduced into the amide bond through click chemistry, and 20 new thiadiazole-linked compounds were designed and synthesized (Figure 1). Their in vitro inhibitory activities against plant pathogenic fungi were tested using a mycelium growth inhibition assay, and the relationship between the antifungal activity of the target compounds and their molecular structures was preliminarily discussed.

Figure 1.

Design thiadiazole derivatives to achieve potential antibacterial activity.

Materials and Methods

General Information

All reagents used for the chemical synthesis were purchased from Xiya Reagent Company. The solvents were distilled before use. The progress of all reactions was monitored by thin layer chromatography (TLC), and the TLC plates were visualized by exposure to ultraviolet light (254 and 365 nm). The products were purified using column chromatography. All NMR spectra (¹H-NMR and ¹³C-NMR) were recorded on a Bruker AV-300 instrument, using CDCl₃ as the solvent and TMS as the internal standard. Chemical shifts are expressed in ppm and coupling constants in Hertz. All chemical shifts are given in parts per million relative to that of tetramethysilane. The mass spectra were measured using an HP1100LC instrument (Agilent Technologies, USA).

General Synthetic Procedures

General Procedure for the Synthesis of Compounds A1-A20

A stirring mixture of substrates benzoic acid (8.0 mmol), thiosemicarbazide (729.1 mg, 8.0 mmol) and POCl₃ (6 mL) was heated at 80 °C for 2.5 h. After cooling to room temperature, water (16 mL) was added. The reaction mixture was refluxed for 4 h. After cooling, the mixture was basified to pH 8 by dropwise addition of a 40% NaOH solution under stirring. The precipitate was filtered and recrystallized from ethanol to obtain the intermediate compound A as a white solid with a Yield of 81.1%-83%.

General Procedure for the Synthesis of Compounds B1-B20

To a solution of benzoic acid (122.1 mg, 1 mmol) in dichloromethane (DCM, 15 mL) the compounds A1-A20 (2.0 mmol), 1-Hydroxybenzotrizole (HOBt, 70.3 mg, 0.52 mmol), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 210.9 mg, 1.1 mmol), 4-Dimethylaminopyridine (DMAP, 134.4 mg, 1.1 mmol) and triethylamine (111.3 mg, 1.1 mmol) were added. The mixture was then stirred under nitrogen at room temperature for 16-24 h. When TLC showed completion of the reaction, the reaction mixture was poured into water and extracted with DCM. The organic phase was washed with 2% HCl and water and dried over anhydrous Na₂SO₄. Evaporation of the solvent yielded a residue that was purified by chromatography to yield the amide product. The yields of the purified compounds ranged between 41.0% and 74.5%.

General Procedure for the Synthesis of Compounds C1-C20

To a suspension of K₂CO₃ (207.3 mg, 1.5 mmol) in acetone (15 mL) was added a solution of appropriate compounds B1-B20 (1 mmol). After the reaction was heated to 60 °C for 30 min, a solution of propargyl bromide (142.8 mg, 1.2 mmol) in acetone (10 mL) was added in a drop wise manner and the mixture was refluxed for 3 h (monitored by TLC). The reaction mixture was poured into water, extracted with DCM, dried over anhydrousNa₂SO₄ and concentrated under vacuum, and purified by column chromatography to obtain the desired product. Yield: 74%-86%.

General Procedure for the Synthesis of Compounds D1-D20

In a round bottomed flask, compounds C1-C20 (1 mmol) were added to a mixture of CuSO₄·5H₂O (30 mg, 0.1 mmol), azidobenzene solution (119.1 mg, 1 mmol) and sodium ascorbate (13.3, 0.1 mmol) dissolved in1:1 of t-BuOH and H₂O (16 mL) at room temperature. The reaction mixture was stirred for 12 h at room temperature and then poured into water (20 mL). The aqueous layer was extracted thrice with DCM (10 mL). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford desired products D1-D20 in 74%-83.1% yield.

Bioassays

Antifungal activities of the title compounds in vitro was evaluated against five types of fungi (R. solani, B. cinerea, F. graminearum, S. lycopersici, C. lunata) by the typical mycelium growth inhibition method from previously reported method.^13‐15 A commercial fungicide (difenoconazole) was used as the positive control. Each compound was dissolved in dimethyl sulfoxide (DMSO) and mixed with sterile molten PDA to obtain a concentration of 50 mg/L for the initial preliminary screening with three replicates. The compounds with good activity were evaluated further by the determination of EC₅₀ values with the concentration gradients of 50, 12.5, 3.13, 0.78 mg/L, which were calculated using log-probit analysis via SPSS v.18.0 software.

The relative inhibition rate of the synthetic compounds was calculated via the following equation:

I = (C - T) / C \times 100 %

where I is the rate of inhibition (%), C is the diameter of mycelia in the blank control test (mm), and T is the diameter of mycelia in the presence of the tested compounds (mm).

Statistical Analyses

SPSS 18.0 software (IBM, Chicago Illinois, USA) is used for statistical analysis.

Results

Compound Design

Thiadiazole derivatives exhibit a wide variety of antibacterial activities.¹⁶ Therefore, many antibacterial compound designs have introduced thiadiazole.^17‐19 Consulting the literature, it was found that substituted 5-phenyl-1,3,4-thiadiazol-2-amine synthesizes derivatives with good antibacterial activity through condensation with acid to increase the lipophilic region of the phore. Amjad. Qandil et al synthesized 1,3,4-thiadiazole derivatives and tested their antimicrobial activities using the broth macrodilution method. The most potent member was compound 4c (Figure 1), showing selectivity to Gram-positive S. aureus at the minimum inhibitory concentration (MICs) (2 μg/mL).²⁰ Mali et al designed and synthesized a series of fatty acid-thiadiazole derivatives using a molecular hybridization approach. In vitro antimycobacterial potential was established by screening synthesized compounds against Mycobacterium tuberculosis H37Rv strain. Compound 5a (Figure 1) exhibited a minimum inhibitory concentration of 2.34 μg/mL against M.tb H37Rv.²¹ Benzotriazole can significantly enhance the activity of the compound owing to its single structure²²; therefore, this article is inspired by the above design to introduce benzotriazole into the thiadiazole amide structure to synthesize D1-D20.

Chemistry

The synthetic outlines of the starting and target compounds are shown in Figure 2. Compound A1-A20 were obtained by refluxing different substituted benzoic acids and POCl₃ for a period of time, and then adding a certain amount of water to continue the reflux reaction.²³ EDCI and DMAP were used as condensing agents to obtain target compounds B1-B20 through a condensation reaction.²³ Compounds B1-B20 and propargyl bromide generate compounds C1-C20 through a simple substitution reaction under basic conditions.²⁴ With a simple nucleophilic substitution and click chemistry, the final compounds D1-D20²⁴ were obtained and were structurally characterized by nuclear magnetic resonance hydrogen spectroscopy (¹H-NMR), nuclear magnetic resonance carbon spectroscopy (¹³C-NMR), and high-resolution mass spectrometry (HRMS) (Figure S1-S60).

Figure 2.

Synthetic route of target compounds. Reagents and conditions: (Ⅰ) POCl₃, reflux, 2.5 h; (Ⅱ) benzoic acid, EDC, DMAP, HOBt, DCM, r.t., 5 h; (Ⅲ) propargyl bromide, acetone, K₂CO₃; (Ⅳ)Ph-N₃, CuSO₄·5H₂O, sodium ascorbat, H₂O:t-BuOH = 1:1(V:V), rt.

Biological Assay

The fungicidal activities of all target compounds against five phytopathogenic fungi (Rhizoctonia solani, Botrytis cinerea, Stemphylium lycopersici, Curvularia lunata, Pythium aphanidermatum) were tested using an in vitro mycelium growth inhibition assay, and the commercial fungicide difenoconazole was used as the positive control. The synthetic compound thiadiazole was also used as a positive control to compare the difference between the pre-and post-structure optimizations. The inhibition of mycelial growth was evaluated by measuring colony diameters in the presence and absence of the tested compounds.

As shown in Table 1, most of the title compounds exhibited significant fungicidal activity; however, there were significant differences among the fungicidal activities of the target compounds. In particular, compounds D16, D13 and D10 showed pronounced fungicidal activities against R. solani with EC₅₀ values of 0.0028, 0.0079 and 0.0107 μmol·L⁻¹ respectively, D12 and D7 against B. cinerea with EC₅₀ values of 0.0024 and 0.0045 μmol·L⁻¹ respectively, D5 against S. lycopersici with EC₅₀ value of 0.0105 μmol L⁻¹, D5 and D13 against C. lunata with EC₅₀ values of 0.0051 and 0.0119 μmol·L⁻¹respectively, D14 against P. aphanidermatum with EC₅₀ value of 0.0180 μmol·L⁻¹. Based on the experimental results, EC₅₀ values of the target compounds were evaluated to conﬁrm their fungicidal effects on the five phytopathogenic fungi.

Table 1.

The Fungicidal Activity of Target Compounds Against Five Phytopathogenic Fungus.

Compound	R	EC₅₀ (95%Cl, μmol /L)
Compound	R	R. solani	B. cinerea	S. lycopersici	C. lunata	P. aphanidermatum
D1	2-F	0.0285 (0.0182-0.0444)	0.8424 (0.1543-4.5952)	0.1432 (0.0387-0.5306)	0.4226 (0.0982-1.8173)	—
D2	3-F	2.4311 (0.1997-29.5919)	—	0.0374 (0.0211-0.0663)	0.0237 (0.0151-0.0372)	—
D3	4-F	0.1297 (0.0556-0.3027)	7.7911 (0.2289-265.1846)	1.2300 (0.1343-11.2583)	—	—
D4	2-Cl	0.1586 (0.0671-0.3751)	1.2954 (0.1914-8.7661)	—	—	—
D5	3-Cl	0.0466 (0.0268-0.0807)	—	0.0105 (0.007-0.0159)	0.0051 (0.0033-0.0079)	0.1603 (0.0541-0.4748)
D6	4-Cl	0.0415 (0.0246-0.0699)	0.1422 (0.0514-0.3936)	1.0919 (0.1423-8.3788)	1.1636 (0.1493-9.0658)	0.7236 (0.1306-4.0105)
D7	2-Br	—	0.0045 (0.0028-0.0074)	—	—	0.2273 (0.0680-0.7604)
D8	4-Br	—	—	0.0590 (0.0248-0.1402)	0.0359 (0.0203-0.0634)	0.2717 (0.0918-0.8040)
D9	2-CH₃	0.1303 (0.0550-0.3089)	0.1169 (0.0499-0.2733)	1.8938 (0.2149-16.6890)	0.2065 (0.0740-0.5765)	—
D10	3-CH₃	0.0107 (0.0069-0.0167)	—	3.6669 (0.1942-69.2204)	0.3369 (0.0908-1.2504)	—
D11	4-CH₃	0.0328 (0.0212-0.0507)	0.9588 (0.1441-6.3798)	—	—	0.0334 (0.0198-0.0562)
D12	2-OCH₃	1.5904 (0.2144-11.7984)	0.0024 (0.0013-0.0046)	2.9342 (0.2294-37.5329)	0.4719 (0.1210-1.8401)	—
D13	3-OCH₃	0.0079 (0.0051-0.0121)	0.9994 (0.1209-8.2611)	0.0993 (0.0392-0.2517)	0.0119 (0.0077-0.0186)	0.0355 (0.0209-0.0605)
D14	4-OCH₃	0.0857 (0.0397-0.1852)	—	—	—	0.0180 (0.0111-0.0292)
D15	3-CF₃	0.0160 (0.0106-0.0241)	0.1465 (0.0482-0.4456)	0.0481 (0.0221-0.1047)	0.3058 (0.0805-1.1619)	0.0270 (0.0167-0.0437)
D16	4-CF₃	0.0028 (0.0015-0.0052)	—	0.0359 (0.0206-0.0625)	1.0790 (0.1881-6.1873)	1.9811 (0.1390-28.2328)
D17	2,4-DiCl	0.0547 （0.0279-0.1073）	0.0347 （0.0218-0.0551）	0.2990 （0.0888-1.0070）	0.2019 （0.0642-0.6351）	—
D18	2,6-DiF	0.0159 (0.0105-0.0242)	0.1419 (0.0470-0.4282)	8.2794 (0.2091-327.8576)	—	0.4482 (0.1076-1.8665)
D19	3,4-DiOCH₃	0.0181 (0.0114-0.0289)	0.1708 (0.0689-0.4232)	0.2725 (0.0762-0.9745)	0.0318 (0.0191-0.0532)	3.5046 (0.1622-75.7357)
D20	3,4,5-TriOCH₃	1.8869 (0.1760-20.2336)	0.1614 (0.0580-0.4492)	0.1054 (0.0305-0.3637)	0.0198 (0.0124-0.0306)	0.1971 (0.0591-0.6575)
Thiadiazole		0.1938 (0.0852-0.4406)	0.4975 (0.1725-1.4349)	0.2864 (0.1043-0.7869)	0.4597 (0.1926-1.0972)	0.3156 (0.1213-0.8211)
Difenoconazole		0.0019 (0.0009-0.0040)	0.0042 (0.0025-0.0073)	0.0124 (0.0084-0.0182)	0.0014 (0.0006-0.0034)	0.0001 (0.00002-0.0012)

Discussion

In summary, we designed and synthesized a series of derivatives and evaluated their antimicrobial activity against five pathogenic bacteria, R. solani, B. cinerea, S. lycopersici, C. lunata and P. aphanidermatum. As shown in results, the order of activity against R. solani was 3-CF₃> 4-OCH₃> 4-CH₃> 2,6-DiF > 4-CF₃> 2-F. Except for the meta-substitution activity of CF₃ and F, which was better than the para-substitution activity, the best activity of other element substitutions was the para-position, and the meta-substitution was better than the para-position. Only the presence of OCH₃ and Br substitutions had a good antibacterial effect against B. cinerea. Only the para-Cl substituted compound showed the same activity as the positive control drug against S. lycopersici.

Therefore, in the present study, a preliminary investigation of the potential antifungal activity of thiadiazole and its derivatives was carried out and the relationship between the antimicrobial effect and the moiety was explored, which is of positive significance for the future development of new fungicides that are more effective and environmentally friendly.

Due to various factors, this research is still at a relatively early stage and has many limitations. For example, we focused on the antibacterial aspect of plant pathogens, but although the compounds had antibacterial activity, they did not achieve the good results we expected, so we did not carry out subsequent research on the cellular level of plants and animals for the time being, and if the activity of the series of compounds is further improved in subsequent research, we will carry out cell-related experiments in the subsequent research.

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241304621 - Supplemental material for Design, Synthesis and Fungicidal Activity of N-(5-Phenyl-1,3,4-Thiadiazol-2-yl)-N-((1-Phenyl-1H-1,2,3-Triazol-4-yl) Methyl) Benzamide Derivatives

Supplemental material, sj-docx-1-npx-10.1177_1934578X241304621 for Design, Synthesis and Fungicidal Activity of N-(5-Phenyl-1,3,4-Thiadiazol-2-yl)-N-((1-Phenyl-1H-1,2,3-Triazol-4-yl) Methyl) Benzamide Derivatives by Ziyi Kong, Xinyu Zhang, Ming Bian and Danni Fu in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The authors declare that they haveno competing interests.

Ethical Approval

Ethical Approval is not applicable for this article.

Funding

This study was supported by the Inner Mongolia Natural Science Foundation Project (2019BS08016), and Inner Mongolia University for Nationalities Doctoral Research Initiation Fund (No.BS579).

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

ORCID iD

Ziyi Kong

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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Design,Synthesis and Fungicidal Activity of N-(5-Phenyl-1,3,4-Thiadiazol-2-yl)-N-((1-Phenyl-1 H -1,2,3-Triazol-4-yl) Methyl) Benzamide Derivatives

Abstract

Keywords

Introduction

Materials and Methods

General Information

General Synthetic Procedures

General Procedure for the Synthesis of Compounds A1-A20

General Procedure for the Synthesis of Compounds B1-B20

General Procedure for the Synthesis of Compounds C1-C20

General Procedure for the Synthesis of Compounds D1-D20

Bioassays

Statistical Analyses

Results

Compound Design

Chemistry

Biological Assay

Discussion

Supplemental Material

sj-docx-1-npx-10.1177_1934578X241304621 - Supplemental material for Design, Synthesis and Fungicidal Activity of N-(5-Phenyl-1,3,4-Thiadiazol-2-yl)-N-((1-Phenyl-1H-1,2,3-Triazol-4-yl) Methyl) Benzamide Derivatives

Footnotes

Declaration of Conflicting Interests

Ethical Approval

Funding

Statement of Human and Animal Rights

Statement of Informed Consent

ORCID iD

Supplemental Material

References

Supplementary Material