Synthesis,Characterization, and Herbicidal Activities of New 1,3,4‐Oxadiazoles, 1,3,4‐Thiadiazoles,and 1,2,4‐Triazoles Derivatives Bearing (R)‐5‐Chloro‐3‐fluoro‐2‐phenoxypyridine

Synthesis of some novel 1,2,4‐triazoles, 1,3,4‐oxadiazoles and 1,3,4‐thiadiazoles bearing a (R) 5‐(1‐(4‐(5‐chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl) unit, as a moiety of commercial herbicide, using their thiosemicarbazides in an alkaline, iodine and acidic media is reported, respectively. The structure of the synthesized compounds was characterized by IR, ¹H, ¹³C NMR spectroscopic data, and elemental analyses. The herbicidal activities of synthesized compounds were evaluated against Echinochloa cruss‐galli, Avena fatua, and Sorgum halepense weeds. Compounds 7 and 12a showed potential herbicidal activity against gramineous weeds. Our results may provide some guidance for synthesis development of some novel oxa or thiadiazole and triazole‐based herbicidal lead structures.     

Design,Synthesis, and Biological Evaluation of Novel 1,3,4‐Thiadiazolylpyrazolines Compounds Containing Ferrocene

The synthesis of 1,3,4‐thiadiazole skeleton compounds exhibiting high fungicidal activities has been demonstrated. Thirteen novel 1,3,4‐thiadiazolyl‐pyrazolines compounds containing ferrocene were designed and synthesized from the ferrocenylchalcones intermediates 3a – 3m and the 2‐hydrazino‐5‐phenyl‐1,3,4‐thiadiazole intermediate 8 . All compounds were characterized by ¹H NMR, ¹³C NMR, FT‐IR spectra, and HR‐MS, and the structure of one of the new compounds N‐(4‐phenyl‐1,3,4‐thiadiazol‐2‐yl)‐3‐ferrocenyl‐5‐phenyl‐pyrazoline 9a was further determined by X‐ray diffraction analysis. The preliminary results of a biological activity assay indicated that all the title compounds exhibited significant fungicidal activities against Pythium solani, Gibberella saubinetii, and Gibberella nicotiancola. Furthermore, compounds 9e and 9h displayed even higher fungicidal activities against the three fungal species compared with the control drug pyraclostrobin.     

Synthesis and Herbicidal Activities of Sulfonylureas Bearing 1,3,4‐Thiadiazole Moiety

In this article, we report the synthesis and herbicidal activities of sulfonylureas bearing the 1,3,4‐thiadiazole moiety. The target compounds 9a , 9b , 9c , 9d , 9e , 9f , 9g , 9h , 9i , 9j , 9k , 9l were synthesized using 2‐hydrazinocarbonyl benzenesulfonamide ( 4 ) and phenyl pyrimidinecarbamates as starting materials. The key intermediate, 2‐(4,5‐dihydro‐5‐thioxo‐1,3,4‐thiadiazol‐2‐yl)benzenesulfonamide ( 5 ), was prepared from 4 and CS₂ via a conventional method or an improved method. The improved method, in which sulfonamido group acts as a directing group for the cyclization reaction, is more concise and efficient. The structures of the target compounds were determined by IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analysis. Their herbicidal activities were screened by Petri dish tests and pot tests. As the results, sulfonylureas 9h and 9j inhibited Brassica napus, Amaranthus retroflexus, and Echinochloa crusgalli at the 15 g/ha level, which is at the same level as azimsulfuron. Moreover, the safety tests showed that 9j was safe to wheat at dosage of 60 g/ha and might develop further into a herbicide in wheat field.     

Synthesis and Herbicidal Activity of Acylpyrazole Derivatives Containing 1,2,3‐Thiadiazole Moiety

A series of novel acylpyrazole derivatives containing 1,2,3‐thiadiazole ring 3a – 3m were synthesized by the condensations of 1‐phenyl‐3‐methyl‐4‐(substituted benzal or 4‐methyl‐1,2,3‐thiadiazole‐5‐carbonyl)‐5‐hydroxypyrazole 2 with 4‐methyl‐1,2,3‐thiadiazole‐5‐carbonyl chloride or substituted benzoyl chloride. Their structures were confirmed by IR, ¹H‐NMR, mass spectroscopy, and elemental analyses. The results of preliminary bioassays showed that some of the title compounds 3 exhibited moderate to good herbicidal activities against dicotyledonous plants (Brassica campestris L.) at the concentration of 100 mg/L. For example, compounds 3e , 3f , 3g , and 3k possessed 74.6%, 72.2%, 70.3%, and 84.5% inhibition against B. campestris L., respectively, whereas commercially available herbicide Sulcotrione showed only 35.0% inhibition at the same concentration. Moreover, these compounds displayed higher herbicidal activity against B. campestris L. than Echinochloa crus‐galli. However, these compounds showed weak activities at the concentration of 10 mg/L.     

Novel Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives: Synthesis,Characterization, Molecular Docking Study,and Investigation of Their In Vitro Antifungal Activities

In this study, a new series of substituted imidazo[2,1‐b][1,3,4]thiadiazole derivatives were synthesized. To this end, first 2‐amino‐1,3,4‐thiadiazole derivatives (compounds 2a and 2b ), the starting materials, were synthesized with high yields (82% and 79%, respectively). Then imidazo[2,1‐b][1,3,4]thiadiazole derivatives ( 4 – 16 ), the target compounds, were synthesized from reactions of 2‐amino‐1,3,4‐thiadiazole derivatives ( 2a and 2b ) with 2‐bromoacetophenone derivatives ( 3a – 3i ) (in yields of 52% to 71%). All of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, Fourier transform infrared, elemental analysis, mass spectroscopy, and X‐ray diffraction analysis (compounds 4 – 12 , 14 , and 15 ) techniques. In vitro antifungal activity tests were performed for all of the synthesized compounds. Inhibition zones, percentage of inhibition, minimum fungicidal activity, minimum inhibitory concentration, and lethal dose values of the target compounds were determined against some plant pathogens. According to the results of the biological activity tests, all of the synthesized compounds showed moderate to high levels of antifungal activity. Theoretical calculations were performed to support the experimental results. The geometric parameters of selected compounds ( 5 , 6 , and 8 ) were optimized using the density functional theory B3LYP/6‐31G(d) method in the Gaussian 09W package program, and the frontier molecular orbitals (highest occupied molecular orbital–lowest unoccupied molecular orbital) were calculated theoretically. Finally, molecular docking studies were performed for antifungal activity studies of the selected compounds and to determine whether or not these compounds could be inhibitor agents for the 2RKV protein structure.     

New 1,3,4‐Thiadiazole Derivatives: Synthesis,Characterization, and Antimicrobial Activity

In the present study, 2,5‐bis(mercapto‐acetichydrazide)‐1,3,4‐thiadiazole ( 1 ) was utilized by different reagents, namely, ethoxymethylene malononitrile, ethoxymethylene ethyl cyanoacetate, triethyl orthoformate, phenyl isothiocyanate, carbon disulfide, isatin, acetophenone, cyclohexanone, different aldehydes, and different anhydrides, to yield a new series of 2,5‐disubstituted‐1,3,4‐thiadiazoles 2 – 18 . The chemical structure of these products was characterized by the spectral data IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analysis. All the synthesized compounds were screened for their antibacterial activity.     

Synthesis,Antimicrobial, and Antioxidant Activities of Some Fused Heterocyclic [1,2,4]Triazolo[3,4‐b][1,3,4]thiadiazole Derivatives

In the present work, we synthesized a series of [1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole derivatives ( 6a , 6b , 6c , 6d , 6e , 6f and 7a , 7b , 7c , 7d , 7e , 7f ) by using simple starting materials, namely, β‐amino acids and different aromatic acid hydrazides. The newly synthesized compounds were characterized by mass, IR, ¹H, and¹³C‐NMR spectral data analysis. The newly synthesized compounds were tested for their antimicrobial activities and antioxidant properties. Compound 6c was a potent microbial agent particularly against Staphylococcus aureus (MIC 3.12 µg/mL) and Candida albicans (MIC 6.25 µg/mL) when compared with the reference drugs ciprofloxacin and fluconazole, respectively. The antioxidant activity of the synthesized compounds was also evaluated by 1,1‐diphenyl‐2‐picryl hydrazyl, nitric oxide, and hydrogen peroxide radical scavenging methods. Compounds 6c , 6f , 7c , and 7f showed good radical scavenging activity due to the presence of electron‐donating group on phenyl ring.     

Synthesis and Fluorescent Properties of 2‐Arylamino‐5‐(3‐Aryl‐1‐Phenyl‐Pyrazol‐4‐Yl)‐1,3,4‐Thiadiazoles

A series of novel pyrazolyl‐substituted 1,3,4‐thiadiazole derivatives ( 6a‐6d, 7a‐7d, 8a‐8d ) were prepared by cyclization of the intermediate 3‐aryl‐l‐phenyl‐pyrazol‐4‐ylformaldehyde 4′‐phenylthiosemicarbazones with 0.5 M ferric chloride solution. The structures of the new compounds were confirmed by IR, ¹H NMR and elemental analysis. Simultaneously, the compounds were detected by fluorescence spectrophotometer and had preferable fluorescence activity.     

Synthesis of Some Novel Pyrido[2,3‐d]pyrimidine and Pyrido[3,2‐e][1,3,4]triazolo and Tetrazolo[1,5‐c]pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

A novel series of pyrido[2,3‐d]pyrimidines 3a – d , 4a – d , 5a – d , 6a – d , and 7a – d ; pyrido[3,2‐e][1,3,4]triazolo; and tetrazolo[1,5‐c]pyrimidines 10a – d and 11a – d was synthesized through different chemical reactions starting from 2‐amino‐3‐cyano‐4,6‐diarylpyridines. The newly synthesized heterocycles were characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral data. Compounds have been screened for their antibacterial and antifungal activities. The data showed that the presence of electron‐donating group such as p‐methoxyphenyl increases the antimicrobial activity. Also, the compounds have shown anticancer activity for colon and liver cancer cells.     

Synthesis and Herbicidal Activity of Novel 4‐Acyl‐2,5‐disubstituted‐3‐hydroxypyrazoles and 4‐Arylcarbonyl‐3‐substitutedisoxazol‐5‐ones

Two series of novel 4‐acyl‐2,5‐disubstituted‐3‐hydroxypyrazoles 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h and 4‐arylcarbonyl‐3‐substitutedisoxazol‐5‐ones 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i were synthesized by the Scotton–Baumann reaction of 2,5‐disubstituted‐2,4‐dihydro‐pyrazol‐3‐ones 1 or 3‐substituted‐4H‐isoxazol‐5‐ones 6 and various acyl chlorides, followed by the Fries rearrangement in the presence of calcium hydroxide and calcium oxide as the catalyst. Their structures were confirmed by IR, ¹H NMR, mass spectroscopy, and elemental analyses. ¹H NMR indicated that compounds 3 existed in enol forms and compounds 7 in keto configurations. The results of preliminary bioassays showed that some of the title compounds 3 and 7 exhibited moderate to good herbicidal activities against Brassica campestris L. at the concentration of 100 mg/L. Isoxazole compounds 7 showed better herbicidal activity against B. campestris L. than pyrazole compounds 3 did at the concentration of 100 mg/L. Moreover, most of the isoxazole compounds displayed higher herbicidal activity against B. campestris L. than Echinochloa crus‐galli. However, these compounds showed weak herbicidal activities at the concentration of 10 mg/L.     

Design,Synthesis and Antiproliferative Activities of Diaryl Thiourea Derivatives as Anticancer Agents

Two new series of diaryl thiourea containing sorafenib derivatives 9a – 9t were designed and synthesized, and their antiproliferative activities against PC‐3, HCT116 and MDA‐MB‐231 cell lines were evaluated. All compounds generally showed antiproliferative activity to PC‐3 cells, most of the analogs exhibited potent antiproliferative activity to HCT116 cells, and compounds 9e , 9f , 9o and 9p demonstrated inhibitory activities against all three cell lines. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

Synthesis and Biological Evaluation of Some Heterocyclic Compounds from Salicylic Acid Hydrazide

Different heterocyclic compounds were prepared starting from 2‐hydroxy benzohydrazide; for example, cyclization of hydrazide hydrazone 3 derived from 2‐hydroxybenzohydrazide 2 with acetic anhydride or concentrated sulfuric acid gave 1,3,4‐oxadiazole derivatives 4 – 5 . On the other hand, direct cyclization of 2‐hydroxy benzohydrazide 2 with one carbon cyclizing agent gave a new derivative of 1,3,4‐oxadiazole 7 , 8 , 9 , 10 , 11 . Heating of hydrazide hydrazone 3 with thioglycolic acid in pyridine gave thiazolidinone 12 . When 2‐hydroxy benzohydrazide 2 reacted with aliphatic carboxylic acids such as formic acid or acetic acid, it gave the corresponding N‐formyl or N‐acetyl derivatives 6 . Subsequent cyclization of 6 using phosphorous pentasulphide in pyridine gave 1,3,4‐thiadiazoles 13 . Cyclization of 2‐hydroxy benzohydrazide with ethyl acetoacetate gives pyrazolone derivative 14 . Finally, when an ethanolic solution of acid hydrazide 2 was treated with ammonium thiocyanate in 35% HCl, it gave the thiosemicarbazide 15 . Subsequent treatment of 15 with concentrated sulfuric acid or 10% sodium hydroxide gave 5‐amino‐1,3,4‐thiadiazole 16 and 1,2,4‐triazole 17 , respectively. The structures of all newly isolated compounds were confirmed using ¹H NMR, IR spectra, and elemental analyses. The antimicrobial activities for all isolated compounds were examined against different microorganisms.     

Structural characterization of the aquaporin inhibitor 2‐nicotinamido‐1,3,4‐thiadiazole

Nicotinamides are a class of compounds with a wide variety of applications, from use as antimicrobial agents to inhibitors of biological processes. These compounds are also cofactors, which are necessary components of metabolic processes. Structural modification gives rise to the activities observed. Similarly, 1,3,4‐thiadiazoles have been shown to possess antioxidant, antimicrobial, or anti‐inflammatory biological activity. To take advantage of each of the inherent characteristics of the two aforementioned functional groups, 2‐nicotinamido‐1,3,4‐thiadiazole, C₈H₆N₄OS, was synthesized. Since defining chemical connectivity is paramount in understanding biological activity, in this report, the structural characterization of 2‐nicotinamido‐1,3,4‐thiadiazole has been carried out using X‐ray crystallographic methods. The NMR‐derived assignments were made possible by utilizing one‐ (1D) and two‐dimensional (2D) NMR techniques. In addition, UV–Visible and IR spectroscopies, and elemental analysis were used to fully characterize the product synthesized by the one‐step reaction between nicotinoyl chloride hydrochloride and 2‐amino‐1,3,4‐thiadiazole. Computational parameters related to blood–brain barrier permeability are also presented.     

Convenient Synthesis and Biological Activity of Mono and Diacyl 2,5‐Dimercapto‐1,3,4‐thiadiazole Derivatives

New derivatives of 2,5‐dimercapto‐1,3,4‐thiadiazole substituted both at one or two exocyclic sulfur atoms with a series of aroyl or ethoxycarbonyl groups were synthesized in reactions of 2,5‐dimercapto‐1,3,4‐thiadiazole salts with appropriate acid chlorides or ethyl chloroformate in mild conditions. The products were characterized by spectroscopy (¹H NMR, ¹³C NMR, IR, and HRMS). Some from the synthesized compounds were screened in vitro and in vivo for antibacterial and antifungal activities against a panel of reference strains of microorganisms. The study revealed that ethyl S‐(5‐mercapto‐1,3,4‐thiadiazol‐2‐yl) carbonothioate seems to be the most active and versatile compound against Gram‐positive bacteria, Gram‐negative bacteria, and plant pathogenic fungi.     

Synthesis,Structure and Biological Activities of Novel 2‐(Trifluoromethyl)‐ 6‐arylimidazo[2,1‐b][1,3,4]‐thiadiazole (bis‐)Mannich Base Derivatives Containing Substitutedpiperazine Moiety

A convenient and practicable method for the synthesis of the novel 2‐(trifluoromethyl)‐6‐arylimidazo[2,1‐b][1,3,4]‐thiadiazole (bis‐)Mannich base derivatives containing various substitutedpiperazine motif has been developed based on the fused‐heterocycle intermediate. The new structures were identified through melting points, ¹H NMR, ¹³C NMR, ¹⁹F NMR, elemental analysis (or HRMS) and X‐ray single‐crystal diffraction. The pesticidal bioassays showed that some of compounds exhibited good fungicidal activities against Cercospora arachidicola, Physalospora piricola and Rhizoctonia cereali at 50 mg/L; some of them displayed favourable insecticidal activities against oriental armyworm (Mythimna separata Walker) at 200 mg/L, particularly, Vk and Vm with mortality rate of 75% and 80% respectively, could be considered as new insecticidal lead compounds for further structural optimization.     

Synthesis and Characterization of Some New Heteroaromatic Compounds Having Chirality Adjacent to a 1,3,4‐Thiadiazole Moiety and Their Antimicrobial Activities

Through a cyclization reaction of 2‐phenylbutyric acid with N‐ phenylthiosemicarbazide and POCl₃, novel 1,3,4‐thiadiazole derivatives were synthesized. Their structures were confirmed using IR, ¹H NMR, and ¹³C NMR spectroscopies and elemental analysis. The antibacterial activities of the obtained 1,3,4‐thiadiazole derivatives were tested against Gram‐negative bacteria (Salmonella enteritidis , Salmonella typhimurium , Enterobacter aerogenes , Salmonella infantis , Salmonella kentucky , and Escherichia coli ) and Gram‐positive bacteria (Staphylococcus aureus , Bacillus subtilis , and Enterococcus durans ) using a disk diffusion method. Moreover, an antifungal activity experiment was performed against Candida albicans using the disk diffusion method. It was observed that the synthesized 1,3,4‐thiadiazole derivatives exhibited effective antimicrobial activity against S. aureus , E. coli , and C. albicans . Based on these results, the 1,3,4‐thiadiazole derivatives can be considered as a source of bioactive agents for pharmacological and medicinal applications.     

Synthesis of Some Novel 3,6‐Bis(1,2,3‐triazolyl)‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazole Derivatives

The cyclization of 1‐amino‐2‐mercapto‐5‐[1‐(4‐ethoxyphenyl)‐5‐methyl‐1,2,3‐triazol‐4‐yl]‐1,3,4‐triazole which was synthesized from p‐ethoxyaniline with various triazole acid in absolute phosphorus oxychloride yields 3,6‐bis(1,2,3‐triazolyl)‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazole derivatives 9a?j , and their structures are established by MS, IR, CHN and ¹H NMR spectral data.     

Synthesis and Evaluation of 1,3,4‐Thiadiazole Derivatives Containing Cyclopentylpropionamide as Potential Antibacterial Agent

This study aimed to identify new strategies for the control of these plant bacterial diseases by combining a pharmacophoric group of different bioactive compounds. A series of 3‐cyclopentylpropionamide containing 1,3,4‐thiadiazole derivatives was synthesized and characterized via ¹H‐NMR, ¹³C‐NMR, and HRMS. Bioassay results indicated that compounds 7a , 7d , 7j , 7m , 7n , and 7s had excellent antibacterial activity compared with the positive control. Among them, compound 7a exhibited remarkable inhibitory effect against Xoo with an EC₅₀ of 21.41 μg/mL, which surpassed that of thiodiazole copper (67.71 μg/mL) and bismerthiazol (69.05 μg/mL). Greenhouse condition tests further revealed that 7a had approximately equal curative activity and better protection activity (41.58%) against bacterial leaf blight of rice than that of thiodiazole copper and bismerthiazol (46.86 and 42.25%, respectively). Structure–activity relationship analysis exhibited that sulfone fragment favored inhibition. Overall, this study suggested that derivatives containing 1,3,4‐thiadiazole 3‐cyclopentylpropanamide can be used as new lead compounds for bactericide studies.     

Synthesis and Biological Activity of Ethyl 4‐Alkyl‐2‐(2‐(substituted phenoxy)acetamido)thiazole‐5‐carboxylate

A series of novel ethyl 4‐(methyl or trifluoromethyl)‐2‐(2‐(substituted phenoxy)acetamido)thiazole‐5‐carboxylates 7a , 7b , 7c , 7d , 7e and 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p , 8q , 8r were synthesized, and their structures were confirmed by IR, ¹H‐NMR, MS spectra and elemental analysis. The results of preliminary bioassays show that some of the title compounds exhibit moderate to good herbicidal activities. Compared with the fluorine free compounds 7a , 7b , and 7e , the compounds bearing fluorine 8g , 8j , and 8q showed higher herbicidal activities with 70–100% inhibition against Capsella bursa‐pastoris, Amaranthus restroflexus, and Eclipta prostrata at the dosage of 150 g/ha, which indicated that the trifluoromethyl on the thiazole ring was beneficial for the herbicidal activity. Furthermore, compounds 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p , 8q , 8r were tested for fungicidal activity against Pseudoperonospora cubensis at 500 µg/mL. Compounds 8f and 8q showed the best fungicidal activity with more than 80% inhibition.     

Synthesis and Herbicidal Activity of Novel N‐(2‐Fluoro‐5(3‐methyl‐2,6‐dioxo‐4‐(trifluoromethyl)‐2,3‐dihydro‐pyrimidin‐1(6H)‐yl)phenyl)‐2‐phenoxyacetamide Derivatives

Thirteen novel N‐(2‐fluoro‐5‐(3‐methyl‐2,6‐dioxo‐4‐(trifluoromethyl)‐2,3‐dihydropyrimidin‐1(6H)‐yl)phenyl)‐2‐phenoxy)acetamides were designed and synthesized utilizing 4‐fluoro‐aniline and ethyl 3‐amino‐4,4,4‐trifluoro‐but‐2‐enoate as starting materials. The chemical structures of all compounds were confirmed by ¹H NMR, IR, mass spectrum and elemental analyses. Subsequently, the herbicidal activities of the as‐prepared compounds were evaluated in the greenhouse. Bioassay results indicated that most of compounds had better herbicidal activities against dicotyledonous weeds. Among all the tested compounds, compounds 4a – 4i showed good herbicidal activities at both pre‐emergence and post‐emergence treatment against two or three kinds of dicotyledonous weeds, such as Abutilon theophrasti Medic, Amaranthus ascendens L, and Chenopodium album L at the dosage of 75 g ai/ha.