Synthesis and evaluation of some new 5-(hetaryl)thiazoles as potential antimicrobial agents

In continuing our efforts to find new effective antimicrobial agents for overcoming the problem of microbial resistance, a new series of functionalized 5-hetarylthiazoles have been designed and synthesized starting from readily accessible 1-(2-allylamino-4-methylthiazol-5-yl)ethanone (3). The structures of newly synthesized compounds were confirmed by elemental analyses, spectral data, and chemical transformations. The synthesized compounds were evaluated in vitro for their antimicrobial activity against some human pathogenic bacterial and fungal strains. The compounds 7, 18, and 24 exhibited higher antibacterial activity with minimum inhibitory concentration (MIC) values ranging from (0.03–0.06?µg/mL) than ampicillin (MIC, 0.12?µg/mL) against Streptococcus pneumoniae. Whereas compounds 4, 22, and 24 revealed higher antifungal potency than amphotericin B against Aspergillus fumigatus. The structure and antimicrobial activity relationship was also discussed.     

酰基硫脲衍生物的合成、结构表征及生物活性研究

在超声波辐射下, 以PEG-400为固-液相转移催化剂, 用芳胺与双酰基异硫氰酸酯反应, 合成出了15种新的结构不对称的双酰基硫脲类化合物(6和6')和9种新的分子中含酰胺基团的单酰基硫脲类化合物(7和7'). 利用元素分析, IR, ¹H NMR, ¹³C NMR, APT, 1D NOE及2D NMR技术确定了所合成化合物6和6'及7和7'的结构, 并对它们NMR谱中低场C, H进行了归属. 杀菌、杀虫和除草活性筛选测定实验结果表明, 所测试化合物对瓜炭疽病菌均具有抑制作用, 其中6e抑制率最高, 达到62.4%; 目标化合物7a对黄瓜白粉病菌有一定的抑制作用. 单胺氧化酶活性测定实验表明：大部分目标化合物对单胺氧化酶具有一定的抑制活性, 其中浓度在1×10^－3 mol•L^－1时目标化合物6'c和6'd的抑制活性较强, 明显高于其它化合物. 目标化合物没有抗惊厥活性.     

Two new eremophilenolides from the roots of Ligulariopsis shichuana and their anti-phytopathogenic fungal and antifeedant activities

Two new eremophilenolides, ligushicins A (1) and B (2), and two known compounds including β-sitosterol and ursolic acid were isolated from Ligulariopsis shichuana. The structures of new compounds were established on the basis of 1D and 2D NMR data and HRESIMS data interpretation. The absolute configuration of new compounds was assigned by ECD spectroscopy, and that of ligushicins A (1) was confirmed by X-ray diffraction analysis. The antifungal and antifeedant activities of new compounds were evaluated against four plant pathogenic fungi and third-instar larvae of Plutella xylostella, respectively. Ligushicins A (1) and B (2) exhibited potent antifungal activity against Botrytis cinerea and Fusarium oxysporum with minimum inhibitory concentration (MIC) values ranging from 50 to 100 mg/L, while they also exhibited weak antifeedant activities.     

2-(Benzo[d]thiazol-2-yl) phenyl-4-nitrophenyl alkyl/aryl substituted phosphoramidates: Synthesis,characterization and antimicrobial activity evaluation

A series of new 2-(benzo[d]thiazol-2-yl) phenyl-4-nitrophenyl alkyl/aryl substituted phosphoramidate derivatives (7a-j) of biological interest are synthesized in two steps via an in situ process without the isolation of the intermediate. 2-(Benzo[d]thiazol-2-yl) phenol (3) was treated with 4-nitrophenyl phosphorodichloridate(4) to obtain the monochloro intermediate, 2-(benzo[d]thiazol-2-yl)phenyl (4-nitrophenyl) phosphorochloridate(5). It was subsequently reacted with various amines, 6(a-j) to afford the desired title products. IR, NMR (¹H, ¹³C and ³¹P), mass spectral and elemental analysis are used to characterize the structures of the newly synthesized compounds. The antibacterial and antifungal activities are determined by the growth of inhibition of bacteria and fungi of the title compounds at two concentrations, 50 and 100 µg/mL, and minimum inhibitory concentrations to the active compounds. The compounds 7e, 7f and 7j exhibited promising inhibition activity against bacterial strains and 7c, 7e and 7i against A. niger and C. albicans and MIC values are in the range of 10.0–15.0 µg/mL.     

Isolation and structural elucidation of novel antimicrobial compounds from maggots of Chrysomyis megacephala Fabricius

The excretions/secretions from the maggot of Chrysomyis megacephala Fabricius are traditionally used to treat serious infections in China. In this study, bioassay-guided fractionation led to the isolation of three novel antibacterial compounds (1–3), including important fluorinated compounds (3 and 5), together with other nine known compounds from 70% methanol extract of C. megacephala. The structures of the new compounds were elucidated by NMR spectroscopic analysis and high-resolution mass spectroscopy. The antibacterial activities of the isolated compounds were evaluated using agar disc diffusion method. New compounds 1 and 2 exhibited moderate activity against Bacillus subtilis with a minimum inhibitory concentration (MIC) of 250 μg mL^? 1. The most active compounds 3 and 5 displayed a broad spectrum of antimicrobial activity with an MIC of 125 μg mL^? 1 against G⁺ and G^?  bacteria. The structure of the above-mentioned novel compounds and their antimicrobial activities are herein reported for the first time from the natural product of insects.     

Bis coumarinyl bis triazolothiadiazinyl ethane derivatives: Synthesis,antiviral activity evaluation,and molecular docking studies

A series of novel 3,3′-(3,3′-(dihydroxy/hydroxyethane-1,2-diyl)bis(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6,3-diyl))bis(2H-chromen-2-ones) were prepared by the condensation of thiocarbohydrazide with tartaric acid or malic acid followed by various 3-(2-bromoacetyl)-2H-chromen-2-ones in two steps with good yields. All the synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR, and mass) data. These synthesized bis(triazolothiadiazinyl coumarin) compounds were evaluated for broad spectrum of antiviral activity. Among all the tested compounds, compound 5f exhibited antiviral activity against H1N1 virus. The molecular docking studies of these compounds against H1N1 neuraminidase enzyme were performed. The binding affinity and binding values were compared with standard drugs.     

Design,Synthesis, and Antiviral Activity of α-Aminophosphonates Bearing a Benzothiophene Moiety

Abstract

A series of α-aminophosphonates containing a benzothiophene moiety was designed and synthesized. All synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, ³¹P NMR, infrared spectroscopy, and elemental analysis. The half-leaf method was used to determine the in vivo efficacy of α-aminophosphonates bearing a benzothiophene moiety against the tobacco mosaic virus (TMV). Bioassay results showed that all compounds exhibited certain anti-TMV activity at 500 μg/mL concentration. Compound 2f exhibited a curative effect of up to 48.1% against TMV, which was almost similar to that obtained from the standard ningnanmycin (51.9%).

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures, and tables.]     

Synthesis,structural characterization,biological activity,and theoretical studies of some novel thioether-bridged 2,6-disubstituted imidazothiadiazole analogues

In this study, thioether-bridged imidazo[2,1-b][1,3,4]thiadiazole derivatives that contained both imidazole and 1,3,4-thiadiazole (compounds 7a-7i and 8a-8i ) were synthesized from the reactions of 2-amino-1,3,4-thiadiazole with phenacyl bromide ( 6a - 6i ) (at yields of 59% to 74%). The structure of the synthesized compounds was characterized using ¹H NMR, ¹³C NMR, Fourier-transform infrared spectroscopy, elemental analysis, mass spectroscopy, and X-ray diffraction analysis. Mycelial growth, mycelial growth inhibition, minimum inhibitory concentration, minimum fungicidal concentration, and lethal dose values against various plant pathogenic fungi were determined for all of the target compounds synthesized in the study. The test results showed that most of the compounds had moderate to good antifungal activity. In addition, the absorption, distribution, metabolism, excretion (ADME) parameters of the compounds were calculated, and it was observed that all of the compounds met the drug-likeness rules in general. Finally, using docking simulations, it was found that compounds 7h , 7i , 8h , and 8i showed high affinity to PDB ID:5TZ1, which is an CYP51 antifungal target structure.     

Synthesis and characterization of oxazine bearing pyridine scaffold as potential antimicrobial agents

A series of novel compounds 1-((1-(4-(2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)ethylidene)amino)-6-((benzylidene)amino)-2-oxo-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitriles (7a–o) were synthesized by a sequence of multistep reactions. IR, ¹H NMR, ¹³C NMR, and mass spectral techniques were used to confirm the structures newly synthesized compounds. Antimicrobial activity of the title compounds (7a–o) was studied against strains of bacteria (Staphylococcus aureus and Streptococcus pyogenes, Escherichia coli and Pseudomonas aeruginosa) and fungi (Candida albicans, Aspergillus niger and Aspergillus clavatus) by serial dilution method. Compounds 7f and 7k exhibited significant antimicrobial activity.     

Novel Steroidal (6R)‐Spiro‐1,3,4‐thiadiazoline Derivatives as Anti‐bacterial Agents

Novel steroidal (6R)‐spiro‐1,3,4‐thiadiazoline derivatives have been synthesized by the cyclization of steroidal thiosemicarbazones. Thiosemicarbazones have been synthesized by the reaction of steroidal ketones with thiosemicarbazide. All the compounds have been characterized by IR, ¹H NMR, mass and elemental analyses. The antibacterial activities of these compounds have been first tested in vitro by the disk diffusion assay against two Gram‐positive and two Gram‐negative bacteria, and then the minimum inhibitory concentration (MIC) values have been determined with the reference of standard drug amoxicillin. The results showed that steroidal thiadiazoline derivatives exhibited better antibacterial activity than the steroidal thiosemicarbazone derivatives. Chloro and acetoxy substituents on the 3β‐position of the steroidal thiadiazoline ring increased the anti‐bacterial activity. Among all the compounds, compounds 7 and 8 were found better inhibitors as compared to the respective drug amoxicillin.     

Synthesis,ABTS-Radical Scavenging Activity,and Antiproliferative and Molecular Docking Studies of Novel Pyrrolo[1,2-a]quinoline Derivatives

A new 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-radical scavenging and antiproliferative agents of pyrrolo[1,2-a]quinoline derivatives have been synthesized. An efficient method for the synthesis of 14 novel diversified pyrrolo[1,2-a]quinoline derivatives has been described using 4-(1,3-dioxolan-2-yl)quinoline and different phenacyl bromides in acetone and followed by reacting with different acetylenes in dimethylformamide/K₂CO₃. The structure of the newly synthesized compounds was determined by infrared, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. The in vitro antioxidant activity revealed that among all the tested compounds 5n exhibited maximum scavenging activity with ABTS. Compound 5b has showed good antiproliferative activity as an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase.     

Synthesis and antimicrobial screening of pyrano[3,2-<Emphasis Type="Italic">c</Emphasis>]chromene derivatives of 1<Emphasis Type="Italic">H</Emphasis>-pyrazoles

A new series of twenty four derivatives of pyrano[3,2-c]chromene IVa-x bearing 1H-pyrazole were synthesized by a one pot, base-catalyzed cyclocondensation reaction of 1H-pyrazole-4-carbaldehyde Ia-l, malononitrile II and 4-hydroxycoumarin IIIa-b. All the synthesized compounds were characterized by elemental analysis, FT-IR, ¹H NMR and ¹³C NMR spectral data. All the synthesized compounds were screened against six bacterial pathogens, namely B. subtilis, C. tetani, S. pneumoniae, S. typhi, V. cholerae, E. coli and for antifungal activity against two fungal pathogens, A. fumigatus and C. albicans using the broth microdilution MIC method. Some of the compounds were found to be equipotent or more potent than commercial drugs against most of employed strains, as evident from the screening data.      

Design,synthesis, antitubercular and antibacterial activities of pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives and in silico docking studies

Abstract

A novel series pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives have been designed, synthesized and confirmed by FT-IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, MS, and elemental analysis. The synthesized compounds were screened for their antitubercular activity using microplate alamar blue assay method and antibacterial activity. Among the tested compounds, 4- fluorophenyl (8m), 4- chlorophenyl (8n) and 4-methoxyphenyl (8i) showed potent anti-TB activity (3.12?µg/mL) in comparison with reference drug, Pyrazinamide ((3.12?µg/mL). In addition, all compounds were docked into DprE1 (PDB code: 4KW5) to explore their binding interactions at the active site. The compounds exhibited essential key interactions as that of reported DprE1 inhibitors and hence, the synthesized compounds may be considered as molecular scaffolds for antitubercular activity. Compounds, 4-chlorophenyl (8n) and 4-flurophenyl (8m) showed significant antibacterial activity against Escherichia coli and Staphylococcus aureus strains. In silico prediction of toxicities, druglikeness and drug score profiles of the tested compounds are promising.     

Synthesis and In Vitro Antibacterial Activity of Novel Steroidal (6R)‐Spiro‐1,3,4‐thiadiazoline Derivatives

Novel steroidal (6R)‐spiro‐1,3,4‐thiadiazoline derivatives were synthesized by the cyclization of steroidal thiosemicarbazones with acetic anhydride, screened in vitro against antibacterial activity using disc‐diffusion method and the minimum inhibitory concentration. The results showed that steroidal thiadiazoline derivatives exhibited better antibacterial activity than the steroidal thiosemicarbazone derivatives. Chloro and acetoxy substituents on the 3β‐position of the steroidal thiadiazoline ring increased the antibacterial activity. Among all the compounds, compound 7 and 8 were found better inhibitors of both types of bacteria (Gram‐positive and Gram‐negative) as compared to the respective drug amoxicillin. All the synthesized compounds were well characterized by spectroscopic methods such as IR, ¹H‐NMR, ¹³C‐NMR mass, and elemental analysis and their stereochemistry was also discussed.     

4-硫醚基喹唑啉类化合物的合成及抑菌活性研究

以4-氯喹唑啉和巯基化合物为原料, 丙酮作溶剂, 碳酸钾作缚酸剂, 合成了7个新型4-硫醚基喹唑啉类化合物. 采用¹H NMR, ¹³C NMR, IR及元素分析对目标化合物的结构进行了表征. 生物活性测试表明, 化合物1d在50 μg•mL^－1 药剂浓度下对小麦赤霉病菌、辣椒枯萎病菌、苹果腐烂病菌的抑菌活性分别达到69.5%, 71.9%和70.8%, EC₅₀分别为25.88, 17.08和28.77 μg•mL^－1.     

Urea and thiourea derivatives of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo[4,3-a]pyrazine: Synthesis,characterization, antimicrobial activity and docking studies

Abstract

An efficient and robust synthetic procedure was developed primarily for the synthesis of a precursor compound; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo[4,3-a]pyrazine (11), from 2-chloropyrazine (7) through the chemical transformations such as hydrazine substitution, trifluoroacetyl group induction, cyclization and pyrazine ring reduction. A new series of urea derivatives 13a-e and thiourea derivatives 13f-j of compound 11 have been synthesized and the structures of all the compounds were confirmed using spectroscopic analyses such as IR, ¹H NMR, ¹³C NMR, LC-MS and HRMS. The newly synthesized compounds were screened for their in vitro antimicrobial activity against five bacteria and two fungi, in which compounds 13d, 13i and 13j displayed potential activity against bacterial strains and 13a, 13d, 13g and 13j against fungal strains with the MIC values in the range of 6.25–25.0 µg/mL. An overall comparison of the activity results revealed that thiourea derivatives contain better activity than that of urea compounds. Molecular docking studies on poly (ADP-ribose) polymerase 15 (ARTD7, BAL3) demonstrated that all the synthesized compounds possess significant binding energies (-8.1 to -9.8?kcal/mol) with no adverse effect in the active site of protein.     

Synthesis and nematicidal activities of 1,2,3-benzotriazin-4-one containing 4,5-dihydrothiazole-2-thiol derivatives against Meloidogyne incognita

Abstract

A series of novel 1,2,3-benzotriazin-4-one derivatives containing 4,5-dihydrothiazole-2-thiol were synthesized and characterized by ¹H NMR, ¹³C NMR, ¹⁹F NMR and HRMS. The bioassay results showed that compounds 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-7-methoxybenzo[d][1–3]triazin-4(3H)-one, 3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)-6-nitrobenzo[d][1–3]triazin-4(3H)-one, 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one exhibited good control efficacy against the cucumber root-knot nematode disease caused by Meloidogyne incognita at the concentration of 10.0?mg L^?1 in vivo. Compound 7-chloro-3-(3-((4,5-dihydrothiazol-2-yl)thio)propyl)benzo[d][1–3]triazin-4(3H)-one showed excellent nematicidal activity with inhibition 68.3% at a concentration of 1.0?mg L^?1. It suggested that the structure of 1,2,3-benzotriazin-4-one containing 4,5-dihydro-thiazole-2-thiol could be optimized further.     

Design,synthesis and herbicidal activity of novel cyclic phosphonates with diaryl ethers containing pyrimidine

Abstract

Thirteen novel cyclic phosphates were rationally designed and synthesized by introducing diary ethers containing pyrimidine. All the target compounds were characterized by ¹H, ¹³C, ³¹P NMR and HRMS. The test of herbicidal activity indicated that most of the compounds showed good herbicidal activities against Amaranthus retroflexus. The compounds IA-2 (1-(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)propyl-2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzoate) and IA-3 ((5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)(phenyl)methyl-2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzoate) exhibited remarkable post-emergency herbicidal activity against the tested monocotyledonous weed at the dosage of 112.5?g ai/ha.     

Synthesis of novel 1,3-thiazin-4-ones by acetylene diester cyclization and their anticancer activities

A novel series of 1,3-thiazin-4-one derivatives containing a piperidyl ring (7–16) were designed and synthesized efficiently by thioamide and acetylene diester cyclization reaction via aminolysis of the ester group and the elimination of an alcohol molecule. The structures of all the novel compounds were established by their FTIR, Mass, ¹H NMR, and ¹³C NMR spectral techniques. The newly synthesized compounds (7–16) were studied for their in vitro anticancer activity against human liver cancer cell lines Hep G2 using MTT assay. The IC₅₀ values of the tested compounds were ranging in between 7.48 ± 0.71 and 56.57 ± 1.37 µM. Further, the apoptosis evaluation by the mitochondrial membrane potential using JC-1 dye was carried out and the results are in good agreement with the cytotoxicity studies.