Design, synthesis, antibacterial evaluation of isopropylamine linked with different substituted phenol and piperazine novel derivatives.

BACKGROUND: Xanthomonas oryzae pv. oryzae (Xoo) is often considered one of the most destructive bacterial pathogens causing bacterial leaf blight (BLB), resulting in significant yield and cost losses in rice. In this study, a series of novel derivatives containing the isopropanolamine moiety linked to various substituted phenols and piperazines were designed, synthesized and screened. RESULTS: Antibacterial activity results showed that most compounds had good inhibitory effects on Xoo, among which compound W2 (EC50 = 2.74 µg mL-1) exhibited the most excellent inhibitory activity, and W2 also had a certain curative effect (35.89%) on rice compared to thiodiazole copper (TC) (21.57%). Scanning electron microscopy (SEM) results indicated that compound W2 could cause rupture of the Xoo cell membrane. Subsequently, proteomics and quantitative real-time polymerase chain reaction revealed that compound W2 affected the physiological processes of Xoo and may exert antibacterial activity by targeting the two-component system pathway. Interestingly, W2 upregulated Xoo's methyltransferase to impact on its pathogenicity. CONCLUSION: The present study offers a promising phenolic-piperazine-sopropanolamine compound as an innovative antibacterial strategy by specifically targeting the two-component system pathway and inducing upregulation of methyltransferase to effectively impact Xoo's pathogenicity. © 2024 Society of Chemical Industry.

Discovery of tryptanthrin analogues bearing F and piperazine moieties as novel phytopathogenic antibacterial and antiviral agents.

BACKGROUND: Plant bacterial infections and plant viruses seriously affect the yield and quality of crops. Based on the various activities of tryptanthrin, a series of tryptanthrin analogues bearing F and piperazine moieties were designed, synthesized, and evaluated for their biological activities against three plant bacteria and tobacco mosaic virus (TMV). RESULTS: Bioassay results indicated that compounds 6a-6l displayed excellent antibacterial activities in vitro and 6a-6c and 6g exhibited better antiviral activities against TMV than commercial ribavirin. In particular, 6b showed the most effect on Xanthomonas oryzae pv. oryzae (Xoo) with a half-maximal effective concentration (EC50 ) of 1.26 µg mL-1 , compared with the commercial pesticide bismerthiazol (BT; EC50 = 34.3 µg mL-1 ) and thiodiazole copper (TC; EC50 = 73.3 µg mL-1 ). Meanwhile, 6a also had the best antiviral activity at 500 µg mL-1 for curative, protection, and inactivation purposes, compared with ribavirin in vivo. CONCLUSION: Compound 6b could cause changes in bacterial morphology, induce the accumulation of reactive oxygen species, promote apoptosis of bacterial cells, inhibit the formation of biofilm, and block the growth of Xoo cells. Proteomic analysis revealed major differences in the bacterial secretory system pathways T2SS and T6SS, which inhibited membrane transport. Molecular docking revealed that 6a and 6g could interact with TMV coat protein preventing virus assembly. These results suggest that tryptanthrin analogues bearing F and piperazine moieties could be promising candidate agents for antibacterial and antiviral use in agricultural production. © 2023 Society of Chemical Industry.

Design, Synthesis, and Mechanism of Novel 9-Aliphatic Amine Tryptanthrin Derivatives against Phytopathogenic Bacteria.

Taking inspiration from the use of natural product-derived bactericide candidates in drug discovery, a series of novel 9-aliphatic amine tryptanthrin derivatives were designed, synthesized, and evaluated for their biological activity against three plant bacteria. The majority of these compounds exhibited excellent antibacterial activity in vitro. Compound 7c exhibited a significantly superior bacteriostatic effect against Xanthomonas axonopodis pv Citri (Xac), Xanthomonas oryzae pv Oryzae (Xoo), and Pseudomonas syringae pv Actinidiae (Psa) with final corrected EC50 values of 0.769, 1.29, and 15.5 µg/mL, respectively, compared to the commercial pesticide thiodiazole copper which had EC50 values of 58.8, 70.9, and 91.9 µg/mL. Preliminary mechanism studies have demonstrated that 7c is capable of altering bacterial morphology, inducing reactive oxygen species accumulation, promoting bacterial cell apoptosis, inhibiting normal cell growth, and affecting cell membrane permeability. Moreover, in vivo experiments have substantiated the effectiveness of 7c as a therapeutic and defensive agent against the citrus canker. The proteomic analysis has unveiled that the major disparities are located within the bacterial secretion system pathway, which hinders membrane transportation. These discoveries imply that 7c could be an auspicious prototype for developing antiphytopathogenic bacterial agents.

Discovery and Mechanism of Novel 7-Aliphatic Amine Tryptanthrin Derivatives against Phytopathogenic Bacteria.

Rice bacterial leaf blight is a destructive bacterial disease caused by Xanthomonas oryzae pv. oryzae (Xoo) that seriously threatens crop yields and their associated economic benefits. In this study, a series of improved dissolubility 7-aliphatic amine tryptanthrin derivatives was designed and synthesized, and their potency in antibacterial applications was investigated. Notably, compound 6e exhibited excellent activity against Xoo, with an EC50 value of 2.55 µg/mL, compared with the positive control bismerthiazol (EC50 = 35.0 µg/mL) and thiodiazole copper (EC50 = 79.4 µg/mL). In vivo assays demonstrated that 6e exhibited a significant protective effect on rice leaves. After exposure, the morphology of the bacteria was partially atrophied by SEM. Furthermore, 6e increased the accumulation of intracellular reactive oxygen species, causing cell apoptosis and the formation of bacterial biofilms. All the results indicated that 6e could be a potential agrochemical bactericide for controlling phytopathogenic bacteria.

Design, Synthesis and Antitumor Activity of 1H-indazole-3-amine Derivatives.

A series of indazole derivatives were designed and synthesized by molecular hybridization strategy, and these compounds were evaluated the inhibitory activities against human cancer cell lines of lung (A549), chronic myeloid leukemia (K562), prostate (PC-3), and hepatoma (Hep-G2) by methyl thiazolyl tetrazolium (MTT) colorimetric assay. Among these, compound 6o exhibited a promising inhibitory effect against the K562 cell line with the IC50 (50% inhibition concentration) value of 5.15 µM, and this compound showed great selectivity for normal cell (HEK-293, IC50 = 33.2 µM). Moreover, compound 6o was confirmed to affect apoptosis and cell cycle possibly by inhibiting Bcl2 family members and the p53/MDM2 pathway in a concentration-dependent manner. Overall, this study indicates that compound 6o could be a promising scaffold to develop an effective and low-toxic anticancer agent.

Discovery and Mechanism of Azatryptanthrin Derivatives as Novel Anti-Phytopathogenic Bacterial Agents for Potent Bactericide Candidates.

The natural alkaloids of tryptanthrin and their derivatives have a wide range of biological activities. In this research, four series of azatryptanthrin derivatives containing 4-aza/3-aza/2-aza/1-aza tryptanthrin were prepared by condensation cyclization reaction against plant pathogens to develop a new natural product-based bacterial pesticide. Compound 4Aza-8 displayed a remarkable growth inhibitory effect on pathogenic bacteria of Xanthomonas axonopodis pv. citri (Xac), Xanthomonas oryzae pv. Oryzae (Xoo), and Pseudomonas syringae pv. actinidiae (Psa) with the final corrected EC50 values of 0.312, 1.91, and 18.0 µg/mL, respectively, which were greatly superior than that of tryptanthrin (Tryp). Moreover, 4Aza-8 also showed effective therapeutic and protective activities in vivo on citrus canker. Further mechanism studies on Xac elucidated that compound 4Aza-8 was able to affect the growth curve of Xac and the formation of biofilm, cause severe shrinkage in bacterial morphology, increase reactive oxygen species levels, and induce apoptosis in bacterial cells. Quantitative analysis of differential protein profiles found that the major differences were mainly concentrated on the endometrial protein in the bacterial secretion system pathway, which blocked the membrane transport and affected the transfer of DNA to the host cell. In summary, these research results suggest that 4Aza-8 represents a promising anti-phytopathogenic-bacteria agent, which is worth being further investigated as a bactericide candidate.

Design, Synthesis, Antibacterial Evaluation, Three-Dimensional Quantitative Structure-Activity Relationship, and Mechanism of Novel Quinazolinone Derivatives.

Plant bacterial illnesses are common and cause dramatic damage to agricultural goods all over the world, yet there are few efficient bactericides to alleviate them at present. To discover novel antibacterial agents, two series of quinazolinone derivatives with novel structures were synthesized and their bioactivity against plant bacteria was tested. Combining CoMFA model search and the antibacterial bioactivity assay, D32 was identified as a potent antibacterial inhibitor against Xanthomonas oryzae pv. Oryzae (Xoo), with an EC50 value of 1.5 µg/mL, much better in inhibitory capacity compared to bismerthiazol (BT) and thiodiazole copper (TC) (31.9 and 74.2 µg/mL). The activities of compound D32 against rice bacterial leaf blight in vivo were 46.7% (protective activities) and 43.9% (curative activities), better than commercial drug thiodiazole copper (29.3% protective activities and 30.6% curative activities). Flow cytometry, proteomics, reactive oxygen species, and key defense enzymes were used to further investigate the relevant mechanisms of action of D32. The identification of D32 as an antibacterial inhibitor and revelation of its recognition mechanism not only open the possibility of developing new therapeutic strategies for treatment of Xoo but also provide clues for elucidation of the acting mechanism of quinazolinone derivative D32, which is a possible clinical candidate worth in-depth study.

Discovery of Tryptanthrin and Its Derivatives and Its Activities against NSCLC In Vitro via Both Apoptosis and Autophagy Pathways.

In this study, a series of novel tryptanthrin derivatives were synthesized and their inhibitory activities against selected human cancer cell lines, namely, lung (A549), chronic myeloid leukemia (K562), prostate (PC3), and live (HepG2), were evaluated using a methyl thiazolyl tetrazolium colorimetric (MTT) assay. Among the tested compounds, compound C1 exhibited a promising inhibitory effect on the A549 cell line with an IC50 value of 0.55 ± 0.33 µM. The observation of the cell morphological result showed that treatment with C1 could significantly inhibit the migration of A549 cells through the cell migration assay. Moreover, after treatment with C1, the A549 cells exhibited a typical apoptotic morphology and obvious autophagy. In addition, the detection of apoptosis and the mitochondrial membrane potential indicated that C1 induced A549 cell apoptosis via modulating the levels of Bcl2 family members and disrupted the mitochondrial membrane potential. Compound C1 also suppressed the expression of cyclin D1 and increased the expression of p21 in the A549 cells, inducing cell cycle arrest in the G2/M phase in a dose dependent manner. The further mechanism study found that C1 markedly increased the transformation from LC3-I to LC3-II. Taken together, our results suggest that C1 is capable of inhibiting the proliferation of non-small cell lung cancer (NSCLC) cells, inducing cell apoptosis, and triggering autophagy.

Synthesis and biological assessment of indole derivatives containing penta-heterocycles scaffold as novel anticancer agents towards A549 and K562 cells.

Herein, a new series of 2-chloro-N-(5-(2-oxoindolin-3-yl)-4H-pyrazol-3-yl) acetamide derivatives containing 1,3,4-thiadiazole (10a-i) and 4H-1,2,4-triazol-4-amine (11a-r) moiety was designed, synthesised as novel anticancer agents. The antiproliferative activity values indicated that compound 10 b stood as the most potent derivative with IC50 values of 12.0 nM and 10 nM against A549 and K562 cells, respectively. Mechanism investigation and docking studies of 10 b indicated that it possessed good apoptosis characteristic and dose-dependent growth arrest of A549 and K562 cells, blocked cell cycle into G2/M phase. Interestingly, 10 b suppressed the growth of A549 and K562 cells via modulation of EGFR and p53-MDM2 mediated pathway.

Allicin-inspired disulfide derivatives containing quinazolin-4(3H)-one as a bacteriostat against Xanthomonas oryzae pv. oryzae.

BACKGROUND: Plant bacterial diseases have seriously affected the yield and quality of crops, among which rice bacterial leaf blight (BLB), caused by Xanthomonas oryzae pv. oryzae has seriously affected the yield of rice. As plant-pathogenic bacteria gradually become resistant to existing bactericides, it is necessary to find effective bactericides with novel structures. RESULTS: Herein, a series of compounds containing quinazolin-4(3H)-one and disulfide moieties were designed and synthesized using a facile synthetic method. The bioassay results revealed that most target compounds possessed noticeable antibacterial activity against Xanthomonas oryzae pv. oryzae. Particularly, compound 2-(butyldisulfanyl) quinazolin-4(3H)-one (1) exhibited remarkable antibacterial activity with the half effective concentration (EC50 ) of 0.52 µg mL-1 . Additionally, compound 1 was confirmed to inhibit the growth of the bacteria, change the bacterial morphology, and increase the level of reactive oxygen species. Proteomics, and RT-qPCR analysis results indicated that compound 1 could downregulate the expression of Pil-Chp histidine kinase chpA encoded by the pilL gene, and the potting experiments proved that compound 1 exhibits significant protective activity against BLB. CONCLUSIONS: Compound 1 may weaken the pathogenicity of Xanthomonas oryzae pv. oryzae by inhibiting the bacterial growth and blocking the pili-mediated twitching motility without inducing the bacterial apoptosis. This study indicates that such derivatives could be a promising scaffold to develop a bacteriostat to control BLB. © 2022 Society of Chemical Industry.

Antibacterial Activity of Allicin-Inspired Disulfide Derivatives against Xanthomonas axonopodis pv. citri

Xanthomonas axonopodis pv. citri (Xac) belongs to the Gram-negative species, causing citrus canker that seriously affects the fruit yield and quality of many rutaceae plants. Herein, we found that compound 2-(butyldisulfanyl) quinazolin-4(3H)-one exhibited remarkable anti-Xac activity in vitro with a half effective concentration (EC50) of 2.6 µg/mL, while the positive controls thiodiazole-copper with 57 µg/mL and bismerthiazol with 68 µg/mL and this compound showed great anti-citrus canker activity in vivo. This active compound also was confirmed to reduce biofilm formation, increase the level of reactive oxygen species, damage the morphological structure of the bacteria, and cause bacterial death. Proteomics and RT-qPCR analysis results indicated that this compound down-regulated the expression of enzymes in the MEP (2-methyl-D-erythritol 4-phosphate) pathway and might achieve destructive ability of Xac. Overall, this study indicates that such derivatives could be a promising scaffold to develop novel bactericides to control citrus canker.

Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics.

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.

Synthesis and Bioactivities Study of Novel Pyridylpyrazol Amide Derivatives Containing Pyrimidine Motifs.

In this study, thirteen new pyridylpyrazolamide derivatives containing pyrimidine motifs were synthesized via six-step reactions. Bioassay results showed that some of the synthesized compounds revealed good antifungal properties against Sclerotinia sclerotiorum, Phytophthora infestans, Thanatephorus cucumeris, Gibberella zeae, Fusarium oxysporum, Cytospora mandshurica, Botryosphaeria dothidea, and Phompsis sp. at 50 µg/mL, which were similar to those of Kresoxim-methyl or Pyrimethanil. Meanwhile, bioassay results indicated that the synthesized compounds showed a certain insecticidal activity against Spodoptera litura, Mythimna separata, Pyrausta nubilalis, Tetranychus urticae, Rhopalosiphum maidis, and Nilaparvata lugens at 200 µg/mL, which was lower than that of Chlorantraniliprole. To the best of our knowledge, this study is the first report on the antifungal and insecticidal activities of pyridylpyrazol amide derivatives containing a pyrimidine moiety.

Highly Selective and Sensitive Detection of Biogenic Defense Phytohormone Salicylic Acid in Living Cells and Plants Using a Novel and Viable Rhodamine-Functionalized Fluorescent Probe.

Detecting plant-derived signal molecules using fluorescent probes is a key topic and a huge challenge for scientists. Salicylic acid (SA), a vital plant-derived defense hormone, can activate global transcriptional reprogramming to systemically express a network of prominent pathogenesis-related proteins against invasive microorganisms. This strategy is called systemic acquired resistance (SAR). Therefore, monitoring the dynamic fluctuations of SA in subcellular microenvironments can advance our understanding of different physiological and pathological functions during the SA-induced SAR mechanism, thus benefiting the discovery and development of novel immune activators that contribute to crop protection. Here, detection of signaling molecule SA in plant callus tissues was first reported and conducted by a simple non-fluorescent rhodamine-tagged architecture bearing a flexible 2-amino-N,N-dimethylacetamide pattern. This study can markedly advance and promote the usage of fluorescent SA probes for distinguishing SA in the plant kingdom.

Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment.

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.

Microwave-assisted synthesis of 7-azaindoles via iron-catalyzed cyclization of an o-haloaromatic amine with terminal alkynes.

An efficient and practical procedure was developed to prepare 7-azaindole, starting from an o-haloaromatic amine and corresponding terminal alkynes under microwave irradiation and the scope was demonstrated with a number of examples. The valuable features of this procedure included the iron-catalyzed cyclization, short reaction times and convenient operation. Furthermore, iron catalysis is an interesting alternative to homogeneous catalysis for the synthesis of heterocycles.

Synthesis and antiviral activity of 2-substituted methylthio-5-(4-amino-2-methylpyrimidin-5-yl)-1,3,4-oxadiazole derivatives.

A series of novel 2-substituted methylthio-5-(4-amino-2-methylpyrimidin-5-yl-)-1,3,4-oxadiazole derivatives were synthesized and evaluated for antiviral activities against tobacco mosaic virus (TMV) via half-leaf method. The preliminary biological results showed that these compounds exhibited good antiviral activity against TMV in vivo. Among these compounds, compounds 8f, 8h, 8k, 8n, 8q and 8w exhibited the similar curative effect against TMV (EC50=290.98-438.29µg/mL) as the commercial product Ningnanmycin (301.83µg/mL). Notably, compound 8i exhibited the excellent curative effect against TMV, with EC50 value of 246.48µg/mL, which was better than that of Ningnanmycin. To the best of our knowledge, this was the first Letter of 2-substituted methylthio-5-(4-amino-2-methylpyrimidin-5-yl-)-1,3,4-oxadiazole derivatives with potent antiviral against TMV.

Synthesis and antiviral activities of pyrazole derivatives containing an oxime moiety.

Target compounds 4a- n were obtained by the reaction of 1-substituted phenyl-3-methyl-5-substituted phenylthio-4-pyrazolaldoximes (3) with chloromethylated heterocyclic compounds (ClCH 2-R 3) under reflux conditions in ethanol. Subsequently, the oxidation of 4a- e with KMnO 4 in HOAc at room temperature afforded eight new compounds, 5a- h. The synthesized compounds were characterized by physical constants, and the structures of the title compounds were confirmed by IR, (1)H NMR, (13)C NMR, and elemental analysis. The bioassay revealed that the compounds possessed antiviral activities. It was found that title compounds 4a and 4g had the same inactivation effects against TMV (EC 50 = 58.7 and 65.3 microg/mL) as the commercial product Ningnanmycin (EC 50 = 52.7 microg/mL). To the best of our knowledge, this is the first report on the antiviral activity of pyrazole derivatives containing an oxime moiety.

Synthesis and antiviral activity of novel pyrazole derivatives containing oxime esters group.

Fourteen title compounds, 1-substituted-5-substitutedphenylthio-4-pyrazolaldoxime ester derivatives 4a-4n, were synthesized from the starting material 1-substitutedphenyl-3-methyl-5-substitutedphenylthio-4-pyrazolaldoximes 3 by treatment with acyl chloride. The synthesized compounds were characterized by physical constants, and the structures of the title compounds were further confirmed by IR, 1H NMR, 13C NMR and elemental analysis. The bioassay results showed that title compounds possessed weak to good anti-TMV bioactivity with 4l showing significant enhancement of disease resistance in tobacco leaves with high affinity for TMV CP.

Synthesis and antifungal bioactivities of 3-alkylquinazolin- 4-one derivatives.

A simple, efficient, and general method has been developed for the synthesis of various 3-alkylquinazolin-4-one derivatives from quinazolin-4-one treated with alkyl bromides under phase transfer catalysis condition. The structures of the compounds were characterized by elemental analysis, IR, (1)H-NMR and (13)C-NMR spectra. Title compound 6-bromo-3-propylquinazolin-4-one (3h) was found to possess good antifungal activity.