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 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.