Engineering Phenothiazine-Based Functional Mimics of Host Defense Peptides as New Agrochemical Candidates: Design, Synthesis, and Antibacterial Evaluation

In the protracted “arms race” between host and plant pathogenic bacteria, host organisms have evolved powerful weapons known as host defense peptides (HDPs). However, natural HDPs are not suitable for large-scale applications; therefore, researchers have chosen to develop bespoke small-molecule functional mimics. Phenothiazine derivatives were developed as functional HDPs mimics, owing to their broad biological activity and high lipophilicity. The phenothiazine analogues designed in this study exhibited excellent in vitro bioactivity against the three Gram-negative bacteria Xanthomonas oryzae pv oryzae, Xanthomonas axonopodis pv citri, and Pseudomonas syringae pv actinidiae, with optimal EC50 values of 0.80, 0.31, and 1.91 μg/mL, respectively. Preliminary evidence suggests that compound C 2 may act on bacterial cell membranes and interact with bacterial Deoxyribonucleic acid in the groove binding mode. In vivo trials showed that compound C 2 was highly effective against rice leaf blight (51.97–56.69%), with activity superior to those of bismerthiazol (40.7–43.4%) and thiodiazole copper (30.2–37.1%). Our study provides strong evidence to support the development of phenothiazine derivatives into pesticide candidates.