Synthesis of carbazole and naphthyl-pyrimidine-based inhibitors of Xanthomonas for tomato bacterial spot management

Bacterial spot of tomato (BST), caused by Xanthomonas species, is a devastating disease in tomato production, leading to severe yield losses and reduced crop quality. Current control strategies, including cultural management and chemical applications, are increasingly challenged by the emergence of copper- and antibiotic-resistant strains. To address this issue, we are exploring the development of novel small molecule antibacterial as a promising alternative control strategy. Through structural expansion and modification of previously identified anti-Xanthomonas leads (X2, X5, and X12), we synthesized a library of small molecules featuring key pharmacophores, including pyrimidine, oxazole, and imidazole. The synthesized compounds were evaluated for their inhibitory activity against Xanthomonas hortorum pv. gardneri (Xhg). Three derivative 4-(2-(1-(2-hydroxy-3-((2-(naphthalen-1-yl)pyrimidin-5-yl)methoxy)propyl)piperidin-2-yl)ethyl)phenol (X2-c), 4-(2-(1-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)piperidin-2-yl)ethyl)phenol (X12-k), and 1-(9H-carbazol-9-yl)-3-(2-(2-(pyridin-2-yl)ethyl)piperidin-1-yl)propan-2-ol (X12-l) demonstrated promising antibacterial effects, exhibiting minimum inhibitory concentrations (MIC) of 25–50 µM and minimum bactericidal concentrations (MBC) of 50–100 µM. X12-l exhibited rapid bactericidal activity against Xhg within 1 h, whereas X2-c and X12-k required 4 h and 6 h, respectively, in a time–kill assay. Furthermore, in silico predictions for compounds X2-c, X12-k, and X12-l indicate an optimal balance of molecular size, polarity, and lipophilicity, conforming to Lipinski’s rule and exhibiting acceptable absorption, distribution, metabolism, and excretion (ADME) profiles. These small molecules can be potentially developed into a useful tool for controlling Xanthomonas in tomato production. Future studies will focus on elucidating their mode of action and evaluating their safety and efficacy in seeds and seedlings.