Discovery of new 1,2,3,4-tetrahydro-β-carboline derivatives decorated with 3-N-substituted propionyl moiety flexibly bridged-chain as reactive oxygen species inducer for efficient antibacterial treatment

The widespread prevalence of Bacterial plant diseases imposes a severe constraint on global food production and crop security. To address the growing challenge of Bacterial resistance, there is an urgent demand to develop novel agrochemicals that combine high efficacy with low toxicity. In this study, a natural product modification strategy was employed to design new bactericidal candidates with an innovative cation mechanism. Tryptamine was employed as a precursor to synthesize 1,2,3,4-tetrahydro-β-carboline (THC) intermediates via the Pictet-Spengler reaction. Subsequent acylation enabled the introduction of 3-N-substituted propionyl group as flexible bridge chain through an aza-Michael reaction. The resulting racemic THC derivatives were then evaluated for their antimicrobial activity. Notably, molecule B3 demonstrated exceptional inhibitory effects against Xanthomonas oryzae pv. oryzae (Xoo, EC₅₀ = 1.32 μg/mL) and Xanthomonas axonopodis pv. citri (Xac, EC₅₀ = 2.80 μg/mL), significantly outperforming commercial agents such as bismerthiazol (BT; EC₅₀ = 40.3 μg/mL for Xoo and 89.6 μg/mL for Xac) and thiodiazole copper (TC; EC₅₀ = 58.2 μg/mL for Xoo and 37.3 μg/mL for Xac). Moreover, molecule B3 exhibited considerably higher activity than its parent molecule B (EC₅₀ = 7.27 μg/mL for Xoo and 4.89 μg/mL for Xac). In vivo assays at 200 μg/mL, B3 provided protective effects of 53.87 % against Xoo and 91.2 % against Xac, exceeding those of TC. Mechanistic investigations revealed that molecule B3 disrupted the intracellular redox balance, and result in the accumulation of Reactive Oxygen Species (ROS) and subsequent induction of Apoptosis. These findings not only identify B3 as a promising ROS inducer for bactericide development but also offer novel insights into the role of ROS in combating Bacterial diseases.

1,2,3,4-Tetrahydro-β-carboline; Antibacterial activity; Bactericide discovery; Natural products modification; Reactive oxygen species.