Design, Synthesis, and Antibacterial Activity of Novel Sulfone Derivatives Containing a 1,2,4-Triazolo[4,3- a]Pyridine Moiety

Abstract

To develop antibacterial agents with a novel mechanism of action, a series of sulfone compounds containing a 1,2,4-triazolo[4,3-a]pyridine were designed and synthesized by progressive molecular structure optimization. The antibacterial activities of some derivatives against the four plant pathogens Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicola (Xoc), Xanthomonas axonopodis pv. citri (Xac), and Pseudomonas syringae pv. actinidiae (Psa) were evaluated. Among them, compound K3 demonstrated significant antibacterial activities against Xoo, Xoc, and Xac, with EC₅₀ values of 1.5, 1.7, and 4.9 mg/L, respectively. In the greenhouse, compound K3 exhibited a protective activity of 44.49% and a curative activity of 42.51% against rice bacterial leaf blight, which notably surpassed the traditional agents thiodiazole-copper (24.65% and 23.35%) and bismerthiazol (34.69% and 30.78%). Furthermore, compound K3 can inhibit the growth of pathogenic bacteria by inhibiting a variety of virulence factors (extracellular polysaccharides, biofilms, and motile and extracellular enzymes.). It also induced the production of reactive oxygen species (ROS) by the pathogens, leading to their death. Transcriptomic analysis revealed that K3 impacts rice biosynthesis, biofilm formation, and metabolic processes, enhancing the plant's self-defense biochemical processes and affecting carbohydrate transport and metabolism to resist pathogen invasion. Therefore, the inhibition of virulence factors as a strategy for controlling difficult-to-treat plant bacterial diseases presents a promising approach to the discovery of novel antibacterial candidates.

Keywords: 1,2,4-triazolo[4,3-a]pyridine; antibacterial activities; mechanism; sulfone; virulence factors.