New coumarin-cinnamic acid hybrids: potent FtsZ inhibitors as alternatives to bactericides for controlling bacterial...

FtsZ, namely filamenting temperature-sensitive mutant protein Z, is pervasive and highly conserved in the division process of prokaryotic organisms, and thus recently has come to be regarded as a key target for the development of innovative antibacterial agents. However, although its application in pesticides remains limited, initiation of a FtsZ-targeted antibacterial discovery strategy could help to prevent bacterial infection and drug/pesticide resistance.

To discover a new FtsZ inhibitor, the attractive molecular hybridization strategy of introducing isopropanolamine linker was used in which representative active scaffolds for FtsZ inhibitors including coumarin and cinnamic acids were selected to devise new coumarin-cinnamic acid hybrids. Interestingly, compound 4d exhibited excellent in vitro antibacterial activity toward Xanthomonas oryzae pv. oryzae [Xoo, median effective concentration (EC₅₀) = 1.45 mg L^-1], which was better than that of the reference reagent bismerthiazol (EC₅₀ = 33.08 mg L^-1), and demonstrated commendable in vivo anti-Xoo activity (protective activity: 50.46% for 200 mg L^-1). Furthermore, mechanistic assays including fluorescence imaging, guanosine triphosphatase (GTPase) activity assay, fluorometric titration assays, Fourier transform infrared spectroscopy and computational simulations co-elucidated that compound 4d may selectively act on the guanosine 5'-triphosphate (GTP) binding site, further suppress the GTPase activity [median inhibitory concentration(IC₅₀)value of compound 4d of 170.55 μm), thereby inhibiting bacterial reproduction. Toxicity studies accentuated the favorable pharmacological profile and low plant toxicity of compound 4d.

This study provides a new paradigm for extending new bactericides to efficiently control bacterial infections by targeting FtsZ. The work provides new insights for addressing bacterial drug resistance and overcoming bottlenecks in the development of novel pesticides. © 2025 Society of Chemical Industry.