Design and Synthesis of 6-amido-3-carboxypyridazine Derivatives as Potent T3SS Inhibitors of Salmonella enterica Serovar Typhimurium

Background: Salmonella enterica (S. enterica) serovar Typhimurium, an anaerobic enteric pathogene, could cause human and animal diseases ranging from mild gastroenteritis to whole body serious infections. Objective: The goal of this paper was to synthesize new 6-amido-3-carboxypyridazine derivatives with different lengths of side chains with the aim of getting potent antibacterial agents. Methods: Synthesized compounds were analyzed by analytical techniques, such as ¹H NMR, ¹³C NMR spectra, and mass spectrometry. We designed a series of novel 6-amido-3-carboxypyridazines using FA as the lead compound with the scaffold hopping strategy and their inhibitory activity against the effectors of type III secretion system (T3SS) using SDS-PAGE and western blot analysis for two rounds. Also, the preliminary mechanism of action of this series of compounds on T3SS was performed using real-time qPCR. Results: Nine 6-amido-3-carboxypyridazines was synthesized. The inhibitory activities evaluated showed that compound 2i was the most potent T3SS inhibitor, which demonstrated potent inhibitory activities on the secretion of the T3SS SPI-1 effectors in a dose-dependent manner. The transcription of SPI-1 may be affected by compound 2i through the SicA/InvF regulatory pathway. Conclusion: The novel synthetic 6-amido-3-carboxypyridazines could act as potent leads for the development of novel antibacterial agents.