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

• Published in: Medicinal chemistry (Shp-sariqah, United Arab Emirates) Vol. 20; no. 7; p. 689
• Main Authors: Li, Zhenyu, Liu, Zhiyong, Shen, Yuemao, Shen, Chengwu
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2024
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Drug Design; Humans; Microbial Sensitivity Tests; Molecular Structure; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Salmonella typhimurium - drug effects; Structure-Activity Relationship; Type III Secretion Systems - antagonists & inhibitors; Type III Secretion Systems - metabolism; synthesis; inhibitors; Salmonella enterica serovar Typhimurium; 6-Amido-3-carboxypyridazines; Type III secretion system; antibacterial agents
• ISSN: 1875-6638
• DOI: 10.2174/0115734064252833231129062005

serovar Typhimurium, an anaerobic enteric pathogene, could cause human and animal diseases ranging from mild gastroenteritis to whole body serious infections. 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. Synthesized compounds were analyzed by analytical techniques, such as H NMR, C 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. 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 regulatory pathway. The novel synthetic 6-amido-3-carboxypyridazines could act as potent leads for the development of novel antibacterial agents.