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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

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

Author(s): Zhenyu Li, Zhiyong Liu, Yuemao Shen and Chengwu Shen*

Volume 20, Issue 7, 2024

Published on: 08 January, 2024

Page: [689 - 693] Pages: 5

DOI: 10.2174/0115734064252833231129062005

Price: $65

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Abstract

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.

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