Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
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

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.

« Previous Next »
Graphical Abstract

[1]
Li, J.; Sun, W.; Guo, Z.; Lu, C.; Shen, Y. Fusaric acid modulates type three secretion system of Salmonella enterica serovar typhimurium. Biochem. Biophys. Res. Commun., 2014, 449(4), 455-459.
[http://dx.doi.org/10.1016/j.bbrc.2014.05.044] [PMID: 24853802]
[2]
Hensel, M. Evolution of pathogenicity islands of Salmonella enterica. Int. J. Med. Microbiol., 2004, 294(2-3), 95-102.
[http://dx.doi.org/10.1016/j.ijmm.2004.06.025] [PMID: 15493819]
[3]
Shi, Y.; Sun, Z.; Liu, Y.; Shu, J.; Zhang, Y.; Lv, Q.; Wang, J.; Deng, X.; Liu, H.; Qiu, J. Inhibition of the type III secretion system of Salmonella enterica serovar typhimurium via treatment with fraxetin. Microbiol. Spectr., 2022, 10(6), e02949-e22.
[http://dx.doi.org/10.1128/spectrum.02949-22] [PMID: 36377917]
[4]
Shi, Y.; Chen, X.; Shu, J.; Liu, Y.; Zhang, Y.; Lv, Q.; Wang, J.; Deng, X.; Liu, H.; Qiu, J. Harmine, an inhibitor of the type III secretion system of Salmonella enterica serovar Typhimurium. Front. Cell. Infect. Microbiol., 2022, 12, 967149.
[http://dx.doi.org/10.3389/fcimb.2022.967149] [PMID: 36176578]
[5]
Shu, J.; Liu, H.; Liu, Y.; Chen, X.; Yu, Y.; Lv, Q.; Wang, J.; Deng, X.; Guo, Z.; Qiu, J. Tannic acid inhibits Salmonella enterica serovar typhimurium infection by targeting the type III secretion system. Front. Microbiol., 2022, 12, 784926.
[http://dx.doi.org/10.3389/fmicb.2021.784926] [PMID: 35145491]
[6]
Lv, Q.; Lv, Y.; Dou, X.; Wassy, S.L.; Jia, G.; Wei, L.; Yu, Q.; Deng, X.; Zhang, C.; Wang, J. Myricetin inhibits the type III secretion system of Salmonella enterica serovar typhimurium by downregulating the Salmonella pathogenic island I gene regulatory pathway. Microb. Pathog., 2021, 150, 104695.
[http://dx.doi.org/10.1016/j.micpath.2020.104695] [PMID: 33418000]
[7]
Kurtz, J.R.; Goggins, J.A.; McLachlan, J.B. Salmonella infection: Interplay between the bacteria and host immune system. Immunol. Lett., 2017, 190, 42-50.
[http://dx.doi.org/10.1016/j.imlet.2017.07.006] [PMID: 28720334]
[8]
Zhou, D.; Mooseker, M.S.; Galán, J.E. Role of the S. typhimurium actin-binding protein SipA in bacterial internalization. Science, 1999, 283(5410), 2092-2095.
[http://dx.doi.org/10.1126/science.283.5410.2092] [PMID: 10092234]
[9]
Lv, Q.; Chu, X.; Yao, X.; Ma, K.; Zhang, Y.; Deng, X. Inhibition of the type III secretion system by syringaldehyde protects mice from Salmonella enterica serovar Typhimurium. J. Cell. Mol. Med., 2019, 23(7), 4679-4688.
[http://dx.doi.org/10.1111/jcmm.14354] [PMID: 31066220]
[10]
Moest, T.P.; Méresse, S. Salmonella T3SSs: Successful mission of the secret(ion) agents. Curr. Opin. Microbiol., 2013, 16(1), 38-44.
[http://dx.doi.org/10.1016/j.mib.2012.11.006] [PMID: 23295139]
[11]
Figueira, R.; Holden, D.W. Functions of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system effectors. Microbiology, 2012, 158(5), 1147-1161.
[http://dx.doi.org/10.1099/mic.0.058115-0] [PMID: 22422755]
[12]
Hapfelmeier, S.; Ehrbar, K.; Stecher, B.; Barthel, M.; Kremer, M.; Hardt, W.D. Role of the salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar typhimurium colitis in streptomycin-pretreated mice. Infect. Immun., 2004, 72(2), 795-809.
[http://dx.doi.org/10.1128/IAI.72.2.795-809.2004] [PMID: 14742523]
[13]
Ehrbar, K.; Mirold, S.; Friebel, A.; Stender, S.; Hardt, W.D. Characterization of effector proteins translocated via the SPI1 type III secretion system of Salmonella typhimurium. Int. J. Med. Microbiol., 2001, 291(6-7), 479-485.
[http://dx.doi.org/10.1078/1438-4221-00156] [PMID: 11890547]
[14]
Wang, H.; Ng, T.B. Pharmacological activities of fusaric acid (5-butylpicolinic acid). Life Sci., 1999, 65(9), 849-856.
[http://dx.doi.org/10.1016/S0024-3205(99)00083-1] [PMID: 10465344]
[15]
Hidaka, H.; Nagatsu, T.; Takeya, K.; Takeuchi, T.; Suda, H.; Kojiri, K.; Matsuzaki, M.; Umezawa, H. Fusaric acid, a hypotensive agent produced by fungi. J. Antibiot., 1969, 22(5), 228-230.
[http://dx.doi.org/10.7164/antibiotics.22.228] [PMID: 5811396]
[16]
Li, J.; Lv, C.; Sun, W.; Li, Z.; Han, X.; Li, Y.; Shen, Y. Cytosporone B, an inhibitor of the type III secretion system of Salmonella enterica serovar typhimurium. Antimicrob. Agents Chemother., 2013, 57(5), 2191-2198.
[http://dx.doi.org/10.1128/AAC.02421-12] [PMID: 23459474]
[17]
Tucker, S.C.; Galán, J.E. Complex function for SicA, a Salmonella enterica serovar typhimurium type III secretion-associated chaperone. J. Bacteriol., 2000, 182(8), 2262-2268.
[http://dx.doi.org/10.1128/JB.182.8.2262-2268.2000] [PMID: 10735870]
[18]
Li, N.; Fassl, A.; Chick, J.; Inuzuka, H.; Li, X.; Mansour, M.R.; Liu, L.; Wang, H.; King, B.; Shaik, S.; Gutierrez, A.; Ordureau, A.; Otto, T.; Kreslavsky, T.; Baitsch, L.; Bury, L.; Meyer, C.A.; Ke, N.; Mulry, K.A.; Kluk, M.J.; Roy, M.; Kim, S.; Zhang, X.; Geng, Y.; Zagozdzon, A.; Jenkinson, S.; Gale, R.E.; Linch, D.C.; Zhao, J.J.; Mullighan, C.G.; Harper, J.W.; Aster, J.C.; Aifantis, I.; von Boehmer, H.; Gygi, S.P.; Wei, W.; Look, A.T.; Sicinski, P. Cyclin C is a haploinsufficient tumour suppressor. Nat. Cell Biol., 2014, 16(11), 1080-1091.
[http://dx.doi.org/10.1038/ncb3046] [PMID: 25344755]
[19]
Guo, Z.; Li, X.; Li, J.; Yang, X.; Zhou, Y.; Lu, C.; Shen, Y. Licoflavonol is an inhibitor of the type three secretion system of Salmonella enterica serovar typhimurium. Biochem. Biophys. Res. Commun., 2016, 477(4), 998-1004.
[http://dx.doi.org/10.1016/j.bbrc.2016.07.018] [PMID: 27387231]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy