Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-Fused 2-Pyridones: Pilicides with Increased Antivirulence Activity

Abstract

Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X ray crystallography.

Purification, crystallization and preliminary X-ray diffraction analysis of theEscherichia colicommon pilus chaperone EcpB

“…Molecular replacement was attempted with AMoRe (Navaza, 2001), MOLREP (Vagin & Teplyakov, 2010), Phaser (McCoy, 2007 and within MR_Rosetta (Terwilliger et al, 2012) using all known structures of chaperone-usher pathway chaperones as search models: CupB2 (PDB entry 3q48; Cai et al, 2011), SafB (PDB entry 2co7; Remaut et al, 2006), DraB (PDB entry 4djm; Z. Dauter, R. Piatek, M. Dauter & A. Brzuszkiewicz, unpublished work), FimC (PDB entry 1klf; Hung et al, 2002), Caf1M (PDB entry 4ay0; Yu et al, 2012), PapD (PDB entry 2xg5; Chorell et al, 2010), CfaA (PDB entry 4ncd; Bao et al, 2014), SfaE (PDB entry 1l4i; Knight et al, 2002) and FaeE (PDB entry 3gfu; Van Molle et al, 2009). Unfortunately, no solutions were found; however, the sequence identity between EcpB and these homologues is less than 20%.…”

Synthesis and Antibacterial Evaluation of 2-Ethyl-1-(4-substituted)phenyl- 1H-imidazole Derivatives as Open-Chain Analogues of 7-Alkoxyl-4,5-dihydroimidazo[1,2-a]quinolines

“…Procedure for synthesis of 2-ethyl-1-(4-hydroxy)phenyl-1H-imidazole (4) Under ice-salt bath, to a solution of compound 3 (3.74 g, 20 mmol) in sulfuric acid solution (25%, 50 mL), it was added dropwise sodium nitrite solution (1.52 g, 22 mmol, in 22 mL of H 2 O), the reaction temperature was maintained at 0 °C or below. When the addition of the sodium nitrite was complete, it was stirred at 5 °C for 1 h to complete the reaction.…”

“…Structure modification of quinoline led to new efficient antibacterial candidate agents. [1][2][3][4] However, due to clinically significant parasite resistance to antibacterial drugs, there is an urgent need to promote the quest for new efficacious drugs to fight against resistant pathogens. [5][6][7] In the course of searching for newer antibacterial candidates, we focused our attention on modifying the structure of quinoline and its analogues.…”

Solvent-free one-pot efficient and highly regioselective access to functionalized thiazolopyridones from α-enolic dithioesters

“…They exhibit activities like DNA gyrase B inhibitors 8,9 and antibacterial agents. 10,11 Furthermore, thiazolopyridones have also been utilized in the synthesis of natural-product-like heterocycles. 12 Thiazolo ring-fused 2-pyridones have proven to be highly interesting scaffolds for the development of biologically active compounds particularly introducing a variety of substituents in the 2-pyridone part of the heterocycles.…”