38941-47-8Relevant articles and documents
4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors
Gavara, Laurent,Legru, Alice,Verdirosa, Federica,Sevaille, Laurent,Nauton, Lionel,Corsica, Giuseppina,Mercuri, Paola Sandra,Sannio, Filomena,Feller, Georges,Coulon, Rémi,De Luca, Filomena,Cerboni, Giulia,Tanfoni, Silvia,Chelini, Giulia,Galleni, Moreno,Docquier, Jean-Denis,Hernandez, Jean-Fran?ois
, (2021/06/15)
In Gram-negative bacteria, the major mechanism of resistance to β-lactam antibiotics is the production of one or several β-lactamases (BLs), including the highly worrying carbapenemases. Whereas inhibitors of these enzymes were recently marketed, they only target serine-carbapenemases (e.g. KPC-type), and no clinically useful inhibitor is available yet to neutralize the class of metallo-β-lactamases (MBLs). We are developing compounds based on the 1,2,4-triazole-3-thione scaffold, which binds to the di-zinc catalytic site of MBLs in an original fashion, and we previously reported its promising potential to yield broad-spectrum inhibitors. However, up to now only moderate antibiotic potentiation could be observed in microbiological assays and further exploration was needed to improve outer membrane penetration. Here, we synthesized and characterized a series of compounds possessing a diversely functionalized alkyl chain at the 4-position of the heterocycle. We found that the presence of a carboxylic group at the extremity of an alkyl chain yielded potent inhibitors of VIM-type enzymes with Ki values in the μM to sub-μM range, and that this alkyl chain had to be longer or equal to a propyl chain. This result confirmed the importance of a carboxylic function on the 4-substituent of 1,2,4-triazole-3-thione heterocycle. As observed in previous series, active compounds also preferentially contained phenyl, 2-hydroxy-5-methoxyphenyl, naphth-2-yl or m-biphenyl at position 5. However, none efficiently inhibited NDM-1 or IMP-1. Microbiological study on VIM-2-producing E. coli strains and on VIM-1/VIM-4-producing multidrug-resistant K. pneumoniae clinical isolates gave promising results, suggesting that the 1,2,4-triazole-3-thione scaffold worth continuing exploration to further improve penetration. Finally, docking experiments were performed to study the binding mode of alkanoic analogues in the active site of VIM-2.
Synthesis, Dissociation Constants, and Antimicrobial Activity of Novel 2,3-Disubstituted-1,3-thiazolidin-4-one Derivatives
Popiolek, Lukasz,Stefaska, Joanna,Kielczykowska, Malgorzata,Musik, Irena,Biernasiuk, Anna,Malm, Anna,Wujec, Monika
, p. 393 - 402 (2016/04/19)
In this article, a new series of 2,3-disubstituted-1,3-thiazolidin-4-one derivatives have been designed, synthesized, and evaluated as antimicrobial agents. New compounds were prepared by the cyclization reaction of N-substituted carboxylic acid hydrazide derivatives with mercaptoacetic acid. The structures of the obtained compounds were confirmed by means of IR, 1H NMR, and 13C NMR spectra. The dissociation constants were determined using spectrophotometric method. All synthesized compounds were tested for their in vitro antibacterial and antifungal activities using the broth microdilution method.
Acylhydrazone derivative used for treating heart failure
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Paragraph 0042; 0043; 0044, (2016/10/08)
The invention belongs to the technical field of medicines, and relates to design and preparation method for acylhydrazone derivatives shown as a general formula I, and the acylhydrazone derivatives can be used for treating systolic heart failure comprising congestive heart failure.
