20334-86-5Relevant academic research and scientific papers
Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors
Kaya, Cansu,Walter, Isabell,Yahiaoui, Samir,Sikandar, Asfandyar,Alhayek, Alaa,Konstantinovi?, Jelena,Kany, Andreas M.,Haupenthal, J?rg,K?hnke, Jesko,Hartmann, Rolf W.,Hirsch, Anna K. H.
, (2021/12/16)
Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.
Synthesis and anti-parasitic activity of C-benzylated (N-arylcarbamoyl)alkylphosphonate esters
Adeyemi, Christiana M.,Isaacs, Michelle,Mnkandhla, Dumisani,Klein, Rosalyn,Hoppe, Heinrich C.,Krause, Rui W.M.,Lobb, Kevin A.,Kaye, Perry T.
, p. 1661 - 1667 (2017/03/08)
Unexpected substituent-dependent regioselectivty challenges in the synthesis of C-benzylated (N-arylcarbamoyl)phosphonate esters have been resolved. The C-benzylated N-furfurylcarbamoyl derivative showed low micromolar PfLDH inhibition, while one of the C-benzylated N-arylcarbamoyl analogues was active against Nagana Trypanosoma brucei parasites which are responsible for African trypanosomiasis in cattle.
Nucleophilic carbene and HOAt relay catalysis in an amide bond coupling: An orthogonal peptide bond forming reaction
Vora, Harit U.,Rovis, Tomislav
, p. 13796 - 13797 (2008/09/17)
A catalyzed internal redox process provides a route from α-reducible aldehydes and amines to α-reduced amides. The chemistry is catalyzed by nucleophilic carbenes and common peptide cocatalysts such as HOBt and HOAt in a relay fashion. The transformation proceeds in excellent yields using a variety of primary and secondary alkyl and aryl amines. The aldehyde component may be varied from haloaldehydes to epoxy and aziridino aldehydes as well as enals. The latter three substrates provide for a waste-free amide bond forming reaction. Copyright
