6346-07-2Relevant articles and documents
Irreversible inhibitors of the proline racemase unveil innovative mechanism of action as antibacterial agents against Clostridioides difficile
Barbut, Frédéric,Blondel, Arnaud,Gateau, Cécile,Gouault, Nicolas,Melo, Guilherme D.,Minoprio, Paola,Renault, Jacques,Tasseau, Olivier,Uriac, Philippe
, (2022/01/11)
Proline racemases (PRAC), catalyzing the l-proline and d-proline interconversion, are essential factors in eukaryotic pathogens such as Trypanosoma cruzi, Trypanosoma vivax, and Clostridioides difficile. If the discovery of irreversible inhibitors of T.?cruzi PRAC (TcPRAC) led to innovative therapy of the Chagas disease, no inhibitors of CdPRAC have been discovered to date. However, C.?difficile, due to an increased incidence in recent years, is considered as a major cause of health threat. In this work, we have taken into account the similarity between TcPRAC and CdPRAC enzymes to design new inhibitors of CdPRAC. Starting from (E) 4-oxopent-2-enoic acid TcPRAC irreversible inhibitors, we synthesized 4-aryl substituted analogs and evaluated their CdPRAC enzymatic inhibition against eleven strains of C.?difficile. This study resulted in promising candidates and allowed for identification of (E)-4-(3-bromothiophen-2-yl)-4-oxobut-2-enoic acid 20 that was chosen for complementary in vivo studies and did not reveal in vivo toxicity.
Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis
Wang, Penghui,Wang, Xuewei,Wang, Zhengning,Zhao, Junfeng
supporting information, p. 10374 - 10381 (2021/07/26)
Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.
Visible Light-Driven Efficient Synthesis of Amides from Alcohols using Cu?N?TiO2 Heterogeneous Photocatalyst
Singha, Krishnadipti,Ghosh, Subhash Chandra,Panda, Asit Baran
, p. 657 - 662 (2021/02/02)
Amides were synthesized from alcohols and amines in high yields using an in situ generated active ester of N-hydroxyimide with our developed Cu?N?TiO2 catalyst at room temperature using oxygen as a sole oxidant under visible light. The catalyst can be easily prepared, robust, and recycled four times without a considerable change in catalytic activity. This developed protocol applies to a wide substrate scope and has good functional group tolerance. The application of this amidation reaction has been successfully demonstrated for the synthesis of moclobemide, an antidepressant drug, and an analog of the itopride drug on a gram scale.
