613-58-1Relevant academic research and scientific papers
Amide pyridine derivative and application thereof
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Paragraph 0106; 0109; 0110, (2019/02/06)
The invention belongs to the technical field of medicine and relates to an amide pyridine derivative which is shown as a general formula I. The invention further relates to stereoisomer and pharmaceutically-acceptable salt, hydrate, solvate or prodrug of the amide pyridine derivative. The definitions of substituent groups of Ar, M, R and Py are given out in an instruction book. The invention further relates to a method for preparing the compound shown in the general formula I, pharmaceutical composition containing the compound and application of the compound and the pharmaceutical compositionin preparing medicine for treating and preventing superficial-layer fungal diseases and deep-layer fungal diseases.
Design, synthesis and biological evaluation of amide-pyridine derivatives as novel dual-target (SE, CYP51)antifungal inhibitors
Sun, Bin,Dong, Yue,Lei, Kang,Wang, Jian,Zhao, Liyu,Liu, Min
, p. 2427 - 2437 (2019/02/14)
Based on the analysis of the squalene cyclooxygenase (SE)and 14α-demethylase (CYP51)inhibitors pharmacophore feature and the dual-target active sites, a series of compounds with amide-pyridine scaffolds have been designed and synthesized to treat the increasing incidence of drug-resistant fungal infections. In vitro evaluation showed that these compounds have a certain degree of antifungal activity. The most potent compounds 11a, 11b with MIC values in the range of 0.125–2 μg/ml had a broad-spectrum antifungal activity and exhibited excellent inhibitory activity against drug-resistant pathogenic fungi. Preliminary mechanism studies revealed that the compound 11b might play an antifungal role by inhibiting the activity of SE and CYP51. Notably compounds did not show the genotoxicity through plasmid binding assay. Finally, this study of molecular docking, ADME/T prediction and the construction of 3D QSAR model were performed. These results can point out the direction for further optimization of the lead compound.
Docking and Linking of Fragments to Discover Jumonji Histone Demethylase Inhibitors
Korczynska, Magdalena,Le, Daniel D.,Younger, Noah,Gregori-Puigjané, Elisabet,Tumber, Anthony,Krojer, Tobias,Velupillai, Srikannathasan,Gileadi, Carina,Nowak, Rados?aw P.,Iwasa, Eriko,Pollock, Samuel B.,Ortiz Torres, Idelisse,Oppermann, Udo,Shoichet, Brian K.,Fujimori, Danica Galoni?
, p. 1580 - 1598 (2016/03/08)
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600a€ˉ000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ～3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.
Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate-dependent nucleic acid demethylase
Woon, Esther C. Y.,Demetriades, Marina,Bagg, Eleanor A. L.,Aik, Weishen,Krylova, Svetlana M.,Ma, Jerome H. Y.,Chan, Munchiang,Walport, Louise J.,Wegman, David W.,Dack, Kevin N.,McDonough, Michael A.,Krylov, Sergey N.,Schofield, Christopher J.
experimental part, p. 2173 - 2184 (2012/05/20)
2-Oxoglutarate-dependent nucleic acid demethylases are of biological interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiology, their regulatory roles are unclear. Hence, there is a de
Enantioselective solid-phase synthesis of α-amino acid derivatives
O'Donnell, Martin J.,Delgado, Francisca,Pottorf, Richard S.
, p. 6347 - 6362 (2007/10/03)
Wang-resin bound derivatives of glycine Schiff base esters are alkylated in the presence of quaternary ammonium salts derived from cinchonidine or cinchonine using phosphazene bases to give either enantiomer of the product α-amino acid derivatives in 51-89% ee.
