96943-10-1Relevant articles and documents
1-(1-Arylethylpiperidin-4-yl)thymine analogs as antimycobacterial TMPK inhibitors
Boshoff, Helena I. M.,Caljon, Guy,Forbes, He Eun,Hulpia, Fabian,Jian, Yanlin,Munier-Lehmann, Hélène,Risseeuw, Martijn D. P.,van Calenbergh, Serge
, (2020/07/07)
A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).
Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Song, Lijun,Merceron, Romain,Gracia, Bego?a,Quintana, Ainhoa Lucía,Risseeuw, Martijn D. P.,Hulpia, Fabian,Cos, Paul,Aínsa, José A.,Munier-Lehmann, Hélène,Savvides, Savvas N.,Van Calenbergh, Serge
, p. 2753 - 2775 (2018/04/23)
In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure-activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
Pd-catalyzed deoxygenation of mandelate esters
Milne, Jacqueline E.,Murry, Jerry A.,King, Anthony,Larsen, Robert D.
supporting information; experimental part, p. 445 - 447 (2009/04/10)
(Chemical Equation Presented) A new approach to the synthesis of phenylacetic acids and esters has been developed via the palladium-catalyzed deoxygenation of mandelate esters.
