23866-15-1Relevant academic research and scientific papers
Synthesis and Structure–Activity Relationship Studies of Benzo[b][1,4]oxazin-3(4H)-one Analogues as Inhibitors of Mycobacterial Thymidylate Synthase X
Modranka, Jakub,Li, Jiahong,Parchina, Anastasia,Vanmeert, Michiel,Dumbre, Shrinivas,Salman, Mayla,Myllykallio, Hannu,Becker, Hubert F.,Vanhoutte, Roeland,Margamuljana, Lia,Nguyen, Hoai,Abu El-Asrar, Rania,Rozenski, Jef,Herdewijn, Piet,De Jonghe, Steven,Lescrinier, Eveline
, p. 645 - 662 (2019/02/25)
Since the discovery of a flavin-dependent thymidylate synthase (ThyX or FDTS) that is absent in humans but crucial for DNA biosynthesis in a diverse group of pathogens, the enzyme has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous screening efforts and report herein an optimization campaign of a novel series of inhibitors with a unique inhibition profile. The inhibitors display competitive inhibition toward the methylene tetrahydrofolate cofactor of ThyX, enabling us to generate a model of the compounds bound to their target, thus offering insight into their structure–activity relationships.
Development of small-molecule Trypanosoma brucei N-myristoyltransferase inhibitors: Discovery and optimisation of a novel binding mode
Spinks, Daniel,Smith, Victoria,Thompson, Stephen,Robinson, David A.,Luksch, Torsten,Smith, Alasdair,Torrie, Leah S.,McElroy, Stuart,Stojanovski, Laste,Norval, Suzanne,Collie, Iain T.,Hallyburton, Irene,Rao, Bhavya,Brand, Stephen,Brenk, Ruth,Frearson, Julie A.,Read, Kevin D.,Wyatt, Paul G.,Gilbert, Ian H.
, p. 1821 - 1836 (2015/11/10)
The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei. HATs off to diversity! Screening a diverse library against Trypanosoma brucei N-myristoyltransferase (NMT) identified hits based on thiazolidinone and benzomorpholine scaffolds. X-ray crystallography of these compounds bound to Leishmania major NMT revealed novel active site binding conformations. Using the structural information, the benzomorpholine scaffold was optimised to a blood-brain barrier penetrant compound with activity against TbNMT of 0.002 μm.
