286932-39-6Relevant articles and documents
Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design to Minimize Host Kinase Interactions
Wang, Tiansheng,Bemis, Guy,Hanzelka, Brian,Zuccola, Harmon,Wynn, Michael,Moody, Cameron Stuver,Green, Jeremy,Locher, Christopher,Liu, Aixiang,Gao, Hongwu,Xu, Yuzhou,Wang, Shaohui,Wang, Jie,Bennani, Youssef L.,Thomson, John A.,Müh, Ute
supporting information, p. 1224 - 1229 (2017/12/26)
Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 μM (1-2 μg/mL) against the H37Ra isolate of M. tuberculosis.
A convergent synthesis of AR-C123196 utilising reaction between a cyclic carbonate and a phenol for aryl alkyl ether formation
Allsop, Glyn L.,Cole, Andrea J.,Giles, Melvyn E.,Merifield, Eric,Noble, Allison J.,Pritchett, Michael A.,Purdie, Lindsay A.,Singleton, John T.
experimental part, p. 751 - 759 (2010/04/22)
The development of a convergent synthesis of AR-C123196 is reported in which the alkyl aryl ether linkage was formed by nucleophilic attack of a phenolic hydroxyl group onto a cyclic carbonate. This approach was successfully operated on a multikilogram sc