10.1021/ml400359z
The research aims to develop small-molecule MDM2 inhibitors to restore dysfunctional p53 activities for cancer treatment. The study builds on previous work on a non-imidazoline MDM2 inhibitor, RG7388, and explores additional derivatives to expand chemodiversity and identify potent and selective MDM2 antagonists with desirable pharmacological properties. The researchers focused on bioisosteric replacements of the 6-chlorooxindole group in RO8994, leading to the identification of two highly potent, selective, and orally active p53-MDM2 inhibitors, RO2468 and RO5353. These compounds demonstrated excellent in vitro and in vivo pharmacokinetic profiles and significant tumor regression in mouse models at doses comparable to RO8994. The key chemicals used in the research include RO8994, RO2468 (14), and RO5353 (16), along with various analogues such as 4-azaoxindole (I), 5-azaoxindole (II), 7-azaoxindole (III), 2-chloropyrrolo[2,3-d]pyrimidin-6-one (IV), and 2-chlorothienyl[3,2-b]pyrrol-5-one (V). The study concludes that RO2468 and RO5353 have promising potential for clinical development.
10.1002/ejoc.202100172
The research aims to develop new antimicrobial agents targeting thymidylate monophosphate kinase (TMPK), an enzyme essential for DNA synthesis in bacteria. The study explores the synthesis of imidazopyridinones and 7-azaoxindoles, two heterocyclic compounds with limited previous use in medicinal chemistry, to identify robust and safe synthetic methods for these potential inhibitors. The imidazopyridinones were found to be potent inhibitors of E. coli TMPK, with compound 1 showing an IC50 value of 1.4 μM and compound 2 having an IC50 of 5.6 μM. However, the 7-azaoxindole (compound 3) exhibited low activity with an IC50 of 83 μM. Despite their enzymatic activity, none of the compounds showed antimicrobial activity against E. coli or S. aureus cultures, likely due to poor cell wall penetration. The study concludes that while the imidazopyridinones are effective TMPK inhibitors, further research is needed to improve cell membrane permeability and explore alternative applications for the 7-azaoxindole class.
