Fragment-Sized Thiazoles in Fragment-Based Drug Discovery Campaigns: Friend or Foe?
Matic Proj, Martina Hrast, Damijan Knez, Krištof Bozovičar, Katarina Grabrijan, A. Meden, Stanislav Gobec, Rok Frlan · ACS Medicinal Chemistry Letters · 2022
High Resolution Image Download MS PowerPoint Slide Thiazoles exhibit a wide range of biological activities and therefore represent useful and attractive building blocks. To evaluate their usefulness and pinpoint their liabilities in fragment screening campaigns, we assembled a focused library of 49 fragment-sized thiazoles and thiadiazoles with various substituents, namely amines, bromides, carboxylic acids, and nitriles. The library was profiled in a cascade of biochemical inhibition assays, redox activity, thiol reactivity, and stability assays. Our study indicates that when thiazole derivatives are identified as screening hits, their reactivity should be carefully addressed and correlated with specific on-target engagement. Importantly, nonspecific inhibition should be excluded using experimental approaches and in silico predictions. To help with validation of hits identified in fragment screening campaigns, we can apply our high-throughput profiling workflow to focus on the most tractable compounds with a clear mechanism of action.