The Ugi three component reaction (U‐3CR) is a variation of the famous Ugi reaction, discovered almost 60 years ago. Today it is somehow neglected, compared to the classical variation, although the α‐aminoamides, derived from this reaction, have been utilized as inhibitors for various targets and even commercial drugs, offering improved pharmacokinetic properties. In this review, we are describing the scope and limitations of the reaction with a special focus on the developed catalytic protocols, the bioactive compounds, and drugs which are based on the reaction and finally the post modifications that have been reported in order to access drug‐like and privileged scaffolds. A special focus is given to the 3D solid state conformations of the U‐3CR derivatives.

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage‐gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)‐based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single‐crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three‐component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.