Local Anesthetics via Multicomponent Reactions

Abstract

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.

Multicomponent Reactions for the Synthesis of Active Pharmaceutical Ingredients

“…This compound was synthetised by an Ugi-3CR procedure in a single synthetic step by combination of dimethylamine, formaldehyde and 2,6-xylyl isocyanide (Scheme 42) [95]. The same chemistry has allowed for the efficient preparation of many members of the amide type of local anesthetics [96]. Carfentanil, a μ-opioid agonist used as an analgesic and described in Section 2.1, was synthesised by a direct 4CR-Ugi reaction with a 4-piperidone derivative, aniline, propionic acid and 2-bromo-6-isocyanopyridine.…”

“…This compound was synthetised by an Ugi-3CR procedure in a single synthetic step by combination of dimethylamine, formaldehyde and 2,6-xylyl isocyanide (Scheme 42) [95]. The same chemistry has allowed for the efficient preparation of many members of the amide type of local anesthetics [96]. The pioneering work by Ugi in isocyanide multicomponent reactions boosted the interest in combinatorial chemistry as a tool in drug discovery [93].…”

“…This compound was synthetised by an Ugi-3CR procedure in a single synthetic step by combination of dimethylamine, formaldehyde and 2,6-xylyl isocyanide (Scheme 42) [95]. The same chemistry has allowed for the efficient preparation of many members of the amide type of local anesthetics [96].…”

Multicomponent Synthesis of Purines and Pyrimidines: From the Origin of Life to New Sustainable Approaches for Drug‐Discovery Applications

“…Moreover, compared to the precedent literature syntheses, their new method could claim better atom economy, greener reactants and reaction conditions (avoidance of halogenated compounds and use of water as solvent). [34] MCRs' usefulness in the pharmaceutical industry is not limited to early drug discovery since it can also highly contribute to a more sustainable large scale production of pharmaceuticals. The most famous example is likely the onestep synthesis of Nifedipine, which was synthesized by Bayer chemists using the three-component Hantzsch reaction (Scheme 3).…”

Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity

“…In particular, multicomponent reactions, such as Biginelli, 29 could represent a good strategy that allows practically performing small chemical changes, employing just one different chemical per time, and, thereby, conducting easily but robust structure-activity relationships (SARs). [30][31][32][33][34] Indeed, Biginelli's reaction permits the high-yielding obtainment of 3,4-dihydropyrimidin-2-(1H)-ones and -thiones (DHPMs) 35 by reacting the suitable urea or thiourea with an aromatic aldehyde and a β-ketocarboxyl derivative.…”