Applications of Multicomponent Reactions in Drug Discovery – Lead Generation to Process Development

Abstract

With the emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multicomponent reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi [1] and Biginelli [2] reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. This review details the utility of MCRs in the drug discovery process and representative examples will be given demonstrating the successful impact of these reactions at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, traditional small molecules and ''biotech'' therapeutics respectively. Mechanistic details of these reactions are beyond the scope of the chapter and are described elsewhere in the book. The chapter will be organized chronologically around reaction classes, with subsections dealing with their impact on drug discovery. Representative case studies of the discovery of novel ligands spanning GPCR, protease, kinase and other gene-family classes will demonstrate the biological versatility of MCR derived small molecule-based ligands.

1,4‐Thienodiazepine‐2,5‐diones via MCR (I): Synthesis, Virtual Space and p53‐Mdm2 Activity

“…Multicomponent reaction (MCR) is an alternative strategy in different drug discovery stages including lead discovery and preclinical process development (7). MCRs allow the resource and cost effective, fast, and convergent synthesis of diverse compound libraries, and highly improve the efficiency to explore the chemical space with limited synthetic effort (8).…”

Green synthesis of polyhydroquinolines via MCR using Fe3O4/SiO2-OSO3H nanostructure catalyst and prediction of their pharmacological and biological activities by PASS

“…Multicomponent reactions (MCRs) could provide facile, efficient and practical methods in modern medicinal and combinatorial chemistry for the construction of molecular complexity and structural diversity because they have significant features such as simple design, atom-economy, environmental benignity and the possibility to construct target compounds using several assorted elements through one-pot processes and simple chemical procedures [1][2][3][4][5].…”

“…In this purpose, sulfonated silica-based magnetic nanocatalyst (Fe 3 O 4 /SiO 2 -OSO 3 H) was used as a green heterogeneous nanocatalyst in a one-pot MCR starting from diverse aromatic and heteroaromatic aldehyde 1, dimedone/cyclohexandione 2, ethyl-or methyl-acetoacetate 3 and NH 4 OAc.…”

Synergy Effects in the Chemical Synthesis and Extensions of Multicomponent Reactions (MCRs)—The Low Energy Way to Ultra-Short Syntheses of Tailor-Made Molecules

“…With respect to 14: Many capabilities and properties of MCRs make them particularly suitable for Drug Design and Discovery [92,181,192,199,200] primarily with the higher order MCRs, which can easily generate very large libraries as Table 5 clearly indicates. The availability of MCRs has become so diverse that, in combination with each other and with post condensation modifications such as tandem, cascade or domino reactions, we can now look at an extremely high structural diversity of products.…”