A study investigated the chemistry and biology of multicomponent reactions (MCRs) and considers the advantages of MCR flows. Among the advantages of MCRs is their very high bond-forming index.
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Tetrazoles via Multicomponent Reactions Neochoritis, Constantinos G; Zhao, Ting; Dömling, Alexander
Chemical reviews,
02/2019, Volume:
119, Issue:
3
Journal Article
Peer reviewed
Open access
Tetrazole derivatives are a prime class of heterocycles, very important to medicinal chemistry and drug design due to not only their bioisosterism to carboxylic acid and amide moieties but also to ...their metabolic stability and other beneficial physicochemical properties. Although more than 20 FDA-approved drugs contain 1H- or 2H-tetrazole substituents, their exact binding mode, structural biology, 3D conformations, and in general their chemical behavior is not fully understood. Importantly, multicomponent reaction (MCR) chemistry offers convergent access to multiple tetrazole scaffolds providing the three important elements of novelty, diversity, and complexity, yet MCR pathways to tetrazoles are far from completely explored. Here, we review the use of multicomponent reactions for the preparation of substituted tetrazole derivatives. We highlight specific applications and general trends holding therein and discuss synthetic approaches and their value by analyzing scope and limitations, and also enlighten their receptor binding mode. Finally, we estimated the prospects of further research in this field.
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Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent inhibitors in the late 18th century, the field has advanced ...significantly and currently about 30% of the marketed drugs are covalent inhibitors. The numerous advantages of covalent inhibitors are counteracting the initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. The aim of this review is to provide a short historic overview and focus on recently developed covalent inhibitors (2011-2019), including structural aspects and examples on challenging targets.
In this review we provide a brief historic overview of covalent inhibitors and summarize recent advances focusing on developments in the last decade. Applications in challenging targets and future perspectives are also discussed.
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This year represents the 100th anniversary of the discovery of the Passerini three-component reaction. The related Ugi four-compound reaction was discovered 37 years after the Passerini reaction. ...Undoubtedly, both reactions are very important multicomponent reactions but the Ugi reactions outperform the Passerini reactions in terms of combinatorial space according to the equation xy x is the number of building blocks per component, and y is the order of the multicomponent reaction (for Passerini, y = 3; for Ugi, y = 4). In this work, a historical but contemporary perspective of the discoveries and innovations of the two reactions is given. From a bird’s eye view and in a more general sense, the discovery of novel reactions is discussed and how it relates to inventions and innovations.
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5.
The Groebke‐Blackburn‐Bienaymé Reaction Boltjes, André; Dömling, Alexander
European journal of chemistry,
November 14, 2019, Volume:
2019, Issue:
42
Journal Article
Peer reviewed
Open access
Imidazo1,2‐apyridine is a well‐known scaffold in many marketed drugs, such as Zolpidem, Minodronic acid, Miroprofen and DS‐1 and it also serves as a broadly applied pharmacophore in drug discovery. ...The scaffold revoked a wave of interest when Groebke, Blackburn and Bienaymé reported independently a new three component reaction resulting in compounds with the imidazo1,2‐a‐heterocycles as a core structure. During the course of two decades the Groebke Blackburn Bienaymé (GBB‐3CR) reaction has emerged as a very important multicomponent reaction (MCR), resulting in over a hundred patents and a great number of publications in various fields of interest. Now two compounds derived from GBB‐3CR chemistry received FDA approval. To celebrate the first 20 years of GBB‐chemistry, we present an overview of the chemistry of the GBB‐3CR, including an analysis of each of the three starting material classes, solvents and catalysts. Additionally, a list of patents and their applications and a more in‐depth summary of the biological targets that were addressed, including structural biology analysis, is given.
Over the past 20 years, the Groebke‐Blackburn‐Bienaymè reaction, one of the youngest IMCRs, has gained much interest. Since 1998, a total of >200 peer reviewed publications and >100 patent applications have been reported. This overview describes the development of the GBB reaction and includes a tabular analysis to show exactly which reagents were reported as one of three components in the GBB reaction.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Discovering novel synthetic routes for rigid nitrogen-containing polyheterocycles using sustainable, atom-economical, and efficient (= short) synthetic pathways is of high interest in organic ...chemistry. Here, we describe an operationally simple and short synthesis of the privileged scaffold dihydropyrrolo1,2-apyrazine-dione from readily accessible starting materials. The alkaloid-type polycyclic scaffold with potential bioactivity was achieved by a multicomponent reaction (MCR)-based protocol via a Ugi four-component reaction and Pictet–Spengler sequence under different conditions, yielding a diverse library of products.
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Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of ...disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenylmethanol induce an enlarged interaction interface that results in the open “face-back” tunnel through the PD-L1 dimer.
Multicomponent reactions, particularly the Passerini reaction, serve as efficient tools for the synthesis of druglike molecules and the creation of compound libraries. Despite the effectiveness of ...the Passerini reaction, the limited alternatives to the crucial carboxylic acid component pose a structural constraint. Here, we have discovered that the phthalimide moiety and its derivatives react in the Passerini reaction as an acid component. We explored their potential in synthesizing diverse and intricate molecules. The phthalimide moiety stands out as a favorable building block due to its oxidative stability, heat-stable characteristics, and resistance to solvents. Our approach introduces a novel perspective to multicomponent reactions by incorporating NH-based acid components, addressing the ongoing need for the development of innovative molecular scaffolds.
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•TNF-α is a major driver of inflammatory diseases.•TNF- α is among the top five drug targets, therapeutically and economically.•TN- α market is dominated by biologics.•New oral small molecule TNF-α ...antagonists show comparable activity to antibodies in disease models.
In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira® generated US$165.8 billion in cumulative sales and snatched the crown for the industry’s most successful drug from Lipitor (atorvastatin). TNF-α is a major component in beneficial and disease-related inflammation and TNF-α-inhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-α inhibitors, such as Alzheimer’s disease (AD) or major depression. However, the nature of TNF-α-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Isocyanide 2.0 Patil, Pravin; Ahmadian-Moghaddam, Maryam; Dömling, Alexander
Green chemistry,
10/2020, Volume:
22, Issue:
2
Journal Article
Peer reviewed
Open access
The isocyanide functionality due to its dichotomy between carbenoid and triple bond characters, with a nucleophilic and electrophilic terminal carbon, exhibits unusual reactivity in organic chemistry ...exemplified for example in the Ugi reaction. Unfortunately, the over proportional use of only a few isocyanides hampers novel discoveries about the fascinating reactivity of this functional group. The synthesis of a broad range of isocyanides with multiple functional groups is lengthy, inefficient, and exposes the chemist to hazardous fumes. Here we present an innovative isocyanide synthesis overcoming these problems by avoiding the aqueous workup which we exemplify by parallel synthesis from a 0.2 mmol scale performed in 96-well microtiter plates up to a 0.5 mol multigram scale. The advantages of our methodology include an increased synthesis speed, very mild conditions giving access to hitherto unknown or highly reactive classes of isocyanides, rapid access to large numbers of functionalized isocyanides, increased yields, high purity, proven scalability over 5 orders of magnitude, increased safety and less reaction waste resulting in a highly reduced environmental footprint. For example, the hitherto believed to be unstable 2-isocyanopyrimidine, 2-acylphenylisocyanides and even
o
-isocyanobenzaldehyde could be accessed on a preparative scale and their chemistry was explored. Our new isocyanide synthesis will enable easy access to uncharted isocyanide space and will result in many discoveries about the unusual reactivity of this functional group.
Isocyanides are important chemicals, with limited availability, thus reducing their general use. Our highly improved isocyanide synthesis performed on mole to μ-mole scale, individually or in a 96-well parallel fashion enables unprecedented exploration of novel chemistries.
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