Eman M. M. Abdelraheem

Versatile Multicomponent Reaction Macrocycle Synthesis Using α-Isocyano-ω-carboxylic Acids

The direct macrocycle synthesis of α-isocyano-ω-carboxylic acids via an Ugi multicomponent reaction is introduced. This multicomponent reaction (MCR) protocol differs by being especially short, convergent, and versatile, giving access to 12-22 membered rings.

Two‐Step Synthesis of Complex Artificial Macrocyclic Compounds

The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and works over a wide range of medium (8-11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug-like compounds. As an application of these artificial macrocycles we highlight potent p53-MDM2 antagonism.

Concise Synthesis of Tetrazole Macrocycle

A concise two step synthesis of tetrazole containing macrocycles from readily accessible starting materials is presented. The first step comprises a chemoselective amidation of amino acid derived isocyanocarboxylicacid esters with unprotected symmetrical diamines to afford diverse α-isocyano-ω-amines. In the second step, the α-isocyano-ω-amines undergo an Ugi tetrazole reaction to close the macrocycle. Advantageously, this strategy allows short access to 11–19-membered macrocycles in which substituents can be independently varied at three different positions.

2-(Piperidin-1-yl)-6-(1H-pyrrol-1-yl)pyridine-3,5-dicarbonitrile.

The piperidine ring of the title compound, C16H15N5, adopts a chair conformation. The pyridine ring is essentially planar, with a maximum deviation of 0.035 (3) Å. The pyrrole and pyridine rings are almost coplanar, forming a dihedral angle of 3.48 (14)°. In the crystal, no classical hydrogen bonds were found. In the crystal, the molecules are linked by aromatic π–π stacking [centroid–centroid separations = 3.4984 (16) and 3.9641 (15) Å between pyrrole and pyridine rings and between pyridine rings, respectively].

Focusing on shared subpockets – new developments in fragment-based drug discovery

Introduction: Protein–protein interactions (PPIs) are important targets for understanding fundamental biology and for the development of therapeutic agents. Based on different physicochemical properties, numerous pieces of software (e.g., POCKETQUERY, ANCHORQUERY and FTMap) have been reported to find pockets on protein surfaces and have applications in facilitating the design and discovery of small-molecular-weight compounds that bind to these pockets. Areas covered: The authors discuss a pocket-centric method of analyzing PPI interfaces, which prioritize their pockets for small-molecule drug discovery and the importance of multicomponent reaction chemistry as starting points for undruggable targets. The authors also provide their perspectives on the field. Expert opinion: Only the tight interplay of efficient computational methods capable of screening a large chemical space and fast synthetic chemistry will lead to progress in the rational design of PPI antagonists in the future. Early drug discovery platforms will also benefit from efficient rapid feedback loops from early clinical research back to molecular design and the medicinal chemistry bench.

2,2'-[Ethane-1,2-diylbis(-oxy)]dibenz-alde-hyde.

In the title compound, C16H14O4, the benzene rings are inclined at a dihedral angle of 75.14 (9)°. The torsion angle of the bridging O—C—C—O group is −76.50 (11)°. In the crystal, molecules are linked by C—H⋯O hydrogen bonds, forming C(6) chains along [100]. Furthermore, C—H⋯π interactions and π–π stacking interactions [centroid–centroid distances = 3.6957 (7) and 3.6735 (8) Å] contribute to the stability of the crystal packing.

2-(Morpholin-4-yl)-6-(1H-pyrrol-1-yl)­pyridine-3,5-dicarbonitrile

In the title compound, C15H13N5O, the morpholine ring adopts a chair conformation. The dihedral angle between the pyrrole ring and the pyridine ring is 28.93 (14)°. In the crystal, the molecules are linked by C—H⋯O hydrogen bonds occur, and aromatic weak π–π stacking [centroid–centroid separation = 4.178 (2) Å] and C—H⋯π interactions consolidate the packing.

Two-Step Macrocycle Synthesis by Classical Ugi Reaction

The direct nonpeptidic macrocycle synthesis of α-isocyano-ω-amines via the classical Ugi four-component reaction (U-4CR) is introduced. Herein an efficient and flexible two-step procedure to complex macrocycles is reported. In the first step, the reaction between unprotected diamines and isocyanocarboxylic acids gives high diversity of unprecedented building blocks in high yield. In the next step, the α-isocyano-ω-amines undergo a U-4CR with high diversity of aldehydes and carboxylic acids in a one-pot procedure. This synthetic approach is short and efficient and leads to a wide range of macrocycles with different ring sizes.

Macrocycles: MCR synthesis and applications in drug discovery

Macrocycles are an emerging and largely underexploited part of chemical space where potential drugs for difficult genomic targets can be discovered. Macrocycles can have advantages over their natural twins such as better control over synthesis, physicochemical properties and target binding. Fast and convergent synthesis pathways are underdeveloped. Multicomponent reaction (MCR) chemistry is very well suited for the synthesis of a diverse range of macrocycles and is also able to generate great levels of molecular diversity and complexity at low synthetic costs.

Ugi Multicomponent Reaction Based Synthesis of Medium-Sized Rings

An Ugi multicomponent reaction based two-step strategy was applied to generate medium-sized rings. In the first linear expansion phase, a series of diamines reacted with cyclic anhydrides to produce different lengths of terminal synthetic amino acids as the starting material for the second phase. The Ugi-4-center 3-component reaction was utilized to construct complex medium-sized rings (8–11) by the addition of isocyanides and oxo components. This method features mild conditions and a broad substrate scope.