Diversity oriented, efficient and sustainable synthetic protocol for the synthesis of structurally diverse drug-like complex heterocycles, incorporating privileged heterocyclic systems

A diversity oriented, efficient and sustainable synthetic protocol has been presented for the synthesis of structurally diverse drug-like small heterocycles with structural complexity. The present synthetic strategy involves a three-component domino reaction of 2-aminobenzothiazoles, thiophene-2-carbaldehyde and carbonyl compounds in the presence of a catalytic amount of sulfamic acid as a recyclable ecofriendly acid catalyst.

Switchable multicomponent heterocyclizations for diversity oriented synthesis

The present comprehensive review1 contains the analysis of literature data concerning switchable multicomponent heterocyclizations and demonstrates the application of these types of reactions to solve the matters of Diversity Oriented Synthesis.

One-Pot Synthesis of Dibenz[b,f][1,4]oxazepines via Mg(ClO4)2-Catalyzed Ugi Four-Component Reaction and Microwave-Assisted Intramolecular SNAr

A general one-pot synthesis of dibenz[b,f][1,4] oxazepine-11(10H)-carboxamides is described. The Ugi four-component reaction (U-4CR) of 2-aminophenols, cyclohexyl isocyanide, 2-chloro-5-nitrobenzaldehyde, and 2-bromobenzoic acids in MeOH in the presence of 25 mol% Mg(ClO

Towards drugging the ‘undruggable’: enhancing the scaffold diversity of synthetic small molecule screening collections using diversity-oriented synthesis

Medicinal chemistry research has traditionally focused upon a limited set of biological targets. Many other human disease-related targets have been termed ‘undruggable’ as they have proved largely impervious to modulation by small molecules. However, it is becoming increasingly evident that such targets can indeed be modulated; they are simply being challenged with the wrong types of molecules. Traditionally, screening libraries were composed of large numbers of structurally similar compounds. However, library size is not everything; the structural diversity of the library, which is largely dictated by the range of molecular scaffolds present, is crucial. Diversity-oriented synthesis (DOS) generates small molecule libraries with high levels of scaffold, and thus structural, diversity. Such collections should provide hits against a broad range of targets with high frequency, including ‘undruggable’ targets. Examples in the area of scaffold diversity generation taken from the author’s laboratories are given.

Diversity-Oriented Synthesis of Peptidomimetics: How and Why

Based on oligopeptide sequences, structural diversity elements from side chain substitutions and backbone amide modifications are used for the preparation of bioactive peptide mimetics, including δ-amino-b,γ-alkenyl, δ-amino-b,γ-cyclopropyl, and γ-amino-a,b-cyclopropyl dipeptide isosteres. The hybrid molecule XJB-5-131 is composed of an alkene dipeptide isostere, a regular tripeptide sequence extracted from the cyclodecapeptide antibiotic gramicidin S (GS), and the free radical scavenger 4-AT. This agent is highly enriched in mitochondria, and, among other positive functions in cells and animal models, it has demonstrated efficacy in improving neurocognitive outcome after traumatic brain injury in rats. It slows down the aging phenotype in Ercc1 progeria models and reduces oxidative damage to mitochondrial DNA, enhancing neuronal survival and improving mitochondrial function in a mouse model of Huntington’s disease. The shortened alkene dipeptide isostere JP4-039 also folds into a b-turn secondary structure in the solid state and mediates several desired physiological and cell-protective effects, including radiation damage prevention and mitigation.

Generation of Molecular Shape Diverstiy. From Privileged Scaffolds to Diverted Total Synthesis

Molecular shape is a presentation of a molecule’s three-dimensional structure and its volume of space and surface electrostatic potential map collectively define the function, e. g. as a modulator or probe to biological targets. Molecular shape diversity for compound libraries with multiple scaffolds (rich skeletal diversity) is recognized as a prerequisite for discovering broad bioactivity. Established strategies and methodologies for diversity-oriented synthesis (DOS) are useful for generating molecular shape diversity by synthesizing natural product-like compounds. On the other hand, diverted total synthesis (DTS) offers natural products and analogues with a higher degree of structural diversity and complexity. Examples of DOS of privileged heterocycles and DTS of amphidinolide T marine macrolides from the author’s laboratories are illustrated.