Approaches for introducing high molecular diversity in scaffolds: Fast parallel synthesis of highly substituted 1H-quinolin-4-one libraries

Abstract

We have developed a two steps strategy for the parallel synthesis of highly diversified quinolin-ones. In the first step we have combined and improved different synthetic methods for generating quinolin-4-ones bearing four different substitutions at specific positions using round bottomed flasks. The synthesis was assessed for a large number of substituted quinolin-4-ones. In the second step, the improved method was adapted to a parallel array synthesis using a 12 positions carrousel as demonstrated for the synthesis of 42-variable quinolin-4-ones. The first combinatorial library set 14(a-x) was obtained with a chemical purity of more than 95% without purification, the second library set 15(a-r), which included two synthetic steps, needed combinatorial purification using an innovative parallel purifier. The proposed approach contributes to a more extensive diversification of molecular scaffolds in general and provides access to highly substituted quinolinones in particular.

The methods of synthesis, modification, and biological activity of 4-quinolones (review)

“…The cyclization of the enamines 16 is realized by the action of heat in high-boiling solvents such as biphenyl [44], biphenyl ether [1, 26,32,34,36,37,41,42,[45][46][47], Dowtherm A [35,38,39,48,49], and mineral oil [1] or by using effective cyclization agents such as polyphosphoric acid or its esters [1, 2], the halogen derivatives of phosphorus [1], ZnCl 2 [1], conc. sulfuric acid in mixture with acetic anhydride [1], and Eaton's reagent (a mixture of phosphorus(V) oxide and methanesulfonic acid) [37,40].…”

“…In addition N-methyl-4-quinolone is again isolated, and this can be explained by the fact that the nitrogen atom of the quinolone ring is involved in the demethylation process [52]. Although the authors in [45,53,54] do not postulate the intermediate formation of an enamine these methods were assigned to type d since they are examples of the known method of construction of the quinoline system by the Conrad-Limpach method. During the reaction of substituted anilines with ethyl aroylacetate in the presence of polyphosphoric acids the substituted 2-aryl-4-quinolones 23 and 24 are formed [53].…”

Design of Small-Sized Libraries by Combinatorial Assembly of Linkers and Functional Groups to a Given Scaffold: Application to the Structure-Based Optimization of a Phosphodiesterase 4 Inhibitor

“…Indeed, chemists succeeded over the years to apply combinatorial synthesis strategies to simple rings and chains to form small organic molecules , and not stay limited to peptide and oligonucleotide polymers. Thus, the virtual combinatorial library has to be designed in order to have its physical counterpart and to guarantee that all compounds are synthesizable.…”

“…10 On the basis of homology and molecular diversity concepts, combining a limited number of linkers and functional groups (cations, anions, hydrogen bond acceptor-donor systems, aromatics/lipophilics) easily affords small-sized polyfunctionalized compounds. 11,12 Indeed, chemists succeeded over the years to apply combinatorial synthesis strategies to simple rings and chains to form small organic molecules 13,14 and not stay limited to peptide and oligonucleotide polymers. Thus, the virtual combinatorial library has to be designed in order to have its physical counterpart and to guarantee that all compounds are synthesizable.…”

Diversity-Orientated Synthesis and Biological Properties of Compounds Based on the N-Phenylquinoneimine Scaffold

“…Since many natural products and druglike compounds include heterocyclic subunits, the ability to synthesise efficiently diverse heterocyclic compounds is critical. NPQs can be used to access aromatic heterocyclic structures largely used as scaffolds for generating combinatorial libraries in drug-discovery research [ 18 ]. Sulfones that can be synthesised from multistep reactions of NPQs are found in many medicines and drug candidates under development for the treatment of a host of diseases impacting human health worldwide [ 19 ].…”