Tractable synthesis of multipurpose screening compounds with under-represented molecular features for an open access screening platform

Abstract

The layout of multipurpose screening libraries must address criteria for the compounds such as novelty, diversity potential, innovative design, and last but not least synthetic tractability. While academic compound collections are often innovative, novel, and highly divers, synthesis of analogs or larger substance quantities is often hampered by complex multistep syntheses with low overall yields. In addition, covalently binding compounds and interaction motifs designed to bind metal ions were discriminated against by the paradigm that these interaction types must almost inevitably lead to toxic effects. We would like to challenge this hypothesis. The lack of such interactions could be a reason for frequent failure in the disclosure of hits for hitherto undruggable target proteins using commercially available screening collections. Thus, easily synthesizable screening candidates equipped to bind covalently to nucleophiles or to metalloenzymes by chelation are under-represented in public access screening libraries. Within this work, we present the synthesis and deposition of 88 compounds with five distinct functional classes, each of which features under-represented screening motifs, for example, metal ion complexation, reversible covalent binding, or halogen bonding. The collection includes acetohydrazides, acylhydrazones, propylene glycol ethers, 2-cyanoacetamides, and 2-cyanoacrylamides. The rational for the synthesis of most of the compounds was recently published by our group and is now supplemented by additional compounds reported here for the first time. The public access disposition enables academic research groups to collectively expand the druggable space and interdisciplinary collaborate within the scientific field.

Recent advances in organocatalytic cascade reactions for enantioselective synthesis of chiral spirolactone skeletons

“…To check the potential application of the demonstrated asymmetric synthesis, the reaction of 55e with MeI and K 2 CO 3 in acetone led to the formation of methylated analog 56 without damage to the two quaternary spiro stereocenters [Scheme 27C]. Notably, there are two privileged substructures, butyrolactone and pyrazolone [82][83][84][85][86][87] , in one spirocyclic molecular structure of 55, which may potentially be useful in medicinal chemistry. .…”