A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds

Abstract

Historically, chemists' exploration of chemical space has been exceptionally uneven and unsystematic.This feature article outlines a comprehensive conceptual framework that may be used to capture, analyse and plan synthetic approaches that may address this historically uneven exploration. Illustrative examples of synthetic approaches that target, or have potential to target, broad tracts of lead-like chemical space are presented within the context of this conceptual framework. Particular emphasis is placed on synthetic approaches that enable the combinatorial variation of molecular scaffold, particularly within the boundaries of lead-like chemical space.

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…As eries of studies by Nelson and co-workersc ombined the abovementioned idea and the methodology of DOS to generate dozens of scaffolds capable of generating lead-like compound libraries;s everalo ther groups have also contributed to this area. [210][211][212][213] For example, as ynthetic strategy very similar to the B/C/P approach was used to obtain over 20 structurally diversel ead-like scaffolds from only 4 a,a-disubstituted amino acids and 6t ypical transformations. [214] In another example, over 50 lead-like scaffolds were generated by using only 13 startingc ompounds and at oolkit of 6c yclization reactions, which werea pplied sequentially in 2s teps.…”

“…A series of studies by Nelson and co‐workers combined the abovementioned idea and the methodology of DOS to generate dozens of scaffolds capable of generating lead‐like compound libraries; several other groups have also contributed to this area . For example, a synthetic strategy very similar to the B/C/P approach was used to obtain over 20 structurally diverse lead‐like scaffolds from only 4 α,α‐disubstituted amino acids and 6 typical transformations .…”

A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds

“…1 and 2) to the product scaffold (e.g. 4) -may be classified as a bi/bi process 11 or as an ambiphile pairing 13 process.…”

Scaffold Diversity Synthesis with Branching Cascades Strategy

“…Often, scaffolds are directly involved in interactions with protein targets or receptors, either by hydrogen bonds or hydrophobic interactions. Scaffold diversity is therefore a very important parameter to characterize compound libraries and to identify diverse ligands that could interact with diverse protein targets [34,35]. However; a balance between the diversity of core frameworks or scaffolds within a library and the density of representation of each scaffold is nevertheless required.…”