Chemistry Reference
In-Depth Information
theoretical drug optimization strategies are valuable and integral parts of the drug
design process, they may sometimes generate structures that are quite complicated
and, consequently, hard to synthesize by requiring long-step synthesis with
carefully controlled reactions, especially if the stereochemical configuration is a
concern [35]. Therefore, the factors that contribute to make a synthesis difficult to
execute (
i.e.
those which give rise to molecular complexity) [36] must be
considered when selecting a hit or preparing analogs for a hit of interest.
Medicinal chemists typically aim to synthesize as many new compounds as
quickly as possible which can then be tested by biologists against a chosen
biological target [37]. In this context, synthetic accessibility can be considered as
an effort to use the smallest number of chemical steps to synthesize a drug from
common laboratory reactants [38]. However, synthetic accessibility and structural
complexity are not only central issues in determining potential drug candidate
molecules. They also must be carefully analyzed in the subsequent creation,
exploration, and evaluation of short, efficient, safe, reproducible, scalable,
ecological but still economical synthesis for the selected clinical candidates,
i.e.
in
process optimization and scale up synthesis [37].
From the structural point of view, several features contribute to molecular
complexity such as molecular size, element and functional-group content, cyclic
connectivity, stereocenter content, chemical reactivity and structural instability
[36]. Although these factors had been primarily identified based on the experience
of organic chemists regarding what features in the structure of a compound make
it hard to be synthesized, there are also theoretical reasons for recognizing some
of these features as sources of complexity. As stated by Goodwin [39] “the more
functional groups a structure has, the more likely it is that one of those functional
groups will interfere with an attempt to apply a standard chemical reaction to
modify a structure in a predictable way. Similarly, the more structurally unstable a
molecule is, the more likely an attempted chemical modification of it will result in
a range of possible products. Not only are reagents often capable of reacting at
multiple sites in a complex molecule, but also structural complexity can alter the
chemical environment in a way that interferes with the mechanism of a desired
reaction so that it will no longer produce the desired product to the anticipated
extent.”
