Compound library screening is one of the most effective and successful approaches used to identify potential biological targets during the drug development process. While very powerful, the development of new compound members is heavily impacted and limited by advances in synthetic organic chemistry. This comes as no surprise, as a steady increase in the number of diverse members requires a steady increase in the number of synthetic steps, or a continuous supply of different starting materials. While such strategies have proven to be effective for the preparation of small and uniquely diverse sets of compound collections, they fall short upon translation to larger-scale operations. Thus, one could argue that this type of chemical sustainability is one of the most important factors preventing diversification strategies from becoming an integral and necessary part of large-scale drug discovery processes. Our approach converts readily available aromatic compounds to a large set of functionalized compounds using chemistry that diverges significantly from existing methods. Using dearomatization strategy, we were able to showcase how a simple arene could be converted into numerous highly functionalized cyclohexanes, decorated with oxygen- and nitrogen-based functionality. Moreover, by using dearomatization, we were able to fill the missing gap in chemical space by delivering access to hybrid libraries containing fused aromatic (sp2) and sp3-rich motifs. Finally, we converted arenes into novel bioisosteres of common pharmacophores, providing more defined rigid motifs that could enable stronger bindings to biomolecular targets. Several bioisosteric replacements were accomplished, and these compounds are currently under evaluation.
All these efforts are aligned with the frontline of contemporary medicinal chemistry and drug discovery and provide unique solutions for accelerating drug design. Given the urgent need for the generation of novel and drug-like tailored compounds, this project provides specific guidelines and solutions for expanding the chemical space to uncharted, potentially more fertile regions for discovering new drugs.
