Exploiting Molecular Diversity to Access Biologically Relevant Chemotypes

Abstract

Small-molecule libraries with enhanced structural diversity are of value in drug discovery campaigns where novel biologically active hits are desired. As such, multicomponent reactions (MCRs) have proven fruitful to enhance the molecular diversity of chemical collections and expedite forward progression of the drug discovery chain. Bicalutamide (Casodex), an anticancer drug, and Telaprevir (Incivek), an antiviral, are two examples of marketed drugs that can be synthesized using an MCR. The research topic of this dissertation involves the design, discovery, and development of novel MCRs and new combinations of MCRs with post-condensation modifications to generate over twenty-five new drug-like scaffolds in an operationally friendly, atom-economical, time- and cost-effective fashion. The developed chemical methodologies possess inherent 'iterative efficiency','high exploratory power', and 'bond forming efficiency' that allow them to quickly explore chemical space and navigate the 'hypothesis-synthesis-screening' loop that is key for a medicinal chemistry project. The prepared molecules were submitted to the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial screening against pathogens that are known to cause drug-resistance infections.