Microwave Assisted Synthesis of Medicinally Relevant Indole Conjugates Utilizing Modified Hemetsberger-Knittel Indole Synthesis

Indoles are a class of nitrogen containing heterocycles first synthesized by Bayer AG in 1866 that have a broad variety of biological activities. They have widely been recognized as a privileged scaffold and are best known for their medicinal properties in the pharmaceutical industry. The indole nucleus signifies a vast importance in the world as indoles are built into peptides, proteins, are the skeleton of many natural products, and are the core of many successful marketed drugs. To date over 10,000 unique indole derivatives have been discovered as being biologically active compounds due to their excellent binding affinity to various receptors. Upon entering the 21st century, drug discovery and development has experienced a lack of innovative ideas for new chemical entities. It is well known that the FDA has placed stricter safety, quality and efficacy regulations on pharmaceutical companies over the last few decades. This, coupled with long developmental processes and immense financial investments, has placed pharmaceutical companies in innovative strains regarding their small-molecule pipelines. New research over the latter part of the past century has led to new biological drug entities that have many advantages over small molecules, but also some disadvantages as well. Recent scientific advancements have also led to the discovery of peptide-based pharmaceuticals and peptide-drug conjugates. These compounds fill the molecular weight gap between small molecule and protein-based drugs while combining the advantages of both. A novel approach to synthesizing small-molecule indole-peptide conjugates utilizing microwave-assisted Hemetsberger-Knittel indole synthesis that builds upon previous efforts in our laboratory is described in the remainder of this work.