How a single nitrogen atom could transform the future of drug discovery

Researchers at the University of Oklahoma have developed a breakthrough method of adding a single nitrogen atom to molecules, unlocking new possibilities in drug research and development. Now published in the journal Science, this research is already gaining international attention from drug manufacturers.

Nitrogen atoms and nitrogen-containing chemical structures, called heterocycles, play a pivotal role in medicinal chemistry and drug development. A team led by OU associate professor Indrajeet Sharma has demonstrated that by using a short-lived chemical called sulfenylnitrene, researchers can insert one nitrogen atom into bioactive molecules and transform them into new pharmacophores that are useful for making drugs. This process is called skeletal editing and takes inspiration from Sir Derek Barton, the recipient of the 1969 Nobel Prize in Chemistry.

“85% of all existing FDA-approved drugs have one or more nitrogen atoms. And, when you look at the top 200 brand name drugs, 75-80% have nitrogen heterocycles,” he said. “By selectively adding one nitrogen atom to these existing drug heterocycles in the later stages of development, we can change the molecule’s biological and pharmacological properties without changing its functionalities. This could open uncharted regions of chemical space in drug discovery.”

According to Sharma, this skeletal editing process allows for more drug diversity because, rather than developing new drugs from scratch, researchers can incorporate a single nitrogen atom to make a new set of drugs. Nitrogen is important in this process because DNA, RNA, proteins and amino acids are all made with nitrogen, meaning Sharma’s research has far-reaching impacts on potentially treating diseases like cancer and neurological disorders.

Previously published research in this field demonstrated a similar concept but required conventional nitrenes and generated an excessive amount of oxidizing agent, which was not compatible with many drug molecules. Sharma’s team uses a method for producing sulfenylnitrenes that is additive-free, metal-free and compatible with other functional groups within the molecule.

“The cost of many drugs depends on the number of steps involved in making them, and drug companies are interested in finding ways to reduce these steps. By adding a nitrogen atom in the late stages of development, you can make new drugs cheaper. It’s like renovating a building rather than building it new from scratch,” he said. “Not everyone has equal access to healthcare. Even in the United States, per capita health expenditures increase to over $12,000 per year. By making these drugs easier to produce at large scale, we could reduce the cost of healthcare for vulnerable populations around the world.”