Science is often told through monumental discoveries—vaccines that halt epidemics, telescopes that reveal galaxies, or machines that split the atom. Yet sometimes, the most powerful stories come from molecules so small they could never be seen with the naked eye. One of those molecules is indole.
At first glance, indole looks deceptively simple: a six-membered benzene ring fused to a five-membered ring that contains nitrogen. But simplicity can be misleading. This tiny structure is the backbone of countless natural and man-made compounds that influence life as we know it. From the smell of jasmine and the flavor of roasted coffee to the neurotransmitters in our brain and the medicines in our cabinets, indole sits quietly at the center of it all.
And now, thanks to new research from scientists at Chiba University in Japan, indole’s potential in drug discovery has grown even greater.
Nature’s Masterpiece
Indole is not just a laboratory curiosity; it is a molecule of life. Plants, fungi, and even humans produce indole derivatives—molecules where hydrogen atoms have been swapped for other chemical groups that change the molecule’s personality and function.
Consider serotonin, the “happiness molecule,” which regulates mood and sleep. Its structure is built on an indole core. Or tryptophan, the essential amino acid in our diet that makes serotonin possible. Even melatonin, the hormone that synchronizes our circadian rhythms, is an indole derivative. In plants, indole-based compounds serve as defense chemicals or growth hormones. In microbes, they influence communication between cells.
This universality is no coincidence. The indole structure offers a flexible chemical framework that can be decorated with different groups to produce molecules with dramatically different properties. It is a biological canvas that evolution has painted on for millions of years.
Indole and Medicine: A Partnership Forged Over Decades
Because of its versatility, chemists have long turned to indole as a starting point for drug design. In fact, indole derivatives have become a pharmaceutical goldmine. Since 2015, the U.S. Food and Drug Administration (FDA) has approved 14 indole-based drugs. These medicines treat conditions as varied as migraines, infections, and hypertension, showcasing how one molecular skeleton can be reshaped into countless therapeutic tools.
And yet, the work is far from done. To keep innovating new drugs, scientists need reliable ways to attach chemical groups at very specific positions on the indole ring. But chemistry, like life, is rarely simple. Some positions on the indole are chemically stubborn, refusing to react even under coaxing. Among these, the C5 carbon—one of the critical “attachment points” on the molecule—has remained notoriously difficult to modify.
A Japanese Breakthrough
Enter Associate Professor Shingo Harada and his team at Chiba University’s Graduate School of Pharmaceutical Sciences. Along with colleagues Tomohiro Isono, Mai Yanagawa, and Professor Tetsuhiro Nemoto, Dr. Harada set out to solve the long-standing problem of selective modification at the C5 position of indole.
Their study, published in Chemical Science on July 15, 2025, describes a method that could reshape how scientists build indole-based drugs. By using a copper-based catalyst—a far more affordable metal than many alternatives—the team developed a way to attach an alkyl group precisely at the C5 position. Even more impressively, their method produced yields as high as 91%, a remarkable success in synthetic chemistry.
“We developed a direct, regioselective C5-H functionalization reaction of indoles under copper catalysis,” Dr. Harada explained. “The resulting compounds contain structural features commonly found in natural indole alkaloids and drug molecules, highlighting the usefulness of this approach for making biologically important compounds.”
The Chemistry Behind the Magic
To a non-chemist, the phrase “direct C5-H functionalization” might sound arcane. But the principle is both elegant and powerful. Imagine indole as a house with many doors (positions on the ring). Chemists often want to hang a decorative lantern (a chemical group) on a specific door. Some doors are wide open and easy to reach, but others—like the C5 position—are tucked away, locked, or blocked. Harada’s team essentially found the right key.
Their strategy relied on carbenes, short-lived but highly reactive carbon species capable of forming new bonds with indole. In earlier work, the team used rhodium-based carbenes to modify the C4 position of indole, guided by an “enone group” at the 3-position that directed the reaction. For the new study, they applied a similar principle but optimized the reaction to target the elusive C5 position instead.
The journey was not straightforward. Early attempts yielded only about 18% of the desired product. But by experimenting with catalysts, the team discovered that a combination of copper and silver salts dramatically improved the yield. Fine-tuning the conditions—such as solvent volume and concentration—pushed the results even further, until the reaction produced some compounds with yields as high as 91%.
The Hidden Pathway Revealed
To understand how this unlikely reaction worked, the researchers turned to quantum chemical calculations. These computer simulations revealed a surprising mechanism. The carbene doesn’t attack the C5 carbon directly. Instead, it first bonds at the C4 position, creating a strained three-membered ring intermediate. Then, almost like a dance, the bond shifts, rearranging itself onto the C5 position.
The copper catalyst is the choreographer of this molecular dance. By stabilizing the fleeting intermediate and lowering the energy barrier for the rearrangement, copper makes the improbable pathway not only possible but efficient.
This insight not only explains the reaction but also opens doors to designing similar strategies for other stubborn positions on indoles and beyond.
Why It Matters
At first glance, modifying a single atom on a molecule might seem like a minor detail. But in drug discovery, such details make all the difference. The biological activity of a compound can change dramatically depending on where a chemical group is attached. A drug that is weak or inactive in one configuration can become powerful and selective in another.
By unlocking the C5 position, Harada’s method provides chemists with a new tool for molecular design. Because copper is relatively inexpensive compared to metals like rhodium or palladium, this approach also offers a practical advantage: it is more affordable and scalable, making it better suited for real-world pharmaceutical production.
Dr. Harada himself acknowledged the significance with cautious optimism: “While it may not cause a significant shift right away, it could foster steady progress in drug discovery, leading to a small yet beneficial long-term impact.”
The Road Ahead
Science is never finished, and neither is this story. Harada’s team is already exploring other metal-carbene reactions, searching for ways to make indole modification even more selective and efficient. Each improvement adds another brushstroke to the vast canvas of molecular creativity, bringing us closer to drugs that can treat diseases more effectively, with fewer side effects.
The implications ripple outward. A better way to build indole-based compounds could accelerate the development of new antidepressants, antibiotics, cancer therapies, or cardiovascular drugs. It could help chemists mimic complex natural molecules found in rare plants or marine organisms—compounds that evolution honed but are too scarce to harvest. It could even enable the design of entirely new molecules, ones evolution never dreamed of, but which humanity may one day need.
A Small Molecule, a Vast Horizon
In the grand sweep of science, it is easy to be dazzled by telescopes and rockets, or overwhelmed by fields like artificial intelligence. Yet progress often begins with something much smaller. In this case, a tiny nitrogen-containing ring that has quietly shaped biology for millions of years may hold keys to the medicines of tomorrow.
Indole is a reminder that science is a story of both scale and subtlety. The same curiosity that asks how galaxies form also asks how a single atom might be persuaded to move from one position to another. Both questions are acts of wonder, and both, in their own ways, bring us closer to understanding the world—and shaping a better future.
More information: Tomohiro Isono et al, Copper-catalyzed direct regioselective C5–H alkylation reactions of functionalized indoles with α-diazomalonates, Chemical Science (2025). DOI: 10.1039/D5SC03417E
