Professor of Organic Chemistry at the University of York and Chairman of the Royal Society of Chemistry’s Heterocyclic and Synthesis Group, Peter O’Brien explores the role of heterocycles in the pharmaceutical industry

In 2017, the Royal Society of Chemistry’s Heterocyclic and Synthesis Group celebrated its 50th anniversary. It thus appears timely to consider how the role of heterocycles in the development of pharmaceutical drugs has evolved over the last 50 years.

Heterocycles are literally everywhere – from the caffeine in a cup of coffee to the building blocks of DNA – and nearly all marketed blockbuster pharmaceutical drugs contain at least one heterocycle. (1)

In chemical terms, heterocycles are cyclic compounds containing at least one non-carbon atom, typically nitrogen, oxygen or sulfur. They come in two flavours: heteroaromatics such as pyridine where the heterocycle also has an aromatic, benzene-like structure, and saturated, non-aromatic like the commonly used solvent tetrahydrofuran.

Why are heterocycles so common in pharmaceuticals? Pharmaceutical drugs generally work by interacting with a binding site in a protein. Common types of interactions include electrostatic, hydrophobic and hydrogen bonding. Heterocycles containing nitrogen, oxygen or sulfur atoms, whether heteroaromatic or not, offer excellent opportunities for hydrogen binding interactions with the functional groups in proteins. However, as well as providing protein binding groups, heterocycles also affect the solubility of drugs and their metabolism profile.

When the Royal Society of Chemistry’s Heterocyclic Group started in 1967, most of the interest was in relatively simple heteroaromatic compounds and, in particular, in the search for new ring types – different ring sizes and different, or often simply more, heteroatoms. This interest was mirrored by researchers in pharmaceutical companies who became very interested in the new intellectual property space afforded by novel heterocyclic scaffolds.

Aside from the development of the beta-lactam antibiotics, which are still going strong (e.g. amoxycillin), the pharmaceutical industry was mostly interested in flat, 2-dimensional heteroaromatic heterocycles. To some extent, this has been compounded by the introduction to the synthetic community of the Nobel prize-winning Suzuki-Miyaura cross-coupling reaction, which is an efficient way of coupling two heteroaromatic rings. As a result, up until around ten years ago, there was a great focus in the pharmaceutical industry on heteroaromatic- based heterocyclic drugs.

However, the last ten years has seen a shift in direction for heterocycles in pharmaceutical drug development. There has been a growing interest in the use of 3-dimensional, non-aromatic heterocycles in drug discovery. A paper entitled “Escape from Flatland” (2) highlighted the fact that 3-dimensional drug molecules performed better than 2-dimensional ones through the whole drug discovery process, which may be due to an associated better solubility profile.

3-dimensional heterocycles have thus become a popular design feature in the pharmaceutical industry and this has spurred on academic groups to develop new methods for the synthesis of 3-dimensional heterocycles. For example, one part of a European Union funded project entitled the “European Lead Factory” (3) focuses on the synthesis of novel, lead-like drug molecules for incorporation in a many-thousand compound library. A number of publications have now appeared from this project and it is clear that scaffold novelty and 3-dimensional heterocycles are key design criteria.

The use of these 3-dimensional scaffolds is not without its issues, however, as carrying out structure-activity studies by changing different parts of the compound and studying its biological activity is generally much harder than with 2-dimensional heteroaromatics. The academic and industrial synthetic community is attempting to meet this challenge head-on with the development of numerous new chemical transformations that had previously been deemed impossible. Research in areas such as sp3–sp2 and sp3–sp3 cross-coupling, photo-redox catalysis, CH activation and late-stage functionalisation is booming and has enabled improved functionalisation of both 2- and 3-dimensional heterocycles.

Nature and chemical structure of heterocycles in pharmaceutical drug development are also changing. The search for new scaffolds and new approaches to controlling drug properties such as metabolism and solubility has led to the use of some more unusual 3- dimensional heterocycles. For example, 4-membered ring heterocycles including oxetanes (4) and azetidines have become commonplace in medicinal chemistry programmes. As well as exploring smaller ring sizes, larger ring sizes have become particularly popular in drug discovery, especially macrocyclic heterocycles – cyclic heterocycles containing 12 or more atoms in the ring. An example is the recently marketed drug Simeprevir, which is used to treat the Hepatitis C virus. Macrocyclic drugs are also proving particularly useful in treating diseases where disrupting protein-protein interactions is crucial.

Finally, over the last 5 years, there has been a shift away from small-molecule drugs to the use of so-called biologics, which are pharmaceutical drugs manufactured in, extracted from or semi-synthesised from biological sources. Examples include vaccines, gene therapies and recombinant therapeutic proteins. Indeed, of the top 10 best-selling drugs of 2016, eight are biologics. Although biologics contain large, protein-sized molecules, if you look hard enough you will find numerous examples of heteroaromatic and non-heteroaromatic heterocycles in these drugs!

Professor Peter O’Brien is Professor of Organic Chemistry at the University of York, U.K. and is currently the Chairman of the Royal Society of Chemistry’s Heterocyclic and Synthesis Group. His group researches the development of new methods for the synthesis of 3-D heterocycles.


1 R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem. 2014, 57, 5845.

2 F. Lovering, J. Bikker and C. Humblet, J. Med. Chem. 2009, 52, 6752.

3 https://www.europeanleadfactory.eu/.

4 G. Wuitschik, M. Roger-Evans, K. Müller, H. Fischer, B. Wagner, F.Schuler, L. Polonchuk and E. M. Carreira, Angew. Chem. Int. Ed. 2006,45, 7736.


Professor Peter O’Brien 

Professor Peter O’Brien

Professor of Organic Chemistry, University of York, U.K

Chairman of the Royal Society of Chemistry’s Heterocyclic and Synthesis Group







Please enter your comment!
Please enter your name here