As hit discovery identifies compounds that require significant optimisation, particularly for fragments, we need to make many compounds to turn hits into lead like compounds . Chemists go down many blind alleys as they try to build the hits up in different ways to find the right path towards a lead compound. When we understand these requirements in structure driven projects the design process can be focussed. However, if we only know the compound kill parasites and not how they work, it is important we make and test a diverse set of compounds to see how they behave in our tests to provide important guidance to the chemists on how to further grow and chemically modify compounds.

At WCAIR we are developing and establishing methods which allow us to explore ‘chemical space’ as fast as possible. Making small amounts of many related compounds all at the same time, array chemistry, to develop structure-activity-relationship (SAR) information, enhances the design of the next round of compounds. We currently make arrays of 20-50 compounds in test tubes based systems. However, the chemistry team is developing 96 or 384 well plate based chemistry to allow the rapid synthesis and testing of un-purified or partially purified compounds.

This approach allows a quick indication of which types of compounds are on the right path to our medicine, as it removes the costly and time consuming purification step. Once we have identified the best types of compound, then we can work on purified compounds. Plate based chemistry involves understanding how tolerant our assays are to reagents, solvents and by-products produced during the chemistry. It also requires easy access to a large number of reagents ready to add to the reactions and an increased level of logistics including robotics to dispense reagents and reactants onto the plates.

We will be looking to generate standard protocols and reagent sets which give the chemists a ‘plug and play’ approach to chemical synthesis. We will be investigating these factors over the coming year, testing and validating our approaches so that we can incorporate them into the DDU’s drug discovery projects. Not all chemical reactions are currently applicable. However it will speed up the initial rounds of optimisation and deal with many common chemical transformations. Giving the chemists more time to handcraft the more complex reactions.

In addition, we will expand our repertoire of available reactions, including developing a set of reactions that allows the addition of different functional groups to a common intermediate.

Compounds often have to be built up through a series of reactions. If a chemist makes the compound using reaction vessels, often glass round bottomed flasks this is called batch production.  At WCAIR we are implementing an alternative approach, flow chemistry. In this process the compounds are still built up through similar chemistry, however the chemistry is carried out in narrow tubes and using pumps to move the chemicals into the reaction tube when required. Flow chemistry has benefits at both a small and large scale. These include:

  • It is easy to pressurise flow reactors so reactions can be carried out at high temperatures speeding up the reaction. The high surface area of the tube allows excellent control of reactions that produce a lot of heat.
  • Because small amounts of reagents are used and mixed rapidly the selectivity of the reaction is often better than in batch synthesis.
  • Small amounts of hazardous intermediates can be made and reacted quickly in a second linked reaction tube increasing safety compared to batch synthesis.
  • The automation of the flow system allows different reaction conditions to be tested very easily to allow rapid optimisation of reaction yields.
  • It allows very precise control of reaction conditions, such as very short reactions of a few seconds, to be performed.


Image shows the equipment required for flow chemistry
Flow chemistry equipment

These agile high throughput chemistry methods combined with the insights from the compound-target interactions identified through biophysical methods and computational chemistry provide a knowledge driven design-make-test cycles which will speed up the journey from hit to pre-clinical candidate.