More efficient method for creating sulfur-based medicines

A key technical challenge in creating new sulfur-based medicines has been overcome by scientists at Nanyang Technological University, Singapore (NTU Singapore), leading to the prospect of new therapeutic weapons in the fight against disease and illness. The breakthrough has been published in the journal Nature.

Every successful drug has a part of it that physically fits into the exact biochemical pathway it is trying to disrupt. This part of the drug is known as a pharmacophore and generating new ones is a key goal in drug discovery.

More than half the drugs used today are chiral, meaning that they can exist in either a left- or right-handed form that are mirror images of each other. While identical in chemical makeup, the different arrangement of its atoms means one form can behave very differently from the other: one may help to alter the course of a disease, while the other could be inactive, or even toxic.

Being able to synthesise a pharmacophore in the desired single form is a crucial goal in the design and development of drugs to eliminate possible side effects. Medicinal chemists are interested in the use of sulfur-based compounds as pharmacophores, but synthesising them into the single left- or right-handed form is challenging and current methods typically focus on making only one type of pharmacophore.

By contrast, the NTU scientists say that their method gives rise to a series of sulfur-based pharmacophores with enough variation to make the drug discovery process more efficient and fruitful. Their sulfur pharmacophores are developed through a process called asymmetric synthesis — a chemical reaction that results in just a single form, rather than a mixture of both forms being produced.

“The process of drug discovery is akin to finding the right key to a lock — it involves testing drug candidates with different pharmacophores until a certain combination proves to be effective in modulating a biological pathway,” said Professor Tan Choon Hong, lead author of the new study. “We essentially developed a method that could allow us to make many different types of sulfur-based pharmacophores that are compatible with different drug compounds.”

The process starts with adding a sulfur compound to an acyl chloride (a derivative of carboxylic acid) and a thiolate (a class of organic chemical compounds similar to the alcohols but containing a sulfur atom in place of the oxygen atom). This reaction is catalysed by pentanidium, a catalyst developed by the NTU scientists which was shown in an earlier study to induce asymmetric synthesis.

The researchers said their method could be used to synthesise a broad range of new pharmacophores that could be paired with different types of molecules to form new drugs. The sulfur pharmacophores could also be used to modify and repurpose existing drugs, potentially leading to new therapies. Indeed, when the team tested their synthesis method on arthritis drug Celecoxib, this resulted in a few different pharmacophores that could be used to develop similar drugs.

“This is exciting to the medicinal chemist because you can now improve on existing drugs or develop new therapies without having to start from scratch,” Prof Tan said.

Image credit: ©stock.adobe.com/au/Caleb Foster

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