Saturated bioisosteres of benzene and their application in drug design

Project Information

BENOVELTY

Grant agreement ID: 101000893

DOI

10.3030/101000893

Project closed

EC signature date 14 December 2020

Start date 1 April 2021

End date 31 March 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 997 500,00

EU contribution

€ 1 997 500,00

Coordinated by

ENAMINE LIMITED LIABILITY COMPANY,RESEARCH AND PRODUCTION ENTERPRISE
Ukraine

Periodic Reporting for period 3 - BENOVELTY (Saturated bioisosteres of benzene and their application in drug design)

Reporting period: 2024-04-01 to 2025-09-30

Summary of the context and overall objectives of the project

The ring of benzene is among the most popular structural elements in chemistry. Every chemist from all disciplines - inorganic, polymer, physical, medicinal and organic chemistry - deals with derivatives of benzene. For example, it is one of the most popular rings in natural products and the most popular ring in bioactive compounds. Moreover, more than five hundred drugs and agrochemicals, including the well-known Aspirin and Paracetamol are benzene-containing molecules.

On the other hand, during the recent years pharmaceutical companies struggle to deliver novel drugs to the market - ca. 96% of all modern medicinal projects fail. In part, it happens because of a lack of innovative, practical approaches leading to novel “drug-like” organic molecules. Medicinal chemists still mostly use the old benzene-containing building blocks discovered the last century - substituted anilines, benzoic acids, phenols, etc.
In this context, at the moment pharmaceutical companies urgently need innovative practical methods and reagents to access the novel “chemical space.” And we - academic scientists - must address this issue to help pharmaceutical companies to decrease the attrition rate.

In this project, we want to (a) develop for the first time the saturated bioisosteres for ortho- and meta-substituted benzenes; (b) study their physichochemical characteristics (solubility, lipophilicity, metabolic stability); (c) incorporate the most promising cores into benzene-containing drugs and agrochemicals (Aceclofenac, Ketoprofen, Boscalid), and to study their biological activity and physico-chemical properties.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The first stepf the project was to develop solid practical approaches to bicyclic scaffolds that could mimic the benzene ring in bioactive compounds. This work is still ongong, and we are still working on developing the novel methods on making such scaffolds, but some good approaches have already been elaborated:
https://pubs.acs.org/doi/10.1021/acs.joc.1c00977
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202205103
https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202213508

Also, we are incorporationg these scaffolds instead of the benzene ring into the real-world agrochemicals and drugs, to see the impact of such substitution (especially in the context of bioactivity). This is the key part, it is ongoing now. And for many analogues of drugs we are waiting right now a feedback from biologists.

However, a tiny part of this project has been finished. This work was posted online at a preprint server ChemRxiv (recently I submitted this work to Nature Chemistry, it already receved a good feedback from both reviewers, and I plan to resubmit a revised version this weekend (12.11.2022)):
https://chemrxiv.org/engage/chemrxiv/article-details/62bd7c24d66f683b75b7a07a

Boscalid (BASF) and Fluxapyrozad (BASF) are the agrochemical fungicides used in the EU, US and the UK. Both compounds have the fragment of the ortho-disubstituted phenyl ring. We have developed water-soluble bioisosteres of the phenyl-ring (2-oxabicyclo[2.1.1]hexanes) and incorporated them into Boscalid and Fluxapyroxad.
The obtained saturated analogues of Boscalid and Fluxapyroxad were more water-soluble, more metabolically stable, less lipophilic, and most importantly - showed inhanced antifungal activity.

This result has a huge potential for medicinal chemistry, agrochemistry and hence for our society: now we have a tool on how to improve physico-chemical properties of drugs and agrochemicals (replace a benzene ring with saturated analogues) and create better ones.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our plan is to develop a library of different saturated bioisosteres for ortho-, meta- and para-disubstituted phenyls rings and validate them in real drugs and agrochemicals.
Many of these sub-projects are at the final stage, and we are waitng for the results from biologists.

Water-soluble bioisosteres of the ortho-substituted Benzene