Profiling and structural investigation of dihydrotriazine-based DHFR inhibitors and hydantoin-derived DprE1 inhibitors in search of novel antimycobacterials

The presented research addresses the urgent need to discover new anti-TB agents with novel mechanism of actions. It was performed within the OpenMedChem EID-ITN project (FP7) between the University of Antwerp and GlaxoSmithKline and had a focus on early hit-to-lead anti-tubercular drug design and development. The project was concentrated on hit exploration and hit-to-lead optimization of two novel chemical series of Mtb DHFR and DprE1 inhibitors to provide potent and selective compounds against M. tuberculosis. The initial hits identified during two different high throughput screening (HTS) campaigns performed by GSK formed the starting point for the research. The first compound family, identified in the whole-cell HTS campaign against M. bovis with hit confirmation in M. tuberculosis, was proven to inhibit the MtbDHFR (dihydrofolate reductase) enzyme. The initial hits demonstrated very good whole-cell and enzymatic potency, coupled however with significant human-cell toxicity. A scaffold hopping approach was then applied in order to overcome toxicity and selectivity issues while preserving the crucial pharmacophore. Unfortunately, the obtained analogues showed no cellular or DHFR inhibition activity. Therefore, this line of research was discontinued. A target-based HTS campaign against the mycobacteria-specific enzyme flavo-enzyme deca-prenylphosphoryl-beta-D-ribose 2-epimerase (DprE1) revealed a novel hydantoin-based family of potent DprE1 inhibitors. The follow-up hit-to-lead optimization program concentrated on removal of potential liabilities and safety evaluation of the series was performed in two rounds producing an extensive SAR around the initial hit. A number of highly active DprE1 inhibitors with sub-micromolar cellular potencies and balanced physicochemical profiles were delivered. Moreover, the discussed series showed no cytotoxicity and was found selective against mycobacteria. The proof-of-concept of in vivo activity was demonstrated.

Publication year:2021

Keywords:Doctoral thesis

Accessibility:Open