1. Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-β-<scp>d</scp>-Ribose Oxidase (DprE1) Inhibitors
- Author
-
Eugenia Meiler, Eva Maria Lopez-Roman, Sophie Huss, Ruth Casanueva, Maciej K. Rogacki, Lluis Ballell, Laura Guijarro, Eleni Pitta, Koen Augustyns, Fraser Cunningham, Olga Balabon, David Barros Aguirre, Monica Cacho, Robert H. Bates, Angel Santos-Villarejo, and Pieter Van der Veken
- Subjects
medicine.drug_class ,Antitubercular Agents ,Hydantoin ,Antimycobacterial ,01 natural sciences ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Bacterial Proteins ,In vivo ,Drug Discovery ,Ribose ,medicine ,Animals ,Humans ,Tuberculosis ,Potency ,Cytotoxicity ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,0303 health sciences ,biology ,Hydantoins ,Pharmacology. Therapy ,Hep G2 Cells ,Mycobacterium tuberculosis ,Periplasmic space ,biology.organism_classification ,3. Good health ,0104 chemical sciences ,Mice, Inbred C57BL ,Alcohol Oxidoreductases ,Chemistry ,010404 medicinal & biomolecular chemistry ,Biochemistry ,chemistry ,Molecular Medicine ,Female ,Mycobacterium - Abstract
In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against M. tuberculosis. The compounds were found to be non-covalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-β-D-ribose-2′-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined sub-micromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising non-covalent lead series for the discovery of novel antituberculosis agents.
- Published
- 2020
- Full Text
- View/download PDF