2. Academic Validation
  3. First bioconjugates in the role of highly effective human dihydroorotate dehydrogenase inhibitors: Synthesis, pharmacological, toxicological and hydrolytic stability studies of α-amino acid-modified pyrrolo[3,4-c]quinoline-1,3-dione scaffold

First bioconjugates in the role of highly effective human dihydroorotate dehydrogenase inhibitors: Synthesis, pharmacological, toxicological and hydrolytic stability studies of α-amino acid-modified pyrrolo[3,4-c]quinoline-1,3-dione scaffold

  • Eur J Med Chem. 2025 Nov 5:297:117972. doi: 10.1016/j.ejmech.2025.117972.
Marina G Dimitrijević 1,  Cornelia Roschger 2,  Stefanie Kehrer 2,  Andreas Zierer 2,  Milica G Paunović 3,  Ana D Obradović 3,  Miloš M Matić 3,  David Klarić 4,  Nives Galić 4,  Andrija Ćirić 1,  Ljubinka Joksović 1,  Miloš Petković 5,  Milan D Joksović 6
Affiliations

Affiliations

  • 1 University of Kragujevac, Faculty of Sciences, Department of Chemistry, R. Domanovića 12, 34000, Kragujevac, Serbia.
  • 2 University Clinic for Cardiac-, Vascular- and Thoracic Surgery, Medical Faculty, Johannes Kepler University Linz, Krankenhausstraße 7a, 4020, Linz, Austria.
  • 3 University of Kragujevac, Faculty of Science, Department of Biology and Ecology, Radoja Domanovića 12, P.O. Box 60, Kragujevac, 34000, Serbia.
  • 4 Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000, Zagreb, Croatia.
  • 5 Faculty of Pharmacy, Department of Organic Chemistry, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia.
  • 6 University of Kragujevac, Faculty of Sciences, Department of Chemistry, R. Domanovića 12, 34000, Kragujevac, Serbia. Electronic address: mjoksovic@kg.ac.rs.
PMID: 40683146 DOI: 10.1016/j.ejmech.2025.117972
Abstract

Human Dihydroorotate Dehydrogenase (hDHODH) represents an attractive target for the treatment of Cancer, diabetes, anti-infective and autoimmune diseases. In drug development, hDHODH inhibitors with great potency, good chemical stability and low toxicity open the broad therapeutic perspectives. Accordingly, this study identified the first bioconjugates as highly effective compounds in inhibition of hDHODH. Pyrrolo[3,4-c]quinoline-1,3-dione scaffold was modified with the selected α-amino acids in a new simple synthetic protocol giving the desired derivatives in good yields and high purity. Tyrosine bioconjugate 4g was found to be the most potent hDHODH inhibitor (IC50 = 32 nM) with an excellent cytotoxic profile on the healthy HaCaT cells and favorable lipophilicity. In the experiments with Enzymes simulating oral, gastric and duodenal digestion, 4g demonstrated good resistance to degradation providing a sufficient level of bioavailability. In addition, the objective of the study was to evaluate the comparative differences in toxicological effects between the 4g and leflunomide on rat liver and kidney injury markers and parameters of redox homeostasis in erythrocytes. The bioactive conformation of 4g on the hDHODH, determined using molecular docking, highlighted key interactions within the hDHODH binding site and provides a rational basis for further optimization.

Keywords

Bioconjugates; Dihydroorotate dehydrogenase; hDHODH inhibitors; pyrrolo[3,4-c]quinolines; α-Amino acids.

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