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

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. Acco...

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Published in:European journal of medicinal chemistry Vol. 297; p. 117972
Main Authors: Dimitrijević, Marina G., Roschger, Cornelia, Kehrer, Stefanie, Zierer, Andreas, Paunović, Milica G., Obradović, Ana D., Matić, Miloš M., Klarić, David, Galić, Nives, Ćirić, Andrija, Joksović, Ljubinka, Petković, Miloš, Joksović, Milan D.
Format: Journal Article
Language:English
Published: France Elsevier Masson SAS 05.11.2025
Subjects:
Amino Acids - chemistry
Amino Acids - pharmacology
Animals
Bioconjugates
Cell Line
Dihydroorotate Dehydrogenase
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
hDHODH inhibitors
Humans
Hydrolysis
Male
Molecular Docking Simulation
Molecular Structure
Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors
Oxidoreductases Acting on CH-CH Group Donors - metabolism
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
pyrrolo[3,4-c]quinolines
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Rats
Structure-Activity Relationship
α-Amino acids
hDHODH inhibitors
α-Amino acids
pyrrolo[3,4-c]quinolines
Bioconjugates
Dihydroorotate dehydrogenase
ISSN:0223-5234, 1768-3254
Online Access:Get full text
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Summary: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. [Display omitted] •A series of α-amino acid bioconjugates has been synthesized.•Tyrosine compound 4g was found to be the most potent hDHODH inhibitor (IC50 = 32 nM).•The bioconjugate 4g showed a protective effect against oxidative disturbance.•The molecular docking studies support biochemical results.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2025.117972