Discovery of a new class of potent pyrrolo[3,4-c]quinoline-1,3-diones based inhibitors of human dihydroorotate dehydrogenase: Synthesis, pharmacological and toxicological evaluation

[Display omitted] •Pyrrolo[3,4-c]quinoline-1,3-diones were prepared by cyclization cascade reactions.•New class of potent hDHODH inhibitory demonstrated better activity than leflunomide.•Very low cytotoxicity against healthy HaCaT cells was observed.•The optimal lipophilicity was determined at physi...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic chemistry Vol. 147; pp. 107359 - 107370
Main Authors: Dimitrijević, Marina G., Roschger, Cornelia, Lang, Kevin, Zierer, Andreas, Paunović, Milica G., Obradović, Ana D., Matić, Miloš M., Pocrnić, Marijana, Galić, Nives, Ćirić, Andrija, Joksović, Milan D.
Format: Journal Article
Language:English
Published: SAN DIEGO Elsevier Inc 01.06.2024
Elsevier
Subjects:
Animals
Biochemistry & Molecular Biology
Cell Line
Chemistry
Chemistry, Organic
Dihydroorotate Dehydrogenase
Dose-Response Relationship, Drug
Drug Discovery
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
hDHODH inhibitors
Humans
Life Sciences & Biomedicine
Lipophilicity
Male
Molecular Structure
Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors
Oxidoreductases Acting on CH-CH Group Donors - metabolism
Physical Sciences
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
Pyrrolo[3,4-c]quinolones
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Quinolones - chemical synthesis
Quinolones - chemistry
Quinolones - pharmacology
Rats
Rats, Wistar
Science & Technology
Structure-Activity Relationship
Toxicology
hDHODH inhibitors
Toxicology
Pyrrolo[3,4-c]quinolones
Dihydroorotate dehydrogenase
Lipophilicity
SURVIVAL
GAMMA
Pyrrolo
CELLS
ASSAY
HEPATOTOXICITY
c ]quinolones
LEFLUNOMIDE
ISSN:0045-2068, 1090-2120
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] •Pyrrolo[3,4-c]quinoline-1,3-diones were prepared by cyclization cascade reactions.•New class of potent hDHODH inhibitory demonstrated better activity than leflunomide.•Very low cytotoxicity against healthy HaCaT cells was observed.•The optimal lipophilicity was determined at physiological pH value.•The toxicological profile of the most active compounds was evaluated. Twenty N-substituted pyrrolo[3,4-c]quinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1H NMR, 13C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC50 values of 0.11 μM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2024.107359