1. Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: synthesis, cytotoxicity, lipophilicity and molecular docking studies
- Author
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Milan D. Joksović, Andreas Zierer, Cornelia Roschger, Sidrah Chaudary, Milena M. Petrović, Katarina Jakovljević, Violeta Marković, Bruno Botta, and Milan Mladenović
- Subjects
Quinoline-4-carboxylic acid ,Oxidoreductases Acting on CH-CH Group Donors ,hDHODH inhibitors ,Stereochemistry ,Cell Survival ,Cytotoxicity ,Doebner reaction ,Dihydroorotate Dehydrogenase ,Antineoplastic Agents ,01 natural sciences ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Structure-Activity Relationship ,Phenols ,Drug Discovery ,Lipophilicity ,Humans ,Enzyme Inhibitors ,Molecular Biology ,Cell Proliferation ,Dihydroorotate dehydrogenase (DHODH) ,Aldehydes ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Vanillin ,Organic Chemistry ,Quinoline ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,HaCaT ,chemistry ,Molecular docking ,Dihydroorotate dehydrogenase ,Quinolines ,Protocatechuic aldehyde ,Hydrophobic and Hydrophilic Interactions - Abstract
A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from -1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.
- Published
- 2020