Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors
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2021
Authors
Petrović, Milena M.Roschger, Cornelia
Chaudary, Sidrah
Zierer, Andreas
Mladenović, Milan
Marković, Violeta
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Trifunović, Snežana S.
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Joksović, Milan D.
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Show full item recordAbstract
Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound’s pharmacology and provide guidelines for further lead optimization.
Keywords:
DHODH inhibitors / Dihydroorotate dehydrogenase / Lipophilicity / Molecular docking / Quinoline-4-carboxylic acidsSource:
Bioorganic & Medicinal Chemistry Letters, 2021, 46Publisher:
- Elsevier
Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200122 (University of Kragujevac, Faculty of Science) (RS-MESTD-inst-2020-200122)
Note:
- Supplementary material: https://cherry.chem.bg.ac.rs/handle/123456789/4551
Related info:
- Referenced by
https://cherry.chem.bg.ac.rs/handle/123456789/4551
DOI: 10.1016/j.bmcl.2021.128194
ISSN: 0960-894X
WoS: 000664981400002
Scopus: 2-s2.0-85107666267
URI
https://www.sciencedirect.com/science/article/pii/S0960894X21004212https://cherry.chem.bg.ac.rs/handle/123456789/4550
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Institution/Community
Hemijski fakultet / Faculty of ChemistryPetrović, M. M., Roschger, C., Chaudary, S., Zierer, A., Mladenović, M., Marković, V., Trifunović, S. S.,& Joksović, M. D.. (2021). Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors. in Bioorganic & Medicinal Chemistry Letters Elsevier., 46. https://doi.org/10.1016/j.bmcl.2021.128194
Petrović MM, Roschger C, Chaudary S, Zierer A, Mladenović M, Marković V, Trifunović SS, Joksović MD. Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors. in Bioorganic & Medicinal Chemistry Letters. 2021;46. doi:10.1016/j.bmcl.2021.128194 .
Petrović, Milena M., Roschger, Cornelia, Chaudary, Sidrah, Zierer, Andreas, Mladenović, Milan, Marković, Violeta, Trifunović, Snežana S., Joksović, Milan D., "Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors" in Bioorganic & Medicinal Chemistry Letters, 46 (2021), https://doi.org/10.1016/j.bmcl.2021.128194 . .