Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors
Само за регистроване кориснике
2023
Аутори
Petrović, Milena M.Roschger, Cornelia
Lang, Kevin
Zierer, Andreas
Mladenović, Milan
Trifunović, Snežana S.
Mandić, Boris
Joksović, Milan D.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen–Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 μM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity again...st the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.
Кључне речи:
chalcones / dihydroorotate dehydrogenase / hDHODH inhibitors / quinoline‐4‐carboxylic acidИзвор:
Archiv der Pharmazie, 2023, 356, 2, e2200374-Издавач:
- Wiley
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200122 (Универзитет у Крагујевцу, Природно-математички факултет) (RS-MESTD-inst-2020-200122)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200168 (Универзитет у Београду, Хемијски факултет) (RS-MESTD-inst-2020-200168)
- FP7RegPot project FCUB ERA GA No. 256716.
Колекције
Институција/група
Inovacioni centar / Innovation CentreTY - JOUR AU - Petrović, Milena M. AU - Roschger, Cornelia AU - Lang, Kevin AU - Zierer, Andreas AU - Mladenović, Milan AU - Trifunović, Snežana S. AU - Mandić, Boris AU - Joksović, Milan D. PY - 2023 UR - http://cherry.chem.bg.ac.rs/handle/123456789/5696 AB - Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen–Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 μM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties. PB - Wiley T2 - Archiv der Pharmazie T1 - Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors VL - 356 IS - 2 SP - e2200374 DO - 10.1002/ardp.202200374 ER -
@article{ author = "Petrović, Milena M. and Roschger, Cornelia and Lang, Kevin and Zierer, Andreas and Mladenović, Milan and Trifunović, Snežana S. and Mandić, Boris and Joksović, Milan D.", year = "2023", abstract = "Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen–Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 μM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.", publisher = "Wiley", journal = "Archiv der Pharmazie", title = "Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors", volume = "356", number = "2", pages = "e2200374", doi = "10.1002/ardp.202200374" }
Petrović, M. M., Roschger, C., Lang, K., Zierer, A., Mladenović, M., Trifunović, S. S., Mandić, B.,& Joksović, M. D.. (2023). Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors. in Archiv der Pharmazie Wiley., 356(2), e2200374. https://doi.org/10.1002/ardp.202200374
Petrović MM, Roschger C, Lang K, Zierer A, Mladenović M, Trifunović SS, Mandić B, Joksović MD. Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors. in Archiv der Pharmazie. 2023;356(2):e2200374. doi:10.1002/ardp.202200374 .
Petrović, Milena M., Roschger, Cornelia, Lang, Kevin, Zierer, Andreas, Mladenović, Milan, Trifunović, Snežana S., Mandić, Boris, Joksović, Milan D., "Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors" in Archiv der Pharmazie, 356, no. 2 (2023):e2200374, https://doi.org/10.1002/ardp.202200374 . .