Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A
3ImPACcell - Plate-forme ImPACcell (Plate-forme ImPACcell Structure Fédérative de Recherche BIOSIT Université de Rennes 1, Bat. 8, Campus de Villejean, 2 Avenue du Pr. Leon Bernard, CS34317, 35043 Rennes cedex, France - France)
7ManRos Therapeutics (Hôtel de Recherche,
Centre de Perharidy,
29680 Roscoff,
02 98 72 59 67
France - France)
Abstract : Here, we report on the synthesis of libraries of new 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones 3 (twenty-two compounds) and new 2-amino-5-arylidene-1,3-thiazol-4(5H)-ones 5 (twenty-four compounds) with stereo controlled Z-geometry under microwave irradiation. The 46 designed final compounds were tested in order to determine their activity against four representative protein kinases (DYR1A, CK1, CDK5/p25, and GSK3α/β). Among these 1,3-thiazolidin-4-ones, the molecules (5Z) 5-(4-hydroxybenzylidene)-2-thioxo-1,3-thiazolidin-4-one 3e (IC(50) 0.028 μM) and (5Z)-5-benzo[1,3]dioxol-5-ylmethylene-2-(pyridin-2-yl)amino-1,3-thiazol-4(5H)-one 5s (IC(50) 0.033 μM) were identified as lead compounds and as new nanomolar DYRK1A inhibitors. Some of these compounds in the two libraries have been also evaluated for their in vitro inhibition of cell proliferation (Huh7 D12, Caco2, MDA-MB 231, HCT 116, PC3, and NCI-H2 tumor cell lines). These results will enable us to use the 1,3-thiazolidin-4-one core as pharmacophores to develop potent treatment for neurological or oncological disorders in which DYRK1A is fully involved.
https://hal.archives-ouvertes.fr/hal-03467664 Contributor : Laurent JonchèreConnect in order to contact the contributor Submitted on : Monday, December 6, 2021 - 4:19:03 PM Last modification on : Wednesday, May 25, 2022 - 11:30:01 AM Long-term archiving on: : Monday, March 7, 2022 - 7:27:20 PM
Khadidja Bourahla, Solène Guihéneuf, Emmanuelle Limanton, Ludovic Paquin, Rémy Le Guével, et al.. Design and Microwave Synthesis of New (5Z) 5-Arylidene-2-thioxo-1,3-thiazolinidin-4-one and (5Z) 2-Amino-5-arylidene-1,3-thiazol-4(5H)-one as New Inhibitors of Protein Kinase DYRK1A. Pharmaceuticals, MDPI, 2021, 14 (11), pp.1086-1117. ⟨10.3390/ph14111086⟩. ⟨hal-03467664⟩